Endocrine Abstracts

Introduction: There are patients who remain symptomatic with hypothyroidism despite apparent adequate replacement on levothyroxine (LT4) therapy. We present an observation where monozygotic twins responded only to combination therapy with liothyroinine (LT3), and were found to have a genetic variation which may have clinical significance in thyroid metabolism.

Case report: A 47-year-old female with polyglandular auto-immune syndrome (APS1) presented with lethargy and cognitive dysfunction on LT4 despite good compliance. FT4 12 pmol/l (9-25); TSH 121miU/l (0.3-5.0). Further LT4 dose increase gave her unpleasant combination of fatigue and palpitations. Symptoms responded promptly and reproducibly to thyroid extract containing LT4 38mcg/LT3 9mcg bought online. Thyroid function stabilised: FT3 5.6pmol/l; FT4 17pmol/l; TSH 0.1miU/l. Her monozygotic twin-sister had hypothyroidism, coeliac disease and elevated ANA of unknown aetiology. She also remained symptomatic on conventional LT4 but improved on combined LT4/LT3 extract. Thyroid function stabilised: FT4 8.2pmol/l; TSH 3.6miU/l. Whole-Genome-Sequencing (WGS) revealed heterozygous mutation in NFκB1 in both twins, and their mother.

Discussion: NFκB is a family of transcription factors that among its functions is the activation of D2 in the hypothalamus. Most T3 is produced locally in the brain by D2, expressed in tancytes lining the 3rd ventricle. In-vivo studies showed that NFκB-mediated activation of D2 can locally increase T3 levels. Conversely, inhibition of p65 subunit of NFκB abolishes the increased D2 in tancytes. Therefore, mutation of NFκB gene might be of relevance in T4/T3 metabolism and action. Interestingly, this variation may impair a functionally significant part of the gene involved in recognition of self in auto-immunity.

Conclusion: This is the first observation of an association between a familial NFκB1 variant and twins with APS1. There was symptomatic response to combination LT4/LT3 therapy only. Possibly, this genetic region is important in auto-immunity and might provide an explanation for the differing responses to thyroid replacement.