Oral thyroxine resistance revisited - how thyroxine transpasses the gut-blood barrier

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Oral levothyroxine (LT4) is one of the most frequently administered hormone treatments word-wide. In-most cases LT4 replacement is uncomplicated, however, some patients require abnormally high LT4 doses to achieve euthyroidism or TSH suppression in case of thyroid cancer. “Levothyroxine malabsorp-tion” comprises a very heterogeneous spectrum of disorders ranging from non-compliance to very rare cases of apparent oral levothyroxine resistance (OTR) of unknown cause. Since thyroid hormone (TH) transporters have been identified as gate-keepers that regulate the in- and efflux of TH across cellular membranes, we propose that genetic alterations in TH transporters could account for OTR and might also explain inter-individual variability in LT4 replacement dosage. This project asks how TH transport across the intestinal epithelium is organized and which molecular mechanisms are implicated in disturbed intes-tinal T4 uptake. To this aim, we will 1) clinically characterize patients with OTR and establish a European database of patients with abnormal thyroid hormone uptake, 2) search for genetic alterations in intestinal TH transporters, first exploring LAT2 in a candidate gene approach, 3) employ the recently described Lat2 knockout mouse model and other specific TH transporter-deficient models to elucidate the role of individual TH transport proteins in intestinal-endothelial T4 transpassage and 4) apply a genome wide approach to identify novel TH transporters that are crucial for intestinal TH passage.