title: Changes in the central component of the hypothalamus-pituitary-thyroid axis in a rabbit model of prolonged critical illness.
abstract: BACKGROUND
  Prolonged critically ill patients reveal low circulating thyroid hormone levels without a rise in thyroid stimulating hormone (TSH). This condition is labeled "low 3,5,3'-tri-iodothyronine (T3) syndrome" or "nonthyroidal illness syndrome (NTI)" or "euthyroid sick syndrome". Despite the low circulating and peripheral tissue thyroid hormone levels, thyrotropin releasing hormone (TRH) expression in the hypothalamus is reduced and it remains unclear which mechanism is responsible. We set out to study whether increased hypothalamic T3 availability could reflect local thyrotoxicosis and explain feedback inhibition-induced suppression of the TRH gene in the context of the low T3 syndrome in prolonged critical illness.
  
  
  METHODS
  Healthy rabbits were compared with prolonged critically ill, parenterally fed animals. We visualized TRH mRNA in the hypothalamus by in situ-hybridization and measured mRNA levels for the type II iodothyronine diodinase (D2), the thyroid hormone transporters monocarboxylate transporter (MCT) 8, MCT10 and organic anion co-transporting polypeptide 1C1 (OATP1C1) and the thyroid hormone receptors alpha (TRalpha) and beta (TRbeta) in the hypothalamus. We also measured the activity of the D2 and type III iodothyronine deiodinase (D3) enzymes.
  
  
  RESULTS
  In the hypothalamus of prolonged critically ill rabbits with low circulating T3 and TSH, we observed decreased TRH mRNA, increased D2 mRNA and increased MCT10 and OATP1C1 mRNA while MCT8 gene expression was unaltered as compared with healthy controls. This coincided with low hypothalamic thyroxine (T4) and low-normal T3 concentrations, without a change at the thyroid hormone receptor level.
  
  
  CONCLUSIONS
  Although expression of D2 and of the thyroid hormone transporters MCT10 and OATP1C1 were increased in the hypothalamus of prolonged critical ill animals, hypothalamic T4 and T3 content or thyroid hormone receptor expression were not elevated. Hence, decreased TRH gene expression, and hereby low TSH and T3 during prolonged critical illness, is not exclusively brought about by hypothalamic thyrotoxicosis, and infer other TRH suppressing factors to play a role.
authors.affiliation: Department of Intensive Care Medicine, Katholieke Universiteit Leuven, Herestraat 49, Leuven B-3000, Belgium. liese.mebis@med.kuleuven.be
authors.forename: Liese
authors.initials: L
authors.lastname: Mebis
authors.forename: Yves
authors.initials: Y
authors.lastname: Debaveye
authors.forename: Björn
authors.initials: B
authors.lastname: Ellger
authors.forename: Sarah
authors.initials: S
authors.lastname: Derde
authors.forename: Eric-Jan
authors.initials: EJ
authors.lastname: Ververs
authors.forename: Lies
authors.initials: L
authors.lastname: Langouche
authors.forename: Veerle M
authors.initials: VM
authors.lastname: Darras
authors.forename: Eric
authors.initials: E
authors.lastname: Fliers
authors.forename: Theo J
authors.initials: TJ
authors.lastname: Visser
authors.forename: Greet
authors.initials: G
authors.lastname: Van den Berghe
mesh_terms: D000818:Animals; D016638:Critical Illness; D005067:Euthyroid Sick Syndromes / Q000235:genetics / Q000503:physiopathology; D005453:Fluorescence; D007031:Hypothalamus / Q000378:metabolism* / Q000503:physiopathology; D007453:Iodide Peroxidase / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D008297:Male; D023421:Models, Animal; D027361:Organic Anion Transporters / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D010902:Pituitary Gland / Q000378:metabolism*; D016133:Polymerase Chain Reaction / Q000379:methods; D012313:RNA / Q000302:isolation & purification; D011817:Rabbits; D017422:Sequence Analysis, DNA; D013489:Suppression, Genetic; D013961:Thyroid Gland / Q000378:metabolism* / Q000503:physiopathology; D013971:Thyrotoxicosis / Q000503:physiopathology; D013973:Thyrotropin-Releasing Hormone / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D000097564:Iodothyronine Deiodinase Type II
chemical_list: D007453:Iodide Peroxidase; D027361:Organic Anion Transporters; D012313:RNA; D013973:Thyrotropin-Releasing Hormone; D000097564:Iodothyronine Deiodinase Type II; C117274:iodothyronine deiodinase type III