Polymorphisms in the brain-specific thyroid hormone transporter OATP1C1 are associated with fatigue and depression in hypothyroid patients

• Published in: Clinical endocrinology (Oxford) Vol. 69; no. 5; pp. 804 - 811
• Main Authors: Van Der Deure, Wendy M., Appelhof, Bente C., Peeters, Robin P., Wiersinga, Wilmar M., Wekking, Ellie M., Huyser, Jochanan, Schene, Aart H., Tijssen, Jan G. P., Hoogendijk, Witte J. G., Visser, Theo J., Fliers, Eric
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-11-2008; Blackwell
• Subjects: Adolescent; Adult; Adult and adolescent clinical studies; Aged; Biological and medical sciences; Brain - metabolism; Cognition - physiology; Depression; Depression - complications; Depression - genetics; Depression - metabolism; Endocrinopathies; Fatigue - complications; Fatigue - genetics; Fatigue - metabolism; Fundamental and applied biological sciences. Psychology; Genetic Linkage; Hormone Replacement Therapy; Humans; Hypothyroidism - complications; Hypothyroidism - drug therapy; Hypothyroidism - genetics; Hypothyroidism - metabolism; Medical sciences; Middle Aged; Mood disorders; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Organ Specificity - genetics; Organic Anion Transporters - genetics; Organic Anion Transporters - metabolism; Polymorphism, Single Nucleotide - physiology; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Randomized Controlled Trials as Topic; Thyroid Hormones - administration & dosage; Thyroid Hormones - metabolism; Thyroid. Thyroid axis (diseases); Vertebrates: endocrinology; Young Adult; Endocrinopathy; Mood disorder; Human; Brain; Genetic variability; Depressions; Thyroid diseases; Central nervous system; Depression; Fatigue; Genotype; Patient; Hypothyroidism; Encephalon; Association; Thyroid hormone; Endocrinology; Polymorphism
• ISSN: 0300-0664; 1365-2265
• DOI: 10.1111/j.1365-2265.2008.03267.x

Summary
Introduction  Some hypothyroid patients continue to have significant impairments in psychological well‐being, despite adequate treatment with levothyroxine (LT4). T4 transport across the blood–brain barrier is one of the crucial processes for thyroid hormone action in the brain. OATP1C1, a thyroid hormone transporter expressed at the blood–brain barrier, is considered to play a key role in delivering serum T4 to the brain.
Objective  To examine whether polymorphisms in OATP1C1 are determinants of well‐being, neurocognitive functioning and preference for replacement therapy with a combination of LT4 and liothyronine (LT3).
Design and participants  We studied 141 patients with primary autoimmune hypothyroidism, adequately treated with LT4 monotherapy and participating in a randomized clinical trial comparing LT4 therapy with LT4–LT3 combination therapy.
Outcome measurements  Different questionnaires on well‐being and neurocognitive tests were performed at baseline. Serum thyroid parameters, OATP1C1‐intron3C > T, OATP1C1‐Pro143Thr and OATP1C1‐C3035T polymorphisms were determined.
Results  Allele frequencies of the OATP1C1 polymorphisms in patients with primary hypothyroidism were similar to those of healthy controls. Both the OATP1C1‐intron3C > T and the OATP1C1‐C3035T polymorphism, but not the OATP1C1‐Pro143Thr polymorphism, were associated with symptoms of fatigue and depression. OATP1C1 polymorphisms were not associated with measures of neurocognitive functioning or preference for combined LT4–LT3 therapy.
Conclusions  OATP1C1 polymorphisms are associated with fatigue and depression, but do not explain differences in neurocognitive functioning or appreciation of LT4–LT3 combination therapy. Future studies are needed to confirm these findings.