RESUMO
Gastrointestinal stromal tumors (GISTs) are resistant to traditional chemotherapy but are responsive to the tyrosine kinase inhibitors imatinib and sunitinib. The use of these agents has improved the outcome for patients but is associated with adverse effects, including hypothyroidism. Multiple mechanisms of this effect have been proposed, including decreased iodine organification and glandular capillary regression. Here we report the finding of consumptive hypothyroidism caused by marked overexpression of the thyroid hormone-inactivating enzyme type 3 iodothyronine deiodinase (D3) within the tumor. Affected patients warrant increased monitoring and may require supernormal thyroid hormone supplementation.
Assuntos
Neoplasias Gastrointestinais/enzimologia , Tumores do Estroma Gastrointestinal/enzimologia , Hipotireoidismo/enzimologia , Hipotireoidismo/etiologia , Iodeto Peroxidase/metabolismo , Hormônios Tireóideos/deficiência , Neoplasias Gastrointestinais/complicações , Neoplasias Gastrointestinais/diagnóstico por imagem , Tumores do Estroma Gastrointestinal/complicações , Tumores do Estroma Gastrointestinal/diagnóstico por imagem , Humanos , Iodeto Peroxidase/genética , Masculino , Pessoa de Meia-Idade , Radiografia AbdominalRESUMO
BACKGROUND: The thyroid hormone-inactivating enzyme type 3 deiodinase (D3) is induced during hypertrophic and ischemic cardiomyopathy, leading to a state of local cardiac hypothyroidism. Whether D3 induction occurs in dilated cardiomyopathy is unknown. METHODS: This study characterized changes in cardiac D3 and thyroid hormone signaling in a transgenic model of progressive dilated cardiomyopathy (TG9 mice). RESULTS: Cardiac D3 was dramatically induced 15-fold during the progression of dilated cardiomyopathy in TG9 mice. This D3 induction localized to cardiomyocytes and was associated with a decrease in myocardial thyroid hormone signaling. CONCLUSIONS: Cardiac D3 is induced in a mouse model of dilated cardiomyopathy, indicating that D3 induction may be a general response to diverse forms of cardiomyopathy.
Assuntos
Cardiomiopatia Dilatada/metabolismo , Iodeto Peroxidase/metabolismo , Miocárdio/metabolismo , Tiroxina/sangue , Tri-Iodotironina/sangue , Animais , Cardiomiopatia Dilatada/patologia , Modelos Animais de Doenças , Progressão da Doença , Camundongos , Camundongos Transgênicos , Miocárdio/patologiaRESUMO
Thyroid hormone is a master regulator of differentiation and growth, and its action is terminated by the enzymatic removal of an inner-ring iodine catalyzed by the selenoenzyme type 3 deiodinase (dio3). Our studies of the zebrafish reveal that the dio3 gene is duplicated in this species and that embryonic deiodination is an important determinant of embryo size. Although both dio3 paralogs encode enzymatically active proteins with high affinity for thyroid hormones, their anatomic patterns of expression are markedly divergent and only embryos with knockdown of dio3b, a biallelically expressed selenoenzyme expressed in the developing central nervous system, manifest severe thyroid hormone-dependent growth restriction at 72 hours post fertilization. This indicates that the embryonic deficiency of dio3, once considered only a placental enzyme, causes microsomia independently of placental physiology and raises the intriguing possibility that fetal abnormalities in human deiodination may present as intrauterine growth retardation. By mapping the gene structures and enzymatic properties of all four zebrafish deiodinases, we also identify dio3b as the first multiexon dio3 gene, containing a large intron separating its open reading frame from its selenocysteine insertion sequence (SECIS) element.
Assuntos
Tamanho Corporal/genética , Iodeto Peroxidase/genética , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Animais , Animais Geneticamente Modificados , Embrião não Mamífero , Desenvolvimento Embrionário/genética , Regulação da Expressão Gênica no Desenvolvimento , Regulação Enzimológica da Expressão Gênica , Células HEK293 , Humanos , Isoenzimas/genéticaRESUMO
Type 3 deiodinase (D3), the physiologic inactivator of thyroid hormones, is induced during tissue injury and regeneration. This has led to the hypotheses that D3 impacts injury tolerance by reducing local T3 signaling and contributes to the fall in serum triiodothyronine (T3) observed in up to 75% of sick patients (termed the low T3 syndrome). Here we show that a novel mutant mouse with hepatocyte-specific D3 deficiency has normal local responses to toxin-induced hepatonecrosis, including normal degrees of tissue necrosis and intact regeneration, but accelerated systemic recovery from illness-induced hypothyroxinemia and hypotriiodothyroninemia, demonstrating that peripheral D3 expression is a key modulator of the low T3 syndrome.