La glándula tiroides Endocrinología Dr. Pablo Alvarez A ME-2012

Anatomía

Exploración

Anatomía microscópica

Digestión y Absorción El yodo está presente en una gran cantidad de alimentos Es absorbido rápidamente en estómago y duodeno Se absorbe como yodo inorgóanico Un pequeño porcentaje se transporta con aminoácidos complejos

Ingesta diaria de yodo

Metabolismo del yodo Kronenberg: Williams Textbook of Endocrinology, 11th ed.

Eje hipotálamo hipofisiario

TRH Tripéptido Localizado en corteza cerebral (eminencia media y núcleo arcuado), tracto gastrointestinal y páncreas Viaja por el sistema porta hipofisiario TRHR(Gq)

TSH Secretada por los tirótropos Glicoproteína de 28 kDa Cadena alfa (análoga a LH, FSH, hCG) Cadena beta

Receptor de TSH Schematic representation of the TSH receptor. The A subunit is the ligand-binding portion of the receptor and the B subunit is the activation portion. The ligands which bind to the receptor include TSH, TSH- stimulating antibody, and TSH-blocking antibody. There are two cleavage sites which allow breakage of the receptor and loss of the A subunit into the serum.

Eje TRH-TSH

El yodo en las hormonas tiroideas

Kronenberg: Williams Textbook of Endocrinology, 11th ed. Figure 10-8 Role of T4 and T3 in the feedback regulation of TRH and TSH secretion. Secreted T4 must be converted to T3 to produce its effects. This conversion may take place in tissues such as the liver (L), kidney (K), and thyroid (T) catalyzed by D1. D2 is present in human thyroid (T), skeletal muscle (SM), possibly cardiac muscle (CM) and the pituitary and hypothalamus. Kronenberg: Williams Textbook of Endocrinology, 11th ed.

Síntesis y liberación

Efectos de la TSH J. Clin. Endocrinol. Metab. 2007 92:3764-3773

Transporte

Desyodinación Endocrine Reviews, December 2008, 29(7):898–938 Cellular and Molecular Basis of Deiodinase-Regulated Thyroid Hormone Signaling Endocrine Reviews, December 2008, 29(7):898–938

Desyodinasas

The thyroid hormone pathway. Abbreviations: D1, deiodinase 1; D2, deiodinase 2; D3, deiodinase 3; rT3, reverse T3; rXr, retinoid X receptor; T2, di-iodothyronine; THr, thyroid hormone receptor; TsHr, TsH receptor.

Transportadores + afín que el MCT8 por T3

Ingreso y activación de hormonas tiroideas al SNC Kronenberg: Williams Textbook of Endocrinology, 11th ed.

Control de síntesis de desyodinasas Endocrine Reviews, December 2008, 29(7):898–938

Mecanismos de acción

Mecanismo de acción

Hormonas tiroideas Secreted T4 and T3 circulate in the bloodstream almost entirely bound to proteins. Normally, only about 0.03% of total plasma T4 and 0.3% of total plasma T3 exist in the free state (Table 41-1). Free T3 is biologically active and mediates the effects of thyroid hormone on peripheral tissues, in addition to exerting negative feedback on the pituitary and hypothalamus (see later). The major binding protein is thyroxine-binding globulin (TBG). TBG is synthesized in the liver and binds one molecule of T4 or T3

Efectos no genómicos Integrina αvβ3 Receptores identificados en endotelio y músculo liso. Aumenta la actividad de: Ca2+ ATPasa Na+/K+ ATPasa NHE Estimula el tráfico de proteínas. Membrane Receptor for Thyroid Hormone: Physiologic and Pharmacologic Implications Annu. Rev. Pharmacol. Toxicol. 2011. 51:99–115

Efectos periféricos

Efectos de las hormonas tiroideas

Tasa metabólica basal Nat Med. 2010 September ; 16(9): 1001–1008

Metabolismo de carbohidratos Aumenta la producción hepática de glucosa Aumenta la disponibilidad de productos para la gluconeogénesis (aa y glicerol) Favorece la expresión de enzimas gluconeogénicas

Metabolismo proteico Hay proteólisis en especial del músculo Aumenta la síntesis proteica

Metabolismo lipídico El glicerol y ácidos grasos libres proveen la energía para mantener la gluconeogénesis hepática Aumenta lipogénesis Niveles altos de T3 favorecen la lipólisis

Metabolismo del colesterol Figure 1. Crosstalk between thyroid hormone signaling and pathways in cholesterol metabolism. (i) Cholesterol in the form of low-density lipoprotein (LDL) is transported from the liver to peripheral tissues by LDL receptor (LDL-R). (ii) Thyroid hormone receptor (TR) and sterol regulatory element binding protein (SREBP)-2 stimulate LDL-R gene expression and increase cholesterol uptake. SREBP-2 gene expression is stimulated by thyroid hormone signaling and feedback regulation by sterols. (iii) Excess cholesterol in liver is converted to bile acids, catalyzed by cholesterol 7-hydroxylase (CYP7A1). This bile acid feedback is modulated by multiple nuclear receptors regulating CYP7A1 gene expression. Liganded TR and peroxisome proliferator activated (PPAR)α inhibit, and hepatic nuclear factor (HNF)4α stimulates, CYP7A1 gene expression and bile acid synthesis (thyroid hormone stimulates CYP7A1 expression in mice, see description in text). (iv) Cholesterol efflux in peripheral tissue relies on the ATP-binding cassette transporter A1 (ABCA1). Cholesterol is transported by ABCA1 to lipid-poor apolipoprotein A1 (ApoA1) to form nascent high-density lipoprotein (HDL). Cholesteryl ester-rich HDL enters the circulation and transports cholesterol back to liver through SRB1 or LDL-R or cholesteryl ester transfer protein (CETP) for disposal. Liver X receptor (LXR) stimulates ABCA1 activity. T3 inhibits LXR-stimulated ABCA1 gene expression by competing for DNA binding sites and for the heterodimer partner retinoid X receptor (RXR). PPARα agonists stimulate cholesterol efflux by increasing expression of LXR. CE, cholesteryl ester; FC, free cholesterol. March 2010, Pages 166-173

Metabolismo lipídico March 2010, Pages 166-173 Figure 2. Crosstalk between thyroid hormone signaling and metabolic pathways in fatty acid synthesis and β oxidation. Fatty acid synthesis and oxidation mobilizes glucose and triglycerides stores, important for thermogenesis and energy homeostasis. (i) Fatty acid synthesis is controlled by the rate-limiting enzyme acetyl–CoA carboxylase (ACC) 1. Thyroid hormone increases ACC1 mRNA expression by directly stimulating the ACC1 promoter that contains a thyroid hormone receptor response element (TRE) and sterol regulating element binding protein response element (SRE). (ii) Liver X receptor (LXR) stimulates fatty acid synthesis by enhancing SREBP-1c gene expression. In the absence of T3, TR competes with LXR for DNA binding and inhibits expression of SREBP-1c. (iii) Peroxisome proliferator-activated receptor (PPAR) α agonist increases fatty acid synthesis by enhancing sterol regulating element binding protein (SREBP) processing enzymes (insig-1 and -2) and SREBP-1c maturation. (iv) Thyroid hormone increases fatty acid oxidation by upregulating expression of the key mitochondrial β oxidation enzyme, carnitine palmitoyltransferase (CPT)-Iα. PPARα also stimulates expression of CPT-Iα and promotes fatty acid β oxidation. Omega-3 long-chain fatty acids are ligands for PPARα. PPARα also stimulates Acyl–CoA oxidase (ACO), a rate-limiting enzyme in peroxisomal β oxidation. Unliganded TR can block stimulation of CPT1α and ACO by PPARα, competing for limiting retinoid X receptor (RXR) and by binding to the PPRE. March 2010, Pages 166-173

Efectos metabólicos de las hormonas tiroideas Trends Endocrinol Metab. 2010 March ; 21(3): 166–173

Actividad de la Na+/K+ ATPasa En músculo, hígado y riñón hay un aumento del consumo de oxígeno paralelo a un aumento en la actividad de la Na/K ATPasa T3 estimula la transcripción de la subunidad α y β

Actividad de la Na+/K+ ATPasa Am J Physiol Cell Physiol 296:C1-C3, 2009. Journal of Endocrinology (1999) 160, 453–460

Efecto termogénico En la grasa parda hay expresión de termogenina, la cual disocia la fosforilación oxidativa de la síntesis de ATP La mitocondria consume O2 y produce calor sin generar ATP Este mecanismo es estimulado por T3 y la activación de receptores β3

Efecto termogénico

Crecimiento y desarrollo Mol Cell Endocrinol. 2008 June 11; 287(1-2): 1–12. Journal of Endocrinology (2006) 189, 189–197

Efectos en hueso Efecto permisivo en hueso y cartílago Journal of Endocrinology (1998) 157, 391–403

Debilidad en hipertiroidismo Efectos en músculo Generación de fuerza en el gastrognemio Debilidad en hipertiroidismo

Efectos cardiovasculares Clin Endocrinol Metab. 2002 Mar;87(3):968-74.

Efectos de las hormonas tiroideas en el músculo cardiaco

Hipertiroidismo

Otros efectos SNC: estimula el crecimiento y desarrollo axonal Hipófisis: regula la síntesis hormonal, estimula la liberación de GH

Tironaminas 3-yodo-tironamina (T1AM) Tironamina (T0AM) Agonistas TAR1: receptor de aminas traza asociado a proteínas G In vivo son antagonistas de las hormonas tiroideas (Activan Gi) Sujetas a sulfatación (significado incierto)

Función tiroidea en enfermedad Sano Enfermo Endocrine Reviews, December 2008, 29(7):898–938