Liliana M. Bergoglio, Bioquímica Endocrinóloga, Universidad Nacional de Córdoba, Córdoba, Argentina.

E-mail: liberg@uolsinectis.com.ar

Jorge H. Mestman, Médico Endocrinólogo, Universidad del Sur de California, Los Ángeles, CA, Estados Unidos.

NACB: Guía de Consenso para el Diagnóstico y Seguimiento de la Enfermedad Tiroidea

Fuente: Revista Argentina de Endocrinología y Metabilismo, Vol 42, N° 2, Año 2005

Mencionamos con reconocimiento los nombres de los profesionales que participaron en la revisión de la traducción del documento original sobre el cual está basada esta monografía:

Claudio Aranda, Hospital Carlos C. Durand, Buenos Aires, Argentina Aldo H. Coleoni,Universidad Nacional de Córdoba, Córdoba, Argentina

N. Liliana F. de Muñoz, Hospital de Niños de la Santísima Trinidad, Córdoba, Argentina

Silvia Gutiérrez, Hospital Carlos C. Durand, Buenos Aires, Argentina; H. Rubén Harach,Hospital Dr. A. Oñativia, Salta, Argentina

Gustavo C. Maccallini, Hospital Carlos C. Durand, Buenos Aires, Argentina; Mirta B. Miras, Hospital de Niños de la Santísima Trinidad, Córdoba, Argentina

Hugo Niepomniszcze, Universidad Nacional de Buenos Aires, Buenos Aires, Argentina; Adriana Oneto, Hospital Carlos C. Durand, Buenos Aires, Argentina

Eduardo Pusiol, Universidad Nacional de Cuyo, Mendoza, Argentina;Gerardo C. Sartorio, Hospital J. M. Ramos Mejía, Buenos Aires, Argentina

La tiroglobulina (Tg), proteína precursora de la síntesis de las hormonas tiroideas se puede detectar en el suero de la mayoría de los individuos normales si se utiliza un método sensible. El nivel de Tg sérica está influido por tres factores principales: (i) la masa de tejido tiroideo diferenciado presente; (ii) cualquier inflamación o lesión de la glándula tiroides que provoque liberación de Tg; y (iii) el grado de estimulación del receptor de TSH (por TSH, hCG o TRAb). Una concentración elevada de Tg sérica es un indicador no específico de disfunción tiroidea. La mayoría de los pacientes con Tg sérica elevada presentan alteraciones tiroideas benignas. La Tg sérica se utiliza como marcador tumoral en los pacientes con diagnóstico de cáncer diferenciado de tiroides (CDT). Aproximadamente dos tercios de estos presentan un nivel pre-quirúrgico elevado de Tg sérica que confirma la capacidad del tumor de secretar Tg y valida su uso como marcador tumoral post-quirúrgico (307). Por el contrario, cuando la concentración prequirúrgica de Tg sérica no supera los valores normales, no existe evidencia de que el tumor secrete Tg, y un valor post-quirúrgico indetectable es menos tranquilizador. En esos pacientes una concentración post-quirúrgica detectable de Tg sérica podría reflejar la presencia de una importante masa tumoral. De hecho, en general, los cambios post-quirúrgicos representan cambios en la masa tumoral, siempre que se mantenga un nivel constante de TSH mediante terapia con L-T4.

La Tg sérica medida durante el estímulo de TSH (TSH endógena o TSH recombinante humana, rhTSH), es más sensible para la detección del CDT residual o metastásico que una determinación de Tg basal realizada durante el tratamiento con L-T4 (Figura 6) (308). La magnitud del aumento de la Tg sérica en respuesta a la TSH es un indicador de la sensibilidad del tumor a la TSH. Los tumores bien diferenciados típicamente muestran una respuesta estimulada a TSH elevada equivalente a ~10 veces el valor basal de Tg (309). Los tumores escasamente diferenciados que no concentran yoduro pueden presentar una respuesta disminuida al estímulo con TSH (310).

1. Estado Actual de los Métodos de Determinación de Tg

Generalmente, la tiroglobulina se mide en suero, pero también es posible realizar las determinaciones en líquido de quistes tiroideos y/o en material obtenido por punción con aguja fina de masas cervicales no tiroideas (311). La determinación de Tg sérica es técnicamente difícil. En la actualidad, los ensayos inmunométricos (IMA), están superando en popularidad a los métodos por radioinmunoensayo (RIA). La tendencia se debe a que los métodos IMA ofrecen la ventaja práctica de un menor tiempo de incubación, un rango dinámico más amplio y una mayor estabilidad del anticuerpo marcado, y en consecuencia una menor susceptibilidad al daño por marcación que los RIA (312). Hoy los laboratorios pueden escoger entre una serie de métodos IMA tanto isotópicos (inmunoradiométricos, IRMA) como no isotópicos (fundamentalmente quimioluminiscencia, ICMA). No obstante, los métodos IMA suelen ser más susceptibles a interferencias por autoanticuerpos antitiroglobulina (TgAb), que provocan una subestimación de los niveles de Tg sérica. En consecuencia, algunos laboratorios han escogido los métodos RIA para determinarla en pacientes TgAb positivos y restringir el uso de los métodos IMA a los pacientes TgAb negativos. Sin embargo, ningún método puede alegar estar totalmente libre de la interferencia por TgAb, la cual puede provocar resultados inapropiados de Tg.
Además de los problemas con la interferencia de TgAb, los actuales métodos IMA tienen diferencias en la estandarización y en la especificidad, deficiencias en la sensibilidad, precisión interensayo por debajo del nivel óptimo, y potencial predisposición a sufrir efecto “hook” (gancho) a concentraciones elevadas (312).

A. Estandarización

Las concentraciones de Tg sérica determinadas por métodos RIA o IMA presentan marcadas diferencias (312, 313). Un reciente esfuerzo en colaboración patrocinado por la Community Bureau of Reference of the Commission of the European Communities ha desarrollado una nueva Preparación de Referencia Internacional para Tg, CRM-457 (298,314). Este material se puede solicitar al Dr. Christos Profilis, BCR, Rue de la Loi 200, B 1049 Bruselas, Bélgica.

El desvío entre los diferentes métodos de determinación de Tg puede provenir de las diferencias entre las matrices libres de Tg utilizadas para la dilución de los estándares y el suero de pacientes, o diferencias en el reconocimiento de los epitopes por parte de los distintos anticuerpos de Tg usados por los diversos fabricantes. Sería ideal que el diluyente utilizado para los estándares fuese suero humano libre de Tg y TgAb o, como alternativa, una matriz no sérica que hubiera sido seleccionada para producir una señal (cuentas radiactivas, unidades relativas de luz, etc.) que fuese idéntica a la del suero humano libre de Tg y TgAb. Es fundamental que se informe a los médicos antes de que el laboratorio cambie su método para Tg para que puedan realizar una nueva determinación de valores basales en los pacientes con CDT.

La adopción generalizada del estándar CRM-457 se proyectó para reducir, aunque no eliminar la significativa variabilidad inter-método que existe entre los inmunoensayos de Tg de los distintos fabricantes. Se esperaba que la estandarización internacional facilitara un mayor acuerdo entre los diversos estudios publicados y mejorara el uso clínico del seguimiento seriado con Tg en los pacientes con CDT, que a veces tienen determinaciones realizadas en distintos laboratorios. Lamentablemente, el uso del estándar CRM-457 no ha eliminado los problemas de variabilidad entre métodos como se esperaba. En la actualidad, los niveles de Tg sérica determinados por métodos que utilizan la estandarización CRM- 457 pueden presentar diferencias de más de cuatro veces en sus resultados (Figura 7).

Estas diferencias intermétodos son mayores que la máxima imprecisión aceptada durante el seguimiento de los pacientes individuales (Tabla 5) y excluye el intercambio de diferentes métodos de Tg para el seguimiento a largo plazo de los pacientes con cáncer de tiroides.

B. Sensibilidad

Algunos métodos de Tg carecen de sensibilidad para detectar el límite inferior de referencia eutiroideo que, dependiendo del ensayo, se sitúa aproximadamente en 1-3 ?g/L (ng/mL). Los métodos que no están en condiciones de detectar Tg en todos los sueros normales son insensibles para la búsqueda de recidivas en los pacientes con CDT. Al igual que para TSH, la sensibilidad funcional del ensayo de Tg se determina con el 20% del CV inter-ensayo. El protocolo utilizado para determinar la sensibilidad funcional del ensayo de Tg es el mismo que se describió para TSH (Recomendación Nº 20) con las tres cláusulas descriptas en la Recomendación Nº 44.

C. Precisión

La precisión intra- e inter-ensayo, expresada como porcentaje del coeficiente de variación (%CV) es un parámetro importante para la validación del comportamiento analítico de un ensayo de Tg. La precisión se debería determinar utilizando mezclas de sueros TgAb negativos con tres niveles diferentes de Tg (ver Recomendación Nº 44).

La precisión intra-ensayo en los inmunoensayos es mejor que la inter-ensayo, como cabría de esperar. Esto se debe a que las mediciones realizadas dentro de una misma corrida no están sujetas a la variabilidad introducida por el uso de lotes diferentes de reactivos ni por  distintas calibraciones de los instrumentos. La precisión intra-ensayo puede ser el parámetro más significativo cuando se evalúa la respuesta de Tg sérica al estímulo con rhTSH (308). En esta prueba, se extrae una muestra basal y una muestra estimulada con rhTSH con 3 a 5 días de intervalo entre sí, y generalmente se determina la Tg de ambas muestras en la misma corrida (Figura 6) (308, 309). En contraste, cuando se utiliza la determinación de Tg para el control seriado, cuanto más prolongado es el intervalo entre corridas mayor la variabilidad y peor la precisión inter-ensayo. Las matrices no humanas utilizadas para determinar la precisión en la zona baja pueden producir una sensibilidad funcional irreal en comparación con las mediciones realizadas con suero humano libre de TgAb como matriz. Es importante que se establezca la sensibilidad funcional y la precisión inter-ensayo con determinaciones distribuidas durante un período entre 6 y 12 meses, ya que éste es el intervalo clínico característico utilizado para el control de los pacientes con CDT.

La máxima imprecisión de las determinaciones de Tg sérica sugerida para el seguimiento de pacientes debe ser < 5% (Tabla 5). Es poco probable que los ensayos actuales de Tg puedan mantener una precisión tan estricta a lo largo del intervalo clínicamente relevante entre 6 y 12 meses típicamente utilizados para el control de los pacientes con CDT. Este problema con la precisión se puede superar repitiendo la determinación en muestras previas almacenadas del paciente en la misma corrida que la muestra actual (9).

D. Efecto “hook” a valores elevados

Los métodos IMA se ven afectados por el efecto hook a valores elevados. Los valores falsamente bajos debido a este “efecto gancho” son particularmente problemáticos en los ensayos de marcadores tumorales como la Tg, en donde es frecuente encontrar valores muy elevados cuando los pacientes presentan metástasis avanzada (307, 310, 315). Se produce efecto hook cuando un exceso de antígeno satura la capacidad de unión del anticuerpo de captura. Esto provoca una señal inadecuadamente baja que se traduce en un resultado bajo o paradójicamente normal para un paciente con una concentración excesivamente elevada de Tg sérica (>1000 ?g/L (ng/mL) (312). Los fabricantes de métodos IMA intentan solucionar el problema del efecto hook mediante uno de estos dos procedimientos:

*Diseños de ensayo de dos pasos. Se realiza una primera incubación de la muestra sérica con el anticuerpo de captura antes de que los constituyentes no ligados se eliminen por lavado y se introduzca el anticuerpo marcado, seguido de una segunda incubación.

*Se realizan dos determinaciones (generalmente sin diluir y con dilución 1/10) para cada muestra.

Existe sospecha de efecto “hook” cuando el tubo con la dilución presenta un resultado más alto que la muestra sin diluir. Se realizan más diluciones hasta que el resultado en el tubo con la dilución disminuya y las concentraciones de Tg séricas de dos diluciones consecutivas concuerden.

E. Interferencia por Autoanticuerpos Anti Tiroglobulina (TgAb)

Los autoanticuerpos anti tiroglobulina (TgAb) se detectan con mayor frecuencia en los pacientes con CDT que en la población general (~20 versus ~10%, respectivamente) (276). Las determinaciones seriadas de los TgAb séricos pueden ser indicadores pronósticos independientes de la eficacia del tratamiento o de la recidiva del CDT en los pacientes TgAb positivos (276-278, 316). Cualquier TgAb presente en la muestra tiene el potencial de interferir con un método de Tg (317, 318). Debido a que los TgAb son heterogéneos, ni la medición de la concentración de estos anticuerpos ni un ensayo de recuperación con Tg exógena permiten predecir si los TgAb causarán interferencia (276, 317, 318). Probablemente el signo característico más confiable de la interferencia por TgAb sea la presencia de discordancia entre los RIA y los IMA. La Tg determinada por RIA se caracteriza por valores más elevados que la Tg determinada mediante IMA si la muestra contiene TgAb que provoquen interferencia (276, 309). En la actualidad se ha logrado consenso acerca de que los ensayos de recuperación de Tg no son un método confiable para la detección de TgAb y se los debería eliminar (276, 318).

Los primeros estudios que informaron recuperaciones bajas en ausencia de TgAb en algunos sueros tenían el problema de la insensibilidad de los métodos iniciales para medir TgAb. Cuando se utilizan inmunoensayos cuantitativos con sensibilidad adecuada, los TgAb deberían detectarse siempre cuando la recuperación es baja.

Los métodos inmunométricos no competitivos (IMA) parecen ser más susceptibles a la interferencia producida por TgAb que los RIA, lo que se evidencia por el hallazgo de valores indetectables de Tg en individuos con enfermedad de Graves (319, 318). Aparentemente, en algunos casos los IMA no pueden cuantificar la Tg acomplejada con los TgAb y esta omisión puede provocar subestimación de la concentración de Tg total. Por el contrario los métodos RIA parecen capaces de cuantificar las fracciones de Tg de la muestra tanto libre como ligada a TgAb y característicamente producen valores más altos que los métodos IMA en presencia de TgAb (276, 309). Existe gran variabilidad en la sensibilidad y especificidad de los diferentes ensayos de TgAb. Es esencial que la medición de TgAb sea realizada por el laboratorio que determinará la Tg porque ese laboratorio es responsable de seleccionar el método de TgAb más apropiado para detectar interferencia por TgAb en el método para Tg que utilice.

Cuando se determina Tg en suero que contiene TgAb con métodos RIA e IMA, con frecuencia se observa una discordancia RIA: IMA equivalente a [Tg RIA ? 2 ?g/L (ng/mL): Tg IMA = indetectable]. Esta discordancia parece caracterizar la interferencia por TgAb en una o ambas clases de métodos. Como el umbral actual para una respuesta de Tg positiva estimulada por rhTSH equivale a 2 ?g/L (ng/mL), el grado de discordancia tiene el potencial de influir en la toma de decisiones clínicas (308). Algunos profesionales creen que las mediciones con RIA producen resultados de Tg sérica con mayor validez clínica para los pacientes TgAb positivos que las mediciones con IMA, según se infiere por las correlaciones con el estado clínico y el paralelismo con determinaciones seriadas de TgAb (276, 320). No obstante, cabe destacar que ningún método RIA es inmune a la interferencia por TgAb en todos los sueros TgAb positivos y que la influencia de estos anticuerpos en los diferentes métodos RIA es bastante variable y se relaciona con los componentes del ensayo y las condiciones de incubación. Específicamente, la 125 calidad del trazador I de la Tg, junto con la especificidad del anticuerpo policlonal para Tg determinan la predisposición del método a la interferencia por TgAb (275, 321, 322).

Aunque no existe garantía de que ningún método actual de Tg esté libre de interferencia por TgAb, la subestimación que se produce con la metodología IMA es la dirección de interferencia más grave, ya que este error tiene el potencial de enmascarar la enfermedad metastásica. En consecuencia, los laboratorios no deberían informar valores indetectables de Tg sérica para pacientes TgAb positivos.

2. Determinación de ARN mensajero (ARNm) para Tg

Se ha utilizado la amplificación de ARNm específico de tejido con la reacción en cadena de la polimerasa con transcriptasa reversa (RTPCR) para detectar células cancerígenas circulantes en sangre periférica de los pacientes con melanoma, cáncer de próstata y de mama (326-328). La disponibilidad de cebadores (primers) específicos de Tg permitió la aplicación de esta técnica a la detección de  transcriptos de ARNm Tg en sangre. El uso de RT-PCR para detectar recidiva de cáncer tiroideo se informó por primera vez en 1996 (329). A partir de entonces, se ha aplicado la técnica a material de punción de metástasis de ganglios cervicales y se ha visto que es más sensible que la determinación de Tg en el aspirado (330).

Todavía tiene que establecerse el valor clínico de la determinación de ARNm Tg en sangre periférica. Antes de que se pueda utilizar este método para la toma de decisiones terapéuticas en el CDT, es necesario resolver ciertas cuestiones sobre la sensibilidad y especificidad tisular del ARNm Tg en sangre periférica (323- 325).

Varios grupos han desarrollado métodos cuantitativos de RT-PCR para la detección de transcriptos de ARNm Tg en sangre (323-325, 331-333). Estos estudios generalmente encuentran ARNm Tg detectable en todos los individuos normales pero presentan una correlación pobre con la Tg sérica determinada por inmunoensayo (331, 332). También hay diferencias en la correlación entre ARNm Tg y masa tumoral. Algunos estudios han informado que la cantidad de ARNm Tg se correlaciona con la presencia o ausencia de metástasis mientras que otros no informan dicha correlación (324, 331, 333). Es probable que estas discrepancias reflejen diferencias (a) en la sensibilidad y en la especificidad de los primers de Tg y los sistemas RT-PCR, (b) en la sensibilidad de las técnicas de imágenes y de los inmunoensayos de Tg utilizados y (c) en el nivel de TSH del paciente.
Los problemas de especificidad (resultados falsos positivos) constituyen una conocida limitación de la metodología RT-PCR (328, 334).
Se necesitan estudios adicionales para determinar si los niveles detectables de ARNm Tg informados para los pacientes atiróticos sin metástasis conocida reflejan enfermedad clínicamente oculta, artefactos del ensayo o transcripción ilegítima.

Es necesario demostrar la correlación entre los resultados de los ensayos de ARNm Tg y la recidiva clínica, en especial en pacientes ARNm Tg positivos con valores indetectables de Tg sérica antes de que se generalice la adopción del ensayo de ARNm Tg en la práctica clínica. Como este método es más costoso que la determinación de Tg sérica, es probable que si se demuestra que las mediciones de ARNm Tg son útiles para la clínica, se reserven para los pacientes de alto riesgo o TgAb positivos en quienes las determinaciones de Tg sérica no son diagnósticamente confiables.

3. Valores de Referencia de Tg Sérica

A. Individuos Eutiroideos Normales

Las concentraciones de Tg sérica presentan una distribución normal logarítmica en los individuos eutiroideos. Los valores suelen ser ligeramente más elevados en las mujeres, pero no es necesario establecer rangos de referencia en relación con el género (335). El hábito de fumar es un factor asociado con bocio y valores elevados de Tg sérica (336). Los rangos de referencia de Tg varían según la zona geográfica, ya que reflejan la disponibilidad e ingesta de yoduro (337, 338). La selección de individuos para la cohorte normal para determinar el rango de referencia de Tg debería respetar los siguientes criterios de exclusión:
* Bocio
*Consumo de cigarrillos
*Antecedentes personales o familiares de
enfermedad tiroidea
*Presencia de autoanticuerpos tiroideos (TgAb o
TPOAb)
*TSH sérica 2.0 mUI/L
*Embarazo

B. Valores de Tg sérica después de la cirugía tiroidea

Como se indica en la Recomendación Nº 48, el intervalo de referencia para Tg citado en los informes de laboratorio no corresponde para los pacientes que han sido sometidos a cirugía tiroidea. Durante las primeras semanas después de la cirugía, la Tg sérica estará determinada por la extensión de la intervención, el grado de liberación de Tg debida al daño quirúrgico, y, lo más importante, si el paciente está o no bajo tratamiento con hormona tiroidea. De hecho, la concentración de TSH sérica es un modulador tan potente del nivel de Tg sérica que siempre es necesario conocer el nivel de TSH del paciente antes de establecer el significado de cualquier determinación de Tg sérica.

En las primeras semanas posteriores a la tiroidectomía, se produce una típica disminución de las concentraciones de Tg con una vida media aproximada entre 2 y 4 días, cuando la administración de hormona tiroidea evita el aumento de la TSH (340, 341). En este contexto, la relación entre los valores pre-y post-quirúrgicos (entre 6 y 8 semanas) de Tg puede aportar información que podría influir en el esquema de tratamiento. Durante el seguimiento a largo plazo, las concentraciones de Tg sérica medidas con y sin tratamiento de LT4 (con TSH suprimida o desenfrenada, respectivamente) proporcionan diferente información. La curva de los valores de Tg sérica (con tratamiento con L-T4) es un indicador más específico de un cambio en la masa tumoral que cualquier valor aislado de Tg sérica (122). La concentración de Tg sérica durante el tratamiento con L-T4 es un indicador más estable de masa tumoral que la Tg sérica determinada cuando la TSH está elevada (suspensión de L-T4 o administración de rhTSH) anterior a un rastreo corporal con yodo radioactivo (RAI). Esto se debe a que la magnitud del aumento de Tg sérica estimulada por TSH está influida por el grado y la cronicidad de la elevación de TSH que puede variar de un rastreo a otro. Sin embargo, según lo muestra la Figura 6, como la TSH normalmente estimula más de 10 veces la Tg sérica, las determinaciones de Tg sérica estimuladas por TSH son más sensibles para detectar enfermedad restringida al cuello, que los niveles de Tg sérica determinados durante la supresión de TSH (308, 309). La magnitud de la respuesta de la Tg sérica estimulada por TSH es un indicador de la sensibilidad del tumor a la TSH. Los tumores metastásicos poco diferenciados que son rastreo corporal con yodo radioactivo negativos presentan respuestas disminuidas de Tg estimulada por TSH (310).

4. Usos clínicos de las determinaciones de Tg sérica

La concentración de Tg sérica refleja la masa tiroidea, el daño tiroideo y el estímulo del receptor de TSH (122). En consecuencia, un aumento en la Tg sérica es un hallazgo inespecífico no asociado virtualmente con ninguna patología tiroidea.

A. Patologías no Neoplásicas

Se produce un aumento de la Tg sérica cuando los pacientes tienen bocio y en la mayoría de las patologías hipertiroideas. La concentración baja de Tg sérica puede ser un parámetro útil para la confirmación del diagnóstico de tirotoxicosis facticia o para la investigación de la etiología de hipotiroidismo congénito (342, 343).

La concentración de Tg a veces también es útil,para confirmar la historia pasada de tiroiditis,en la cual la concentración de Tg es habitualmente el último parámetro bioquímico que se normaliza (hasta los 2 años) (344). Estudios recientes sugieren la determinación de Tg sérica como un parámetro para reflejar el estado de yodosuficiencia en una población determinada (337, 338).

 B. Carcinoma Diferenciado de Tiroides (CDT)

En el contexto del CDT, la concentración de Tg sérica refleja masa tiroidea (tumor o remanente normal), lesión tiroidea (cirugía o PAAF) y estimulación del receptor de TSH (endógena o con rhTSH) (122). Debido a que la TSH es el principal regulador de la concentración de Tg sérica, es difícil interpretar los valores de Tg sin conocer el nivel de TSH del paciente. Aunque no hay un “rango normal de referencia para Tg” para los pacientes con CDT tratados, la relación normal entre la masa tiroidea y la Tg sérica provee un punto de referencia importante. Concretamente, un gramo de tejido tiroideo normal libera ~1 ?g/L (ng/mL) de Tg en la circulación cuando la TSH sérica es normal y ~0,5 ?g/L (ng/mL) cuando se la suprime por debajo de 0,1 mUI/L.

(i) Tg Sérica Pre-quirúrgica

Algunos tumores tiroideos carecen de capacidad para secretar tiroglobulina. En 2/3 de los pacientes con CDT se observa un aumento en el valor pre-quirúrgico de Tg sérica, lo que indica que sus tumores tienen la capacidad de secretar Tg, y por lo tanto el seguimiento postquirúrgico con Tg puede ser de utilidad clínica en ellos. (307). Esta información es fundamental para la interpretación de los resultados post-quirúrgicos de la Tg sérica. Si el nivel pre-quirúrgico está dentro de los límites normales, un valor post-quirúrgico indetectable de Tg sérica es menos tranquilizador porque el tumor pudo ser originariamente no secretor de Tg. La sensibilidad del control postquirúrgico con Tg sérica para la detección de recidiva será mayor cuando el tumor sea relativamente pequeño (

(ii) Determinación de Tg Sérica entre 1 Y 2 meses después de la cirugía Tiroidea

Después de la cirugía tiroidea, las concentraciones de Tg sérica disminuyen rápidamente con una vida media entre ~2 y 4 días (340). La Tg liberada por daño durante la manipulación quirúrgica se debería resolver en gran parte dentro de los primeros dos meses posteriores a la cirugía. Durante este lapso la TSH tendrá una influencia dominante en el nivel de Tg sérica. Si se inicia el tratamiento con hormona tiroidea inmediatamente después de la cirugía para evitar el aumento de TSH, la concentración de Tg sérica declinará a un valor que refleje el tamaño del remanente tiroideo normal más cualquier residuo o metástasis tumoral. Como el remanente tiroideo después de una tiroidectomía casi total habitualmente se aproxima a 2 gramos de tejido, se espera una concentración de Tg sérica equivalente a < 2 ?g/L (ng/mL) cuando la cirugía ha sido exitosa y el nivel de TSH se mantiene por debajo de 0,1 mUI/L.

(iii) Determinación de Tg Sérica durante el seguimiento a largo plazo bajo Tratamiento con L-T4.

Cuando el nivel de TSH es estable durante el tratamiento con L-T4, cualquier cambio en el nivel de Tg sérica reflejará un cambio en la masa tumoral. La recidiva clínica en tumores considerados “secretores deficientes de Tg” (valor pre-quirúrgico de Tg en el rango normal) se puede asociar con valores post-quirúrgicos bajos o indetectables de Tg sérica. Por el contrario, la recidiva de tumores considerados “buenos secretores de Tg” (valores prequirúrgicos elevados de Tg) se asocia normalmente con un aumento progresivo en Tg sérica (122).
El perfil de las determinaciones seriadas de Tg sérica, establecido cuando el paciente tiene TSH estable, es más útil clínicamente que un valor aislado de Tg. Sin embargo, es posible interpretar el significado de un valor aislado de Tg conociendo el rango de referencia del ensayo de Tg, la extensión de la cirugía tiroidea y la concentración de TSH (en un estado estable), según lo muestra la Figura 8.

Condiciones Asumidas 

*Sin lesión tiroidea reciente (cirugía o PAAF)
*Usando la Recomendación N° 48, la media normal de Tg = 13,5, rango 3-40 (2DS) ?g/L (ng/mL)
*Masa de tejido tiroideo normal = 10-15 gramos
*Un gramo de tejido tiroideo normal produce ~1?g/L (ng/mL) Tg en suero si la TSH es normal
*Un gramo de tejido tiroideo normal produce ~0,5?g/L (ng/mL) Tg si la TSH es < 0.1 mUI/L

(iv) Respuesta de Tg Sérica al estímulo con TSH

La magnitud de la respuesta de la Tg sérica a la TSH endógena (suspensión de la hormona tiroidea) o a la administración de rhTSH es un indicador de la sensibilidad del tumor a la TSH (308, 309). Habitualmente, el estímulo con TSH de los remanentes tiroideos normales o de un tumor bien diferenciado produce un aumento >3 veces de Tg sérica por sobre el nivel basal (con TSH suprimida) en los pacientes TgAb negativos (Figura 6). La respuesta de la Tg sérica a un aumento en la TSH endógena es habitualmente dos veces mayor que con rhTSH (308, 345). Además, los tumores pobremente diferenciados, presentan una respuesta disminuida (< 3 veces) de la Tg sérica al estímulo con TSH (310). Cabe observar que los pacientes TgAb positivos habitualmente presentan una respuesta disminuida o ausente de la Tg al estímulo con rhTSH determinada por la mayoría de los ensayos, incluso cuando la concentración basal de Tg es detectable.

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