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

Para una producción normal de hormonas tiroideas y para mantener un estado eutiroideo se necesita una ingesta adecuada de yodo a través de la dieta. Por lo tanto la determinación de la ingesta de yodo proveniente de los alimentos o de medicamentos tiene relevancia clínica. En el laboratorio clínico, las determinaciones de yodo se utilizan fundamentalmente para estudios epidemiológicos o para investigación (3). Hasta la fecha, el interés principal del análisis de yodo es evaluar la ingesta en una población determinada (3, 397, 398). Este es un tema de importancia considerable, ya que se estima que la carencia de yodo y sus consecuencias patológicas (IDD) afecta a unos 2.200 millones de personas en todo el mundo. Incluso en países desarrollados como Estados Unidos y Australia, se ha demostrado una reducción en la ingesta de yodo alimentario, mientras que gran parte de Europa se ubica en el límite de los valores aceptables desde hace mucho tiempo (398, 399). La mayoría de los países de Latinoamérica han re-examinado su estado de yodosuficiencia en los últimos 15 años y han implementado programas para el control de IDD, observándose grandes progresos gracias a la campaña agresiva para el uso de la sal de mesa yodada, aunque aún persisten áreas de deficiencia y exceso (499).

Dado que la mayor parte del yodo ingerido se excreta a través de la orina, la determinación de la excreción urinaria de yodo (IU), brinda una aproximación precisa de su ingesta (399). En la mayoría de los casos la determinación IU brinda escasa información útil sobre el estado nutricional de yodo en un individuo a largo plazo, ya que los resultados obtenidos reflejan simplemente la ingesta reciente. Sin embargo, determinar la excreción urinaria de yodo en una cohorte representativa de individuos de una población específica provee un índice útil del nivel de yodo endémico de esa región. (399, 400). Además de estimar la concentración de IU, también se puede determinar yodo en la leche, los productos alimenticios y el agua potable (401, 402). La determinación de yodo en tejido tiroideo o mamario se ha realizado como parte de algunos estudios de investigación clínica (403). Como las concentraciones séricas bajas de yodo inorgánico (~ 1pg/dL) están asociadas a yodo
hormonal relativamente abundante, la medida de yodo inorgánico plasmático (PII) se ha restringido a estudios de investigación en el embarazo (404).

1. Excreción urinaria de yodo (IU)

El nivel de IU de una población puede brindar una estimación relativamente exacta del estado de ingesta alimentaria de yodo de esa población (399, 400). La mejor manera de determinar la ingesta de yodo es en orina de 24 horas, pero es poco práctico para estudios epidemiológicos. Las diferencias en la yoduria de una micción a otra, cuando se realiza la determinación en muestras de orina aisladas, pueden compensarse expresando los resultados corregidos por creatinina urinaria, es decir, como ?g de yodo excretado/gramo de creatinina (405).Los ciclos diurnos y estacionales de las excreciones de yodo y creatinina son diferentes. Por consiguiente, la relación yodo / creatinina puede variar según el momento del día o la época del año. Además, no existe un sustituto ideal de la muestra de orina de 24 horas, que es más difícil de obtener. Sin embargo, la estimación de la ingesta de yodo mediante el IU es muy importante en los países en desarrollo en donde el índice yodo/creatinina está por debajo del nivel satisfactorio y en donde existe una tasa de excreción de creatinina menor debido a la desnutrición en grados variables (406).También se ha demostrado que la excreción urinaria de yodo puede ser variable, aún en individuos sanos y con una alimentación equilibrada. Por estas razones y para evitar errores introducidos con los diferentes ensayos de creatinina, la Organización Mundial de la Salud (OMS) ha recomendado que para estudios epidemiológicos, la excreción de IU se exprese como ?g de yodo por unidad de volumen (pg/dL o ?g/L) de orina. Las diferencias en los valores inherentes a las variaciones de la yoduria de una micción a otra pueden compensarse, en parte incluyendo un gran número de sujetos (~50) en cada estudio de población. Informes recientes sugieren que el uso de la relación (IU/Cr) ajustadas por edad y sexo en una muestra matinal en ayunas se asemeja a la IU de 24 horas si el estado nutricional, en líneas generales, es adecuado (400, 407). Si bien las variaciones estacionales pueden no ser tan importantes en los climas más cálidos, sí afectan los resultados en el Norte de Europa en donde la leche de vaca constituye la mayor fuente de yodo alimentario. En estas últimas poblaciones, la
alimentación bajo techo del ganado con suplementos ricos en minerales se traduce en una mayor excreción de IU en la población durante los meses de invierno. Más recientemente se ha sugerido que el IU tiene una variación diurna, con valores que alcanzan un nadir a la mañana temprano u 8-12 horas luego de la última comida, sugiriendo que las muestras deberían ser recolectadas en esos horarios (408).

2. Yodo alimentario

En muchos países se logra una ingesta adecuada de yodo mediante la yodación de la sal pero la disponibilidad de sal yodada sólo es obligatoria en algunos países desarrollados, y optativa en muchos otros. También se observa una disminución en el consumo de yodo en algunos países industrializados (399). Dicha disminución puede responder a dietas vegetarianas, especialmente en áreas en las que se cultivan
frutas y hortalizas en suelos deficientes de yodo (409).

3. Unidades de medida del IU

Para estudios epidemiológicos, la excreción de yodo se expresa normalmente como ?g de yodo excretado. Conversión a unidades del Sistema
Internacional (SI):
_ 1,0 ?g/dL= 0,07874 ?mol/L
_ 1,0 pmol/L= 12,7 pg/dL.

4. Aplicaciones de la determinación de yodo

(a) Estudios epidemiológicos

La principal aplicación de las mediciones de yodo es en estudios epidemiológicos. El consumo diario de yodo recomendado es: 90?g/día en niños, 150 ?g/día en adultos y 200 ?g/día en embarazadas o madres que amamantan. En la Tabla 10 se muestran los valores sugeridos para el IU como índices de la severidad de la deficiencia de yodo (398).

(b) Embarazo y neonatos

Afortunadamente, la incidencia de deficiencias de yodo severas causantes de cretinismo endémico se ha reducido como resultado de los programas de suplementos de yodo en la dieta. Sin embargo, la deficiencia de yodo persiste en grandes áreas del mundo. La situación en la que la deficiencia de yodo puede tener consecuencias más serias es en la mujer embarazada, en que puede comprometer el estado tiroideo del feto y del recién nacido (2, 410). Los informes sobre las variaciones en la excreción de IU durante el embarazo no son coincidentes. Algunos estudios muestran una reducción o ningún cambio, mientras que otros informan un incremento (47, 411-413). Estas diferencias pueden reflejar variaciones en el aporte del yodo alimentario (414).No obstante, la utilización de yodo urinario para estimar el aporte de yodo durante el embarazo puede inducir a error ya que este estado incrementa la tasa de excreción de yodo, lo que ocasiona un incremento relativo de su concentración urinaria, dando una falsa impresión de ingesta adecuada (415). Se ha demostrado, que la ingesta insuficiente de yodo alimentario durante el embarazo, influye sobre la función tiroidea, con aumento del volumen tiroideo y de la Tg sérica y disminución relativa de la T4L (47). La administración de yodo a mujeres embarazadas aumenta su excreción en la orina, revirtiendo los cambios tiroideos observados en la deficiencia de yodo. La importancia de evitar cualquier compromiso en la función tiroidea durante el embarazo fue enfatizada recientemente por un estudio que indica que aún los niños de madres levemente hipotiroideas pueden presentar defectos en su desarrollo neuropsicológico (64, 65). Este hallazgo es consistente con informes anteriores que muestran una disminución del yodo inorgánico plasmático PII durante el embarazo. Los primeros métodos para medir PII se basaban en administrar a las pacientes una dosis trazadora de yodo-131, y medir de la actividad específica del radioisótopo en suero y en orina (405). Otros métodos dependían de la relación yodo / cretinina en suero y en orina (405, 416). Un estudio reciente que emplea digestión con perclorato y la fórmula PII = Yodo sérico total – Yodo unido a proteínas, demostró que, al menos en las áreas suficientes en yodo, no existía una tendencia a la disminución del PII durante el embarazo (404).

(c) Ingesta excesiva de yodo

Como se sabe, en individuos susceptibles, el consumo excesivo de yodo puede conducir a la inhibición de la síntesis de hormonas tiroideas (efecto Wolff Chaikhoff) y ser de origen iatrogénico (417, 418). Un exceso de consumo de yodo por parte de individuos con deficiencia previa y autonomía tiroidea puede ocasionar hipertiroidismo (efecto Jod Basedow) (398, 420). La implementación de programas de ingesta de yodo en la población puede influir en la forma en que se presenta la enfermedad tiroidea.

Ello se observa especialmente en el hipertiroidismo, en el que el bocio multinodular tóxico es más prevalente cuando la ingesta de yodo es baja, y la enfermedad de Graves lo es cuando la ingesta de yodo es alta. Sin embargo, se ha demostrado que un programa de ingesta de yodo controlada, si se mantiene durante un tiempo, causa un incremento transitorio de hipertiroidismo durante el primer año, y luego una reducción tanto en el bocio multinodular tóxico como en la enfermedad de Graves (421). Las diferencias en la presentación de la enfermedad pueden, también alterar el perfil epidemiológico del cáncer de tiroides, con un incremento relativo del carcinoma papilar de tiroides junto con un mejor pronóstico al incrementarse el suplemento de yodo (422).

El temor de posibles efectos colaterales por exceso de yodo ha impedido la implementación de programas de profilaxis y aún la posibilidad de administrarlo luego de la liberación accidental de yodo radiactivo. Sin embargo, hay acuerdo general, en que los beneficios de la administración de yodo superan ampliamente los riesgos de una excesiva exposición (398). De este modo, el interés en medir el IU para evaluar el aporte excesivo puede superar al que se tiene para evaluar la deficiencia de yodo. El exceso de yodo puede originarse en el consumo de medicamentos que lo contengan en grandes proporciones, tales como el anti-arrítmico comúnmente prescripto, amiodarona, o
algunos antisépticos (Recomendación Nº 5) (75, 418, 419, 421, 423). Las consecuencias tiroideas del tratamiento con amiodarona pueden depender del nivel subyacente de yodo alimentario del área donde reside el paciente. El hipotiroidismo es más frecuente en áreas con alta ingesta de yodo, tales como los EE.UU., y el hipertiroidismo es más frecuente, donde la ingesta es baja como en algunas regiones de Europa (424).

La ingesta excesiva también está implicada en la mayor prevalencia de tiroiditis autoinmune y en el incremento de anticuerpos anti tiroglobulina positivos luego de la profilaxis yodada. Esto puede deberse al aumento de la antigenicidad de las formas de tiroglobulina con alto contenido de yodo (425, 426). Habitualmente, la evaluación del exceso de yodo se realiza en orina de 24 horas. Es necesario conocer que el yodo orgánico presente en el material de contraste radiológico puede ser captado por la grasa corporal, y una liberación lenta del yodo proveniente de esos depósitos de grasa se ha asociado con una excreción alta de IU que puede persistir por varios meses luego de la administración de este material de contraste (427).

5. Metodología para la determinación de yodo

Tradicionalmente, los métodos que determinan el contenido de yodo en las muestras biológicas se han basado en la transformación de compuestos yodados orgánicos en yodo inorgánico y en la remoción de los interferentes potenciales (Ej: tiocianato) que pueden perturbar la determinación colorimétrica del yodo inorgánico (428). El procedimiento incluye un paso de digestión preliminar seguido de la valoración colorimétrica del yodo a través de su acción catalítica en la reacción de Sandell Kolthoff (SK).

En esta reacción, los Ce 4+(iones céricos) se reducen a Ce3+ (iones cerosos) en presencia de As3+ (iones arseniosos) que luego se oxidan hasta convertirse en As 5+ (iones arsénicos), produciendo un cambio de color de amarillo a incoloro.

Luego de un breve período de incubación, es te cambio puede determinarse colorimétricamente. Como esta reacción es tiempo-dependiente, algunos informes sugieren detenerla con el agregado de sulfato de amonio ferroso y realizar las lecturas colorimétricas más tarde. Con otras modificaciones de la reacción de SK se puede producir un ensayo cinético alterando la relación de los iones Ce/As, procedimiento que puede aumentar la sensibilidad del ensayo (429). Ya ha sido mencionada la necesidad de remoción de sustancias interferentes, tales como tiocianato en la reacción de SK. Un estudio comparativo entre 6 métodos de análisis del yodo, atribuyó muchas de las interferencias en la reacción de SK a procedimientos de digestión inadecuados (428). Esencialmente se usan dos métodos de mineralización de la muestra, el de cenizas secas y el de cenizas húmedas.

(a) Método de cenizas secas

La técnica de cenizas secas se introdujo en 1944, y luego fue modificada. Consiste en un secado preliminar de las muestras en un horno a 100ºC, seguido de la incineración del residuo seco en presencia de álcali fuerte (KOH/K CO ) 2 3 durante unas tres horas a 600°C. La ceniza se reconstituye posteriormente en agua destilada y el contenido de yodo se determina por colorimetría como se describió anteriormente.
El procedimiento es lento y costoso, y requiere tubos de ensayo pyrex de paredes gruesas para resistir las altas temperaturas y un horno de mufla, preferentemente equipado con un microprocesador para controlar la temperatura. Sin embargo, brinda excelentes resultados no sólo para las muestras de orina sino que también es adecuado para determinar el contenido de yodo de los productos alimentarios y de las muestras de tejidos que requieren digestión completa. Para evitar pérdidas de yodo es importante controlar estrictamente la temperatura en caso de que ésta supere los 600°C o se prolongue el tiempo de incineración (429, 430). También es importante que los estándares de yodo se sometan a la incineración, ya que se sabe que el OHK agregado reduce la sensibilidad del ensayo basado en la reacción de SK. Estos métodos se desarrollaron para la determinación del yodo unido a proteínas (PBI) que se usaba para determinar las hormonas tiroideas antes la disponibilidad de los radioinmunoensayos específicos para T4 y T3. Como las muestras se incineran juntas en el horno de mufla, el procedimiento de cenizas secas es particularmente susceptible a la contaminación cruzada por alguna de las muestras que tenga alto contenido de yodo. Para evitar esta posibilidad se ha sugerido efectuar una selección preliminar para detectar tales muestras. El problema de contaminación cruzada afecta fundamentalmente al procedimiento de cenizas secas pero puede afectar potencialmente a todos los métodos de cuantificación de yodo. Por lo tanto es conveniente que el área donde se efectúa la determinación de yodo esté aislada y se mantenga lo más lejos posible de otras actividades del laboratorio, particularmente aquellas que puedan involucrar el uso de reactivos que contengan yodo. Las técnicas de manipulación y la volatilización de grandes volúmenes de orina para estudios epidemiológicos, también hace que sea recomendable contar con un laboratorio o espacio aislado para tal fin.

(b) Cenizas húmedas

Si bien controvertido, el método de digestión más usado es el de cenizas húmedas propuesto en 1951. El método ha sido automatizado y consiste en digerir las muestras de orina con ácido perclórico. El procedimiento automático, aunque actualmente generalizado, se basa en una digestión ácida y requiere un módulo de diálisis, que es susceptible a interferencias significativas por sustancias tales como el tiocianato (428). Se han desarrollado diversas variantes del método de cenizas húmedas, con el propósito de simplificar el procedimiento y optimizarlo para estudios epidemiológicos, además de reducir los costos de procesamiento de las muestras. Han sido descriptos varios procedimientos alternativos que arrojan resultados similares a los de los métodos convencionales (431).En uno de dichos métodos, los autores indican que un solo técnico puede realizar 150 determinaciones diarias con un costo inferior a US $0,50 por determinación (431). Más recientemente, se han descripto métodos aún más sencillos que usan ya sea la digestión ácida o la irradiación UV de las muestras. La desventaja de la técnica de cenizas húmedas es que el ácido perclórico y el clorato de potasio son potencialmente explosivos y su uso requiere una costosa campana especial para gases. Por ello se ha propuesto un método de digestión de orina menos riesgoso que emplea persulfato de amonio como agente oxidante. Sin embargo el uso de este agente no resultó muy eficaz para mineralizar compuestos yodados tales como T3, T4, amiodarona, etc. Ha sido descripta otra modificación que integra los procesos de digestión y de reacción en una tecnología de microplaca (433). También se desarrolló un equipo comercial que permi te una determinación cuantitativa más rápida de la yoduria después de la purificación con carbón. (Urojod, Merck KGaA, Darmstadt, Alemania). Este método parece simple de realizar y puede utilizarse para estudios epidemiológicos u ocasionalmente para evaluar la ingesta excesiva de yodo (434).

(c) Sensibilidad y especificidad de los métodos para determinar yodo

Los ensayos que utilizan la reacción de SK tienen sensibilidades entre 10 y 40 ?g/L, más que adecuadas para determinar la excreción urinaria de yodo. Mayor sensibilidad se logra usando el ensayo cinético (0,01 ?g/L) (429), mientras que la obtenida mediante la espectrometría de masa plasmática acoplada por inducción (ICP-MS) está en el orden de los 2?g/L (413, 434). Siempre que la digestión inicial sea completa, el método de SK es muy específico para el yodo. No obstante una digestión incompleta puede facilitar la interferencia de sustancias tales como
medicamentos que contienen yodo, tiocianato, ácido ascórbico o metales pesados como Hg o Ag (429). En manos expertas, la reacción de SK tiene una excelente precisión intra- e interensayo alcanzando de rutina un CV < 5%, con la condición de que la digestión esté adecuadamente controlada a fin de que la recuperación del estándar de yodo sea de 90 a 100% (429, 430, 432).

(d) Ensayos sin incineración

Además de los métodos basados en digestión alcalina y ácida, otros métodos publicados para la determinación de yodo incluyen el uso de bromo en condiciones ácidas como agente de digestión, o el uso de radiación ultravioleta (430,435). Los electrodos selectivos para yodo y la espectrometría de masa se han utilizado para determinar el contenido en diversos líquidos, incluyendo orina (436, 437). En este caso la actividad medida se aproxima a la concentración de yodo. La desventaja de este método es que los electrodos se recubren de material y deben limpiarse con frecuencia, observándose interferencia de otros iones como los sulfitos. Por consiguiente, esta técnica no es ideal para determinaciones en orina pero puede emplearse para medir el yodo en otros líquidos y en extractos de alimentos. Si bien no es adecuada para determinar la excreción de IU de manera rutinaria, esta técnica puede aplicarse a la evaluación de sobrecarga de yodo en pacientes tratados con amiodarona u otros compuestos ricos en yodo (437). Como el electrodo responde al yodo pero no a compuestos yodados, puede ser un método eficaz para determinar específicamente yodo en presencia de otros compuestos yodados.
Otras técnicas totalmente inadecuadas para uso clínico de rutina incluyen el análisis de activación nuclear o la HPLC. Un método muy empleado es el uso de ICP-MS (432, 438). Este método es bastante consistente con las técnicas de digestión convencionales que usan la reacción de SK. Sin embargo, el equipo requerido es costoso y no muy accesible. El análisis de dilución isotópica se ha aplicado al análisis tanto de orina como de agua potable (402). Las determinaciones in vivo de yodo intra-tiroideo, han sido posibles usando fluorescencia de rayos X, método que puede resultar de interés en la evaluación de pacientes con hipertiroidismo inducido por amiodarona (419).

6. Resumen

Es poco probable que en un futuro inmediato la determinación de yodo en tejidos y líquidos biológicos juegue un rol clave en los laboratorios bioquímicos clínicos de rutina. Sin embargo, teniendo en cuenta la gran cantidad de personas con IDD a nivel mundial (2,2 billones de afectados) y de informes recientes sobre la disminución (en Estados Unidos y en Australia) o la insuficiencia (en Europa) en la ingesta de yodo, la determinación de IU como parte de estudios epidemiológicos continuará siendo de considerable interés. Indudablemente los laboratorios de referencia seguirán empleando las técnicas de cenizas secas y cenizas húmedas, en función de su disponibilidad de equipamiento. Las recomendaciones recientes de que los laboratorios “tengan diversos métodos disponibles para permitir a los usuarios seleccionar el que mejor se adapte a sus necesidades específicas” parecerían prudentes para los centros especializados en la determinación de yodo.

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