Bilirrubina

El papel fisiológico y fisiopatológico, intervalos de referencia y las causas más probables de valores anormales

Bilirrubina

La bilirrubina es el producto final amarillo resultante de la degradación del grupo hemo de la hemoglobina. Se transporta en la sangre desde su lugar de producción (el sistema reticuloendotelial) al hígado, donde se biotransforma antes de su excreción en la bilis. La ictericia, la decoloración amarilla patológica de la piel, se debe a una acumulación anormal de bilirrubina en los tejidos, y siempre se asocia a una concentración sanguínea elevada de bilirrubina (hiperbilirrubinemia).

Intervalo de referencia de la bilirrubina – ejemplos

µmol/L mg/dL Adultos: 0–34 0–2,0 3–5 días (RNT): 68–137 4,0–8,0 3–5 días (RNPT): 171–240 10,0–14 1–2 días (RNT): 103–171 6,0–10 1–2 días (RNPT): 103–205 6,0–12 0–1 día (RNT): 34–103 2,0–6,0 0–1 día (RNPT): 17–137 1,0–8,0 Sangre de cordón (RNT): <34 <2,0 Sangre de cordón (RNPT): <34 <2,0 [4] RNT: recién nacido a término; RNPT: recién nacido pretérmino

Metabolismo de la bilirrubina

La mayoría de la bilirrubina es el producto del catabolismo del hemo de la hemoglobina en eritrocitos envejecidos extraídos de la circulación a elementos reticuloendoteliales en el bazo, el hígado y la médula ósea (Fig. 17). El resto se deriva de una eritropoyesis ineficiente y del catabolismo de otras proteínas que contienen hemo, como la mioglobina, las catalasas y los citocromos. Esta bilirrubina no conjugada se libera en la circulación, donde se une rápidamente a la albúmina para su transporte al hígado. Después de la liberación de la albúmina, la bilirrubina no conjugada se transporta a hepatocitos donde se combina enzimáticamente con ácido glucurónico, produciendo glucurónidos de bilirrubina (es decir, bilirrubina conjugada), que se excretan en la bilis a los intestinos. La acción de las bacterias colónicas desconjuga la bilirrubina y convierte la bilirrubina no conjugada resultante en el producto excretor final, el urobilinógeno, que sale del cuerpo en las heces. Una pequeña proporción de urobilinógeno se reabsorbe en la circulación sanguínea y de vuelta al hígado para una nueva excreción (circulación enterohepática de bilirrubina) o para ser excretada en la orina por los riñones.

FIG. 17: El metabolismo de la bilirrubina.

BC: bilirrubina conjugada; BNC: bilirrubina no conjugada; Hb: hemoglobina; SRE: sistema reticuloendotelial; Ab: albúmina; GlcA: ácido glucurónico; GT: glucuronosiltransferasa; URO: urobilinógeno

Diversos factores propios de la fisiología neonatal contribuyen a la ictericia a esta edad [188]:

  • Aumento de la destrucción de glóbulos rojos y, por lo tanto, aumento de la producción de bilirrubina
  • Hígado inmaduro y, por lo tanto, menor capacidad para conjugar la bilirrubina
  • Aumento de la circulación enterohepática de la bilirrubina
  • Falta de flora bacteriana intestinal para convertir la bilirrubina en productos de excreción

 

En los neonatos, gran parte de la bilirrubina conjugada en los intestinos se hidroliza de nuevo a bilirrubina no conjugada. Esta bilirrubina no conjugada se reabsorbe en el torrente sanguíneo a través de la circulación enterohepática, añadiendo una carga adicional de bilirrubina a un hígado ya sobrecargado [188].

Tipos de bilirrubina que se encuentran en el plasma

  • Bilirrubina no conjugada (indirecta) (unida a la albúmina). Es soluble en agua y no es tóxica. Esta fracción normalmente abarca alrededor del 90% del total de la bilirrubina
  • Bilirrubina libre no conjugada (indirecta) (es decir, no unida a la albúmina). Es poco soluble en agua y es potencialmente tóxica; ya que puede traspasar las membranas lipídicas y causar kernicterus. Esta fracción normalmente abarca <0,1% de toda la bilirrubina no conjugada
  • La bilirrubina conjugada (directa) (unida al ácido glucurónico) es soluble en agua y no es tóxica. Esta fracción normalmente abarca alrededor del 10% del total de la bilirrubina
  • La bilirrubina delta (δ) se une covalentemente a proteínas plasmáticas para formar un complejo conjugado de bilirrubinaproteína. Es soluble en agua, no tóxica y aparece en el suero cuando la excreción hepática de la bilirrubina conjugada se ve afectada en pacientes con enfermedad hepatobiliar [187]

 

La bilirrubina total suele definirse como la no conjugada más la conjugada. Dado que la δ-bilirrubina suele ser baja (0–2% de la bilirrubina total) y difícil de medir, la mayoría de las veces no se incluye en el cálculo total de la bilirrubina.

¿Por qué medir la bilirrubina?

La monitorización de la ictericia neonatal es uno de los motivos más comunes para medir la concentración de la bilirrubina. La mayoría de los recién nacidos tienen algún grado de ictericia, aunque generalmente es leve, benigna y se resuelve sin tratamiento durante la segunda semana de vida. La toxicidad neuronal potencial de la bilirrubina requiere que se monitorice a los recién nacidos con ictericia para identificar a los que podrían, sin tratamiento, desarrollar hiperbilirrubinemia grave, que está asociada a riesgo de encefalopatía bilirrubínica aguda o kernicterus (ver la nota al final de este capítulo) [186].

En los bebés de mayor edad, niños y adultos, la bilirrubina debe medirse cuando hay sospecha de ictericia y/o enfermedad hepática o del tracto biliar.

¿Cuándo debería medirse la bilirrubina?

En recién nacidos cuando hay signos y síntomas de hiperbilirrubinemia [23, 186]:

  • Tinción amarilla de la piel (ictericia)
  • Vómitos
  • Orina oscura
  • Problemas de succión/alimentación
  • Letargo
  • Hipo/hipertonía
  • Llanto desconsolado distintivo
  • Irritabilidad
  • Fiebre

 

En adultos, cuando hay sospecha de, por ejemplo, enfermedad hepática o del tracto biliar, anemia hemolítica o ictericia.

Interpretación de los valores de la bilirrubina

El aumento de la bilirrubina y la ictericia resultante se pueden atribuir a alteraciones en cualquiera de los pasos a lo largo de la vía metabólica descrita anteriormente. En el diagnóstico diferencial de ictericia resulta útil saber si el aumento de la bilirrubina total se debe a un aumento predominante de la bilirrubina conjugada o no conjugada.

Por ejemplo, el aumento de la bilirrubina no conjugada sugiere que la ictericia se debe al aumento de la producción de bilirrubina a partir del hemo o a la reducción de la capacidad de las células hepáticas para conjugar la bilirrubina. Ambos mecanismos se dan en la ictericia neonatal fisiológica. El aumento de la producción de bilirrubina también explica la ictericia que puede darse en personas con cualquier forma de anemia hemolítica (denominada ictericia hemolítica). La reducción de la capacidad de las células hepáticas para conjugar la bilirrubina explica la ictericia que se da en el síndrome de Gilbert, un trastorno genético caracterizado por una deficiencia hereditaria de la enzima necesaria para la conjugación de la bilirrubina [189].

El aumento de la bilirrubina conjugada, por otro lado, implica que la bilirrubina conjugada no se excreta en la bilis tan eficientemente como sería normal, y en su lugar se está derramando en la sangre. Esto puede deberse a un deterioro del aporte de bilirrubina conjugada del hepatocito a los canalículos biliares o a la reducción del flujo biliar (colestasis) dentro del hígado (denominada ictericia hepatocelular o ictericia colestásica); o a la obstrucción del flujo biliar a través del tracto biliar (denominada ictericia obstructiva).

Clasificación fisiológica de la ictericia

Hiperbilirrubinemia no conjugada en recién nacidos [4, 23]

Aumento de la producción de bilirrubina no conjugada del hemo:

  • Enfermedad hemolítica:
    • Incompatibilidad de glóbulos rojos
    • Debido a la incompatibilidad de rhesus (Rh); por ejemplo, madre Rh(–), feto Rh(+) e incompatibilidad de tipo de sangre ABO, madre (O) y bebé (A o B)
  • Ictericia por leche materna:
    • Debido a la α-glucuronidasa en la leche materna, que hidroliza la bilirrubina conjugada en bilirrubina no conjugada en los Intestinos
  • Eritropoyesis ineficaz:
    • Reemplazo rápido del aumento de la masa de glóbulos rojos en neonatos

 

Disminución de la absorción de bilirrubina no conjugada a través de la membrana de los hepatocitos:

  • Inhibición competitiva
  • Drogas
  • Síndrome de Gilbert
  • Sepsis, ayuno

 

Disminución de la biotransformación (conjugación):

  • Ictericia fisiológica
  • Inhibición (fármacos)
  • Hereditaria (síndrome de Crigler-Najjar)
  • Disfunción hepatocelular
  • Síndrome de Gilbert

 

Hiperbilirrubinemia conjugada (colestasis) [4, 23]

Disminución de la secreción de bilirrubina conjugada en los canalículos:

  • Enfermedad hepatocelular:
    • Hepatitis
    • Colestasis (intrahepática)
    • Obstrucción extrahepática
  • Síndrome de Dubin-Johnson
  • Síndrome de RoterDrogas

 

Disminución del drenaje:

  • Obstrucción extrahepática:
    • Piedras
    • Carcinoma
    • Estenosis
    • Atresia

     

  • Obstrucción intrahepática:
    • Drogas:
      • Granulomas
      • Cirrosis biliar primaria
      • Escasez de conductos biliares
    • Tumores

 

Ictericia fisiológica de los recién nacidos

Los neonatos están fisiológicamente predispuestos a la ictericia, debido al aumento de la descomposición de la hemoglobina y una función hepática limitada. La baja concentración de albúmina aumenta el riesgo de aumento de la bilirrubina libre (no conjugada), lo que a su vez aumenta el riesgo de neurotoxicidad y la resultante encefalopatía aguda por bilirrubina (kernicterus) [186, 188] (ver nota al final de este capítulo).

En los bebés a término, la ictericia generalmente se desarrolla después de 24 horas de vida y alcanza su punto máximo en los días 3 o 4 [23]. Puede advertirse como decoloración amarilla de la esclerótica a niveles de aproximadamente 34–51 μmol/L (2–3 mg/dL) [190] y de la piel a niveles superiores (ictericia).

Los bebés prematuros son más propensos a desarrollar ictericia que los bebés a término. En los bebés pretérmino suele comenzar 48 horas después del nacimiento, alcanza su punto máximo en el día 5 y puede durar 2 semanas [23]. Los neonatos necesitan tratamiento si el nivel de bilirrubina total es demasiado alto o está aumentando demasiado rápido.

La ictericia fisiológica suele ser leve y no perjudicial, pero unas concentraciones de bilirrubina por encima de 170 μmol/L (10 mg/dL), junto con la prematuridad, una albúmina sérica baja, la acidosis y las sustancias que compiten por los sitios de unión de la albúmina (por ejemplo, aspirina) pueden aumentar el riesgo de kernicterus [4].

Tratamiento para la hiperbilirrubinemia/ictericia en recién nacidos

  • Fototerapia para convertir la bilirrubina en productos que puedan eludir el sistema de conjugación del hígado y excretarse en la bilis o en la orina sin metabolismo adicional [191]
  • Transfusión de intercambio para eliminar la bilirrubina mecánicamente
  • Agentes farmacológicos administrados para interferir con la degradación del hemo y la producción de bilirrubina, acelerar las vías metabólicas normales para la aparición de la bilirrubina, o inhibir la circulación enterohepática de la bilirrubina

 

¿Límites de acción para el tratamiento de recién nacidos con ictericia?

La Academia Estadounidense de Pediatría [186] proporciona directrices para el uso de la fototerapia y la transfusión de intercambio en bebés (casi) a término con una edad gestacional de 35 semanas o más. Sin embargo, no se trata de directrices basadas en la evidencia, sino que son, principalmente, producto de la opinión de expertos. El uso de fototerapia en bebés con bajo peso al nacer es profiláctico y se basa en el peso al nacer o en la edad gestacional [192]. La concentración de bilirrubina de 340 μmol/L (20 mg/dL) que se ha utilizado tradicionalmente requiriendo acción crítica (fototerapia intensiva, transfusión de intercambio) se está dejando de utilizar [4]. Ahora se recomienda monitorizar el aumento de la concentración total de bilirrubina desde el momento del nacimiento hasta el momento del alta del hospital (36–73 horas). Se debe hacer una gráfica de la concentración de bilirrubina total frente al tiempo (horas) y compararse con una gráfica similar que se encuentra en la directriz de la Academia Estadounidense de Pediatría, Subcomité de Hiperbilirrubinemia [186] para guiar la implementación de la fototerapia.

Nota: La Academia Estadounidense de Pediatría, Subcomité de Hiperbilirrubinemia [186], recomienda que en los bebés se utilice el término "encefalopatía aguda por bilirrubina" para describir las manifestaciones agudas de toxicidad de la bilirrubina observadas en las primeras semanas después del nacimiento, y que el término "kernicterus" se reserve para las secuelas clínicas crónicas y permanentes de la toxicidad de la bilirrubina.

 

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