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Avances en el uso de marcadores bioquímicos y moleculares para el diagnóstico de pancreatitis aguda: revisi= ón bibliográfica

= Advances in the use of biochemical and molecular markers for the diagnosis of acute pancreatitis: a literature review

= ¹	Deyaneyra Mishell Rodríguez Barragán	https://orcid.org/0000-0003-1405-6980
	Facultad de Cienci= as de la Salud. Carrera de Laboratorio Clínico, Universidad Técnica de Ambat= o, Ambato, Ecuador. rodriguezmishell58@gmail.com
= ²	Lourdes Gioconda Tabares Roser= o	https://orcid.org/0000-0002-6706-7045
	Facultad de Ciencias de la Salud. Carr= era de Laboratorio Clínico, Universidad Técnica de Ambato, Ambato, Ecuador. ltabaresr@hotmail.com

	Artículo de Investigación Científica y Tecnológi= ca Enviad= o: 14/04/2023 Revisa= do: 11/05/2023 Acepta= do: 08/06/2023 Public= ado:19/06/2023 DOI: https://doi.org/10.33262/anatomiadigita= l.v6i2.1.2583 = <= /span>

&= nbsp; Cítese:		&= nbsp; Rodríg= uez Barragán , D. M., & Tabares Rosero, L. G. (2023). Avances en el uso de marcadores bioquímicos y moleculares para el diagnós= tico de pancreatitis aguda: revisión bibliográfica . Anatomía Digital, 6(2.1), 18-29. https://doi= .org/10.33262/anatomiadigital.v6i2.1.2583
		ANATOMÍA DIGITAL, es una Revista Electrónica, Trimestral, que se publicará en soporte electrónico tiene como misión contribuir a la formación de profesionales competentes con vi= sión humanística y crítica que sean capaces de exponer sus resultados investigativos y científicos en la misma medida que se promueva mediante = su intervención cambios positivos en la sociedad. https://anatomiadigital.org La revista es editada por la Editorial Ciencia Digital (Editorial de prestigio registrada en la Cámara Ecuatoriana de Libro con No de Afiliación 663) www.celibro.org.ec
		Esta revista está protegida ba= jo una licencia Creative Co= mmons Attribution Non Commerci= al No Derivatives 4.0 International. Copia de la licencia: http://creativecommons.org/licenses/by-nc-nd/4.0/
Palabras claves: Pancreatitis aguda, diagnóstico, marcado= res bioquímicos, marcadores moleculares.<= /o:p>		Resum= en Intr= oducción: La pancreatitis aguda es una inflamación= del páncreas provocada por la activación de sus enzimas, esta patología prese= nta varias etiologías donde las principales son: obstrucción biliar, alcoholi= smo e hipertrigliceridemia. El cuadro diagnóstico= se basa en 3 criterios puntuales: dolor intenso de epigastrio, niveles séric= os de amilasa/lipasa superior a 3 veces su límite normal y pruebas de imagen compatibles con pancreatitis aguda. Los marcadores bioquímicos amilasa, lipasa sérica, amilasa urinaria y tripsinógeno-2 urinario ayudan al diagnóstico, pues cada uno de ellos brindan información valiosa que contribuye a poseer una visión clara de la patología. Hasta el momento no= se ha encontrado un marcador molecular que contribuya significativamente a la evaluación del paciente, considerando además para un diagnóstico correcto= es necesario la utilización de estudios de imagen. Objetivo: Describir los marcadores bioquímicos y moleculares para el diagnóstico de pancreati= tis aguda. Metodología: Estudio documental, descriptivo y retrospectiv= o de estudios vigentes actualizados. Conclusión: La pancreatitis aguda = si no es diagnosticada y tratada a tiempo puede conducir a inflamación sisté= mica y muerte. Los mejores marcadores bioquímicos para el diagnóstico son la amilasa y lipasa séricas puesto que presentan alta sensibilidad y especificidad. Para un diagnóstico correcto es necesario correlacionar los niveles séricos de amilasa y lipasa con los síntomas, especialmente el do= lor intenso en el epigastrio y obligatoriamente con pruebas de imagen. Áre= a de estudio general: Salud. Área de estudio específica: Laboratorio Clínico. Tipo de estudio: Artículo de revisión bibliográfica. &= nbsp;
Keywords: Acute pancreatit= is, diagnosis, biochemical markers, molecular markers.	=	Abstract Introduction: Acute pancreatit= is is an inflammation of the pancreas caused by the activation of its enzyme= s, this pathology presents several etiologies, the main ones being biliary obstruction, alcoholism, and hypertriglyceridemia. The diagnostic picture= is based on three specific criteria: intense epigastric pain, serum amylase/lipase levels higher than three times their normal limit and imag= ing tests compatible with acute pancreatitis. The biochemical markers amylase, serum lipase, urinary amylase and urinary trypsinogen-2 help in the diagnosis, as each of them provide valuable information that contributes to a clear view of the pathology. So far, no molecular marker has been found t= hat contributes significantly to the patient's evaluation, considering that f= or a correct diagnosis it is necessary to use imaging studies. Objective: <= /b>Describe the biochemical and molecular markers for the diagnosis of acute pancreatitis. Methodology: Documentary, descriptive and retrospect= ive study of current and updated studies. Conclusion: Acute pancreatit= is if not diagnosed and treated in time can lead to systemic inflammation and death. The best biochemical markers for diagnosis are serum amylase and lipase since they have high sensitivity and specificity. For a correct diagnosis it is necessary to correlate serum amylase and lipase levels wi= th symptoms, especially severe pain in the epigastrium, and necessarily with imaging tests.

Introducción<= /b>

La pancreatitis aguda es= una de las patologías más prevalentes dentro de las afecciones gastrointestinal= es, cuya etiología está liderada por la obstrucción biliar, alcoholismo y la hipertrigliceridemia. Existen otros tipos de etiología que tienen un índice bajo de prevalencia como la inducida por fármacos, pero presentan las mismas consecuencias y la misma letalidad si no se brinda un tratamiento eficaz y oportuno, ya que genera una falla multiorgánica culminando en una necrosis pancreática.

A nivel mundial su incidencia con el pasar del tiempo ha ido incrementando y varía de 4.9 a 73= .4 casos cada 100 000 habitantes independientemente del sexo ⁽¹⁾, e= sta patología predomina en personas de edad mediana o mayores y las regiones que presentan una incidencia mayor son América del Norte y el Pacifico Occident= al ⁽²⁾. Dentro de los datos que corresponden a América Latina, Brasil es el país que presenta una menor incidencia. Los países como Argentina y Ecuador lideran tasas de alcoholismo y diversos estudios mencionan que son los que presentan mayor recurrencia de padecer pancreatitis aguda. ⁽²⁾

La pancreatitis aguda al= ser una inflamación del tejido pancreático por varias causas, su cuadro clínico= es variado, pero se caracteriza por presentar dolor abdominal en epigastrio, c= on un antecedente de ingesta alcohólica o presencia de cálculos en la vía bili= ar, que puede o no irradiarse hacia región dorsal, suele acompańarse de náuseas, vómito, alza térmica de 37.5 a 38.5 °C. Algunos pacientes suelen presentar escleras ictéricas cuando existe una obstrucción del conducto biliar. ^=
(3,4)

Al ser un dolor de carác= ter agudo se levantan varias sospechas diagnósticas como: infarto agudo al miocardio, ulcera gástrica, aneurisma de la aorta, principios de apendiciti= s. Es aquí cuando la valoración mediante exámenes de laboratorio e imagenológi= cos son una clave fundamental para el diagnóstico correcto y su tratamiento oportuno. ^(3,4)

En individuos sanos el páncreas produce diariamente cerca de 0.2 a 0.3 ml/minuto de jugo pancreáti= co con un volumen diario total de alrededor de 4 litros. Este jugo pancreático además de contener enzimas como la amilasa y la lipasa también secreta otro tipo de enzimas como son la tripsina, quimiotripsina, peptidasas, bicarbona= to y nucleasas, las cuales cumplen diferentes funciones dentro del sistema digestivo. ⁽⁵⁾

Varios autores mencionan= que para el diagnóstico de pancreatitis aguda existen ciertos marcadores de laboratorio clínico que son útiles, dentro de estos los podemos clasificar = en marcadores bioquímicos y moleculares. Los bioquímicos que presentan mayor v= alor diagnóstico son amilasa y lipasa sérica, amilasa y tripsinógeno-2 urinarios= ⁽⁶⁾. En cuanto a los marcadores moleculares hasta el momento no existe ninguno de elección, pero se siguen realizando estudios e investigaciones sobre estos marcadores como por ejemplo el papel que desempeńan las histonas en la pancreatitis aguda.

Por lo tanto, es importa= nte realizar una revisión bibliográfica sobre los marcadores bioquímicos más utilizados para el diagnóstico de la pancreatitis aguda.<= /p>
Discusión=

El páncreas es u= no de los órganos situados en la parte superior del abdomen, detrás del estóma= go y los intestinos, que consta de acinos pancreáticos que terminan en un conduc= to pancreático que desemboca en el intestino junto con el conducto biliar (7). El páncreas participa en la digestión de alimentos mediante la producción de enzimas que ayudan a desdoblar los alimentos y facilitan su absorción, adem= ás cumple con la función de la regulación de glucosa en la sangre mediante la producción de insulina.

La pancreatitis aguda es una inflamación brusca del páncreas provocada por la activación de= sus enzimas que producen autodigestión del tejido pancreático o por alteración = de su medio habitual que conducen a un síndrome de inflación sistémica por lo = que si no he detectado y tratado a tiempo puede llevar a la muerte, además exis= ten otros dańos que se dan en la microcirculación que producen isquemia progres= iva con un aumento de permeabilidad vascular y edematización. ⁽⁷⁾

Cerca del 80% de= los pacientes sufren síntomas leves que con terapias de líquidos y analgesia son suficientes para superar el cuadro, pero una mínima parte de estos pacientes son ingresados a cuidados intensivos debido a una respuesta SIRS que provoca una falla orgánica múltiple. ^(7,8)

Esta patología t= iene diferentes etiologías como: la hipertrigliceridemia que presenta una altera= ción en su medio, la litiasis biliar una obstrucción del conducto lo que genera acumulación de secreción pancreática.

La litiasis bili= ar conduce a un bloqueo de los conductos por la impactación de un cálculo bili= ar, provocando acumulación retrograda de secreción pancreática y activación de enzimas proteolíticas, mientras menor sea el tamańo de la litiasis biliar, mayor es el riesgo de que migre fuera de la vesícula y se quede en el condu= cto bilio pancreático provocando pancreatitis.^{(7, 9)}

La pancreatitis alcohólica representa cerca del 19%-41% de todos los casos. La asociación e= ntre el alcohol y la patología es poco conocida ⁽¹⁰⁾. El alcohol en el organismo es metabolizado por 3 rutas enzimáticas importantes, alcohol deshidrogenasa, citocromo P450 y la catalasa, la primera ruta metaboliza el alcohol a una sustancia altamente tóxica, carcinógena y el exceso me genera= un proceso inflamatorio que se relaciona con la pancreatitis aguda.

La hipertrigliceridemia es una causa no común de pancreatitis aguda y represen= ta entre el 1% - 4% de los casos. Su procedencia es por un exceso de lipoprote= ínas exquisitas en triglicéridos que liberan una concentración elevada de ácidos grasos libres que ocasionan una lesión del endotelio vascular y acinos pancreáticos provocando un medio isquémico y ácido con cierto grado de toxicidad. ^(10,11)

A parte de las etiologías principales también existen otras no muy comunes que generan pancreatitis aguda como la de origen genético donde ciertas mutaciones se asocian a esta patología, por ejemplo, la pancreatitis hereditaria es provo= cada por la mutación del gen del tripsinógeno catiónico (PRSS1), pero esto se as= ocia más con pancreatitis crónica, en los pacientes jóvenes que no tengan causa = de pancreatitis aguda se debe considerar etiología genética. ^(10,11)

La inducida por fármacos (2%-4,8%), varios medicamentos han sido notificados como posibles causantes de la patología, como, 6-mercaptopurina, sulfonamidas, pentamidin= a, esteroides. Los mecanismos que se presentan son reacciones inmunológicas con efecto toxico directo, isquemia y trombosis. ⁽¹¹⁾

De origen infecc= ioso se incluye a virus, bacterias, hongos y parásitos, dentro de las infecciones notificadas que causan pancreatitis aguda están, virus de Coxsackie, hepati= tis B, citomegalovirus. Y los de origen idiopático y los no identificados se estiman que son el 10%-40% de todos los casos. ⁽¹¹⁾

Sus manifestacio= nes clínicas son, dolor abdominal que puede variar de leve y tolerable a intens= o y constante, el dolor se localiza en el epigastrio y región periumbilical, en ocasiones irradia hasta la espalda y los flancos. También se presenta náuse= as, vómitos, distensión abdominal por la hipomotilidad gástrica. ⁽⁷⁾=

La severidad de = la pancreatitis aguda va desde situaciones leves hasta graves y complicadas con una alta morbimortalidad. Diagnosticar la presentación aguda es simple, per= o lo complejo es predecir el resultado y progresión de la enfermedad ^{(12).
Según Atlanta esta patología se clasifica en dos categorías:}

·&nb= sp;        Pancreatitis aguda edematosa intersticial: inflamación aguda del parénquima pancreático y el tejido peripancreático circundante, pero sin te= jido necrótico reconocible. ^(12,13)

·      =    Pancreatitis aguda necrosante: necrosis del parénquima pancreático y = del tejido peripancreático. ^(12,13)

De acuerdo con la gravedad de esta patología se divide en los siguientes tipos:

·&nb= sp;        Pancreatitis aguda leve: insuficiencia orgánica y ausencia de complic= aciones sistémicas. ^(12,14)

·&nb= sp;        Pancreatitis aguda moderadamente grave: existe complicaciones locales= con o sin fallo orgánico con menos de 48 horas. ^(12,14)

·      =    Pancreatitis aguda grave: existe fallo orgánico constante por más de = 48 horas con afección de órganos. ^(12,14)

Según los criter= ios diagnósticos de Atlanta y otras guías internacionales es necesario la prese= ncia de dos de los tres criterios, dolor de epigastrio intenso y persistente, niveles séricos de amilasa/lipasa superior a 3 veces su límite normal, imág= enes compatibles con PA (tomografía computarizada con contraste, resonancia magnética) ^(15,16,17). En ocasiones se considera que el Gold estándar para diagnosticar PA es la prueba radiológica de apoyo, pero este método de vez en cuando es considera como prueba de primera línea, es por e= sto por lo que los biomarcadores pancreáticos brindan criterio esencial para evaluar una Pancreatitis Aguda. Actualmente las enzimas amilasa y lipasa séricas continúan siendo las pruebas mayormente utilizadas para el diagnóstico de pancreatitis aguda, sin embargo estos biomarcadores presentan limitaciones donde se elevan también en situaciones no pancreáticas como la enfermedad renal, apendicitis, no obstante, la lipasa sérica se considera el biomarcad= or diagnóstico preferencial debido a que posee su vida media más prolongada qu= e la amilasa, pues esta permanece detectable 7 a 14 días luego de haber iniciado= sus síntomas, en cambio la amilasa solo permanece 3 a 4 días. ⁽¹⁵⁾ El uso de pruebas imagenológicas en la actualidad poseen un rol cada vez más importante en el manejo de los pacientes gracias al avance tecnológico que estamos viviendo, pues estas brindan información crucial para el diagnóstic= o y curso de la enfermedad. ^(18,19)

La enzima amilasa cataliza reacciones de hidrolisis de enlaces entre unidades de glucosa cuan= do se digiere el glucógeno y almidón para crear pequeńos fragmentos de glucosa, posee diferentes sitios de producción, ovarios, glándulas mamarias, mucosa = del intestino delgado, glándulas salivales, testículos ⁽⁷⁾. Su vida media es corta, pues su inicio de síntomas es de 3-6 horas, alcanzando su p= ico máximo de 10-12 horas, y vuelve a la normalidad luego de 3-5 días, salvo el caso de que exista necrosis pancreática extensa, obstrucción completa de los conductos. Esta prueba se utiliza de una forma general en pacientes que refieran el cuadro clínico de pancreatitis aguda.

La enzima lipasa= es la encargada de digerir triglicéridos, los más abundantes en nuestra dieta = de ahí obtenemos fracciones pequeńas, ácidos grasos libres y glicerol. Esta en= zima en comparación con la amilasa presenta menos sitios de producción, evitando= que ocurran falsos positivos, además se eleva al inicio de los síntomas entre 3= y 6 horas, su pico máximo 24 horas y regresa a la normalidad de 7-14 días. Es frecuente en el diagnóstico de pancreatitis aguda debido a que su actividad aumenta de manera paralela a la de la amilasa y ambas son biomarcadores eficientes para pancreatitis aguda. ^(7,20)

Existen pruebas = que permiten detectar solo la lipasa pancreática y gracias a los nuevos análisis este tipo de pruebas utilizan un cofactor (calcio), con el que se activa la coenzima (colipasa) misma que se encarga de bloquear al resto de lipasa y s= olo reacciona con la lipasa pancreática.⁽²⁰⁾

Según un estudio realizado por Sajjad<= span style=3D'font-size:12.0pt;line-height:115%;font-family:"Times New Roman",se= rif'> & Naqi, en la Revista Europea de Medicina Molecular y Clínica muestra que la amilasa urinaria puede ser utilizada para diagnostic= ar pancreatitis aguda debido a que posee una sensibilidad y especificidad anál= ogas a las de amilasa y lipasa sérica ^(21,22). La amilasa se excreta = en la orina hasta varios días luego de que los niveles séricos hayan vuelto a = su normalidad por lo que se propuso que la excreción urinaria de amilasa séric= a un indicador con mayor sensibilidad y fiabilidad. ⁽²²⁾

Aparte de los marcadores bioquímicos en mención existe uno que ha demostrado ser prometed= or para un diagnóstico precoz de pancreatitis aguda se trata del tripsinógeno-2 urinario, en condiciones normales cantidades pequeńas de tripsinógeno es secretado y entra a circulación, una mínima porción de isoformas de tripsinógeno 1 y 2 se filtran en los individuos sanos, pero cuando hay pacientes con pancreatitis aguda se ha evidenciado que gran aumento de excreción de tripsinógeno 2, lo que lo corrobora como un marcador potencial para diagnóstico ⁽²³⁾. Sin embargo, este marcador no permanece m= ucho tiempo dentro del cuerpo del paciente en comparación con la lipasa.

Amilasa y Lipasa séricas son los marcadores bioquímicos utilizados con mayor frecuencia para= diagnosticar pancreatitis aguda, pues estas deben elevarse 3 veces su límite normal y en= el libro de Pagana 15va edición menciona los siguientes valores referenciales = para Amilasa (60-120 U/L), (Lipasa 0-160 U/L), Amilasa Urinaria (orina 24 horas) hasta 5000 U/24h o 6,5-48,1 U/h ⁽²⁴⁾. En el caso del tripsinógen= o-2 urinario sus valores son 50ng/ml. ⁽²³⁾

En cuanto a los marcadores moleculares hasta el momento no existe ninguno de elección, pero= se conoce que siguen realizando estudios e investigaciones donde Pedro Silva et al. proponen a las histonas como biomarcador molecular. ⁽²⁵⁾

Hay estudios preliminares que reportan que las histonas mostraron correlación en sus niv= eles circulantes y la gravedad de la enfermedad en modelos murinos, además sugie= ren que las histonas circulantes se comportan en forma de patrón de moléculas asociadas con el dańo que provocan inflamación y contribución al SIRS, muer= te, entonces en el caso de sepsis severa estas histonas circulantes son detecta= bles en la sangre ⁽²⁵⁾. En los modelos murinos se encontró un aumento significativo de las histonas circulantes en la pancreatitis necrotizante a= guda por la muerte extensa de células acinares pancreáticas.
Conclusiones<= o:p>

·      =    La pancreatitis aguda es una condición grave que si no es diagnosticada y tratada a tiempo puede conducir a inflamación sistémica y muerte. Los mejores marcadores bioquímicos para el diagnóstico son la amilasa y lipasa séricas puesto que presentan alta sensibilidad y especificidad y se elevan hasta 3 veces por sus límites normales en esta patología. También pueden se= r de gran utilidad clínica los niveles de amilasa y tripsinógeno-2 urinarios. En relación con los marcadores moleculares, las histonas parecen ser de ayuda diagnóstica pero su eficacia sigue en estudio y todavía no hay estudios concluyentes al respecto. Debemos considerar además que para un diagnóstico correcto de pancreatitis aguda es necesario correlacionar los niveles séric= os de amilasa y lipasa con los síntomas, especialmente el dolor intenso en el epigastrio y obligatoriamente con pruebas de imagen.

Conflicto de intereses

Los autores declaran que no existe conflicto de intereses.

Declaración de contribución de los autores<= o:p>

El artículo deberá acompańarse de una nota, que exprese la contribución de cada autor al estudio realizado.

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18.&= nbsp; Zheng Z, Ding Y-X, Qu Y-X, Cao F, Li F. A narrative review of acute pancreatitis and its diagnosis, pathogenetic mechanism, and Management [Internet]. Annals of translational medicine. U.S. National Libr= ary of Medicine; 2021 [cited 2023, Apr24]. Available from: https://www.ncbi.nlm.nih.gov/pmc/= articles/PMC7859757/

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El artículo que se publica es de exclusiva responsabilidad de los autores y no necesariamente reflejan el pensamiento de la Revista Anatomía Digital.

El artículo queda en propiedad de la revista y, por tanto, su publicación parc= ial y/o total en otro medio tiene que ser autorizado por el director de la R= evista Anatomía Digital.

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Vol. 6 No. 2.1, pp. 18= – 29 junio = 2023

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