Biopsychosocial profile of

non-alcoholic fatty liver disease (NAFLD)

associated with liver transplantation and
prevention of risk factors

Tesis Doctoral
Departamento de Personalidad, Evaluación y Tratamiento Psicológicos
Universidad de Sevilla

Jesús Funuyet Salas

2
Tesis presentada por D. Jesús Funuyet Salas y realizada bajo la dirección de la
Dra. Mª Ángeles Pérez San Gregorio, el Dr. Agustín Martín Rodríguez y el Dr.
Manuel Romero Gómez en el Departamento de Personalidad, Evaluación y
Tratamiento Psicológicos de la Universidad de Sevilla, para la obtención del
Grado de Doctor y la Mención Internacional en el Título de Doctor.

En Sevilla, a 28 de julio de 2022.

3
AGRADECIMIENTOS

A todos/as los/as participantes de esta investigación, porque gracias a su tiempo y su

inestimable ayuda ha sido posible la realización de esta Tesis Doctoral, que supone la
culminación del trabajo y el esfuerzo de los últimos cuatro años de mi vida. Gracias:

A la Dra. Mª Ángeles Pérez San Gregorio y al Dr. Agustín Martín Rodríguez, por su infinita
implicación, dedicación y disponibilidad, por su paciencia y generosidad, por arrojar luz en
los malos momentos, y por inspirarme a iniciar mi carrera como investigador. Gracias a ellos
he podido crecer tanto a nivel profesional como personal, y he disfrutado de un contexto y
unas condiciones inmejorables para desarrollar mi trabajo como doctorando. Desde el primer
día me he sentido afortunado de que hayan sido mis directores de Tesis, y ojalá estos hayan
sido los primeros de muchos años trabajando juntos en el mundo de la investigación.

Al Dr. Manuel Romero Gómez, por la confianza depositada en mí a lo largo de este camino.
Esta Tesis ha sido posible gracias a sus valiosas enseñanzas y su sabia guía, que le han
conferido rigor e innovación a la investigación. Gracias por su generosidad a la hora de
proporcionarme ayuda e incalculables recursos para poner en marcha y desarrollar esta Tesis.
Gracias también por su devoción por la investigación y por su interés por abordar la
enfermedad hepática grasa no alcohólica desde una perspectiva psicológica, que permitió el
nacimiento de este proyecto.

Al Dr. Luke Vale y al Dr. Quentin Anstee, de la Universidad de Newcastle, por permitirme
realizar una estancia investigadora en sus instalaciones, gracias a la cual he podido realizar
uno de los trabajos que conforman esta Tesis.

Al equipo de profesionales de la Unidad de Gestión Clínica de Aparato Digestivo del Hospital

Universitario Virgen del Rocío de Sevilla, por su trato y su imprescindible ayuda logística.

A la Universidad de Sevilla, a la Facultad de Psicología y al Departamento de Personalidad,

Evaluación y Tratamiento Psicológicos por darme la oportunidad de realizar mi labor como
investigador y docente durante estos últimos cuatro años. Ha sido una experiencia inolvidable
e impagable.

Al Ministerio de Ciencia e Innovación, y al Ministerio de Educación y Formación Profesional,

por conceder la financiación necesaria para el desarrollo de esta investigación.

4
A mis padres, por apoyarme y hacerme sentir que siempre están ahí. Gracias por haberme
inculcado desde que era pequeño valores tan relevantes como la persistencia, la integridad, el
inconformismo, la ambición por mejorar y, por encima de todo, la importancia de ser una
buena persona. Todo ello he tratado de seguirlo siempre, con mayor o menor acierto, e intento
aplicarlo como docente e investigador. Gracias también por haberme enseñado la cultura del
esfuerzo, lo necesario de formarse y estudiar. Gracias por su infinita paciencia, por soportarme
en tantos momentos de agobio y estrés, y por hacerme la vida tan fácil. En definitiva, por ellos
he llegado a este preciso lugar y, por lo tanto, no puedo sentirme más agradecido.

A mis abuelos, quienes desgraciadamente no podrán leer esto, pero me gustaría deciros: os
echo de menos. Echo de menos cada domingo llegando a vuestra casa y diciendo “abuela,
¿con qué me vas a sorprender hoy?”, para que a continuación salieras con alguno de mis platos
preferidos, que cocinabas siempre con tanto cariño. Echo de menos cada partido que vimos
juntos, abuelo, y cada charla de fútbol que tuvimos. Tus “la semana que viene habrá más
suerte” tras repasar nuestra quiniela, abuelo. Tus “ten cuidaíto” cuando me iba, abuela.
Gracias a vosotros también he llegado a ser quién soy. Siempre os llevaré conmigo.

A Patricia, mi compañera de viaje, por haberse convertido en una persona muy importante en
mi vida, con quien puedo contar tanto en los buenos como en los malos momentos. Gracias
por su esfuerzo por hacernos mejor el uno al otro, por hacerme partícipe de sus cuestiones
vitales más trascendentales, por tantos momentos de felicidad y plenitud juntos, por tantos
planes realizados y por realizar, por todos los sueños que quedan por cumplir. Gracias también
por su integridad, por su afán por mejorar, por su interés en escucharme y apoyarme. Y, por
supuesto, gracias por todas las veces que me ha ayudado con la Tesis. Lo que hoy soy, y esta
Tesis, es también gracias a ella.

Por último, a mis amigos. Gracias a Rubén y Mario, por ser los hermanos que nunca he tenido,
por sus incalculables consejos, por haber estado a mi lado para compartir penas y alegrías.
Rubén, nunca olvidaré aquel paseo por la Barceloneta que despertó en mí la curiosidad por el
mundo de la investigación. Aquel fue el primer paso de un largo camino que llega hasta hoy,
y que espero dure toda la vida, como nuestra amistad. Contigo empezó todo. Gracias también
a Andrés, que es la persona más pura que conozco, con quien comparto una genuina y sincera
amistad. Y gracias a Antonio, Irene, Isa, Manu y Fran, a quienes conocí a lo largo de mi
trayectoria académica, y con los que he vivido grandes momentos que han hecho más fácil el
esfuerzo. Vosotros también habéis contribuido para llegar hasta aquí.

A todos y todas, mi más sincero agradecimiento. De un modo u otro, cada uno de vosotros ha
formado parte de este trabajo que culmina hoy. Nunca lo olvidaré.

5
6
ÍNDICE

1. MARCO LEGISLATIVO DE LA TESIS DOCTORAL ........................................... 11

2. INTRODUCCIÓN ......................................................................................................... 12

3. OBJECTIVES ................................................................................................................ 23

4. TRABAJOS QUE CONFORMAN LA TESIS DOCTORAL .................................... 25

4.1. Primer trabajo titulado “Psychological biomarker profile in NAFLD/NASH

with advanced fibrosis” .................................................................................................. 25

Abstract ........................................................................................................................... 26

Introduction .................................................................................................................... 26

Psychosocial Repercussions of NAFLD ........................................................................ 27

Variables of Potential Interest in NAFLD ................................................................... 31

NAFLD Treatment: A Multidisciplinary Approach ................................................... 35

References ....................................................................................................................... 39

4.2. Segundo trabajo titulado “Psychological biomarkers and fibrosis: An innovative

approach to nonalcoholic fatty liver disease” ............................................................... 54

Abstract ........................................................................................................................... 55

Introduction .................................................................................................................... 55

Methods ........................................................................................................................... 57

Results ............................................................................................................................. 61

Discussion ........................................................................................................................ 76

References ....................................................................................................................... 80

4.3. Tercer trabajo titulado “Health-related quality of life in non-alcoholic fatty liver
disease: A cross-cultural study between Spain and the United Kingdom”................ 86

Abstract ........................................................................................................................... 86

Introduction .................................................................................................................... 86

Methods ........................................................................................................................... 88

Results ............................................................................................................................. 94

7
 Discussion ...................................................................................................................... 103

References ..................................................................................................................... 107

4.4. Cuarto trabajo titulado “Quality of life mediates the influence of coping on
mental health and self-efficacy in patients with non-alcoholic fatty liver disease”. 113

Abstract ......................................................................................................................... 113

Introduction .................................................................................................................. 113

Methods ......................................................................................................................... 115

Results ........................................................................................................................... 118

Discussion ...................................................................................................................... 126

References ..................................................................................................................... 130

4.5. Quinto trabajo titulado “Quality of life and coping in nonalcoholic fatty liver
disease: Influence of diabetes and obesity” ................................................................. 137

Abstract ......................................................................................................................... 138

Introduction .................................................................................................................. 138

Methods ......................................................................................................................... 139

Results ........................................................................................................................... 143

Discussion ...................................................................................................................... 150

References ..................................................................................................................... 153

4.6. Sexto trabajo titulado “Influence of psychological biomarkers on therapeutic

adherence by patients with non-alcoholic fatty liver disease: A moderated mediation
model” ............................................................................................................................ 158

Abstract ......................................................................................................................... 159

Introduction .................................................................................................................. 159

Methods ......................................................................................................................... 161

Results ........................................................................................................................... 165

Discussion ...................................................................................................................... 171

References ..................................................................................................................... 175

5. OVERVIEW OF RESULTS ....................................................................................... 185

8
6. DISCUSIÓN ................................................................................................................. 189

6.1. Primer trabajo: biomarcadores psicológicos que pueden ser relevantes para el
perfil biopsicosocial asociado a la EHGNA ................................................................ 189

6.2. Segundo, tercer y cuarto trabajo: perfil biopsicosocial asociado a los distintos
niveles de gravedad de la EHGNA (esteatohepatitis y fibrosis hepática) ................ 189

6.3. Cuarto y quinto trabajo: perfil biopsicosocial asociado a los principales factores
de riesgo de la EHGNA (diabetes tipo 2 y obesidad) ................................................. 195

6.4. Sexto trabajo: biomarcadores psicológicos relevantes para la adherencia

terapéutica de los pacientes con EHGNA ................................................................... 198

6.5. Limitaciones y procedimientos de minimización de las mismas en los seis

trabajos........................................................................................................................... 200

6.6. Aplicabilidad y utilidad práctica de los resultados en el área de la salud ......... 202

7. CONCLUSIONS .......................................................................................................... 207

8. RESUMEN / SUMMARY ........................................................................................... 211

9. REFERENCIAS ........................................................................................................... 217

10. ANEXOS ......................................................................................................................... I

10.1. Separata del trabajo titulado: “Psychological biomarker profile in

NAFLD/NASH with advanced fibrosis” .......................................................................... i

10.2. Separata del trabajo titulado: “Psychological biomarkers and fibrosis: An

innovative approach to non-alcoholic fatty liver disease” .......................................... xxi

10.3. Separata del trabajo titulado: “Health-related quality of life in non-alcoholic

fatty liver disease: A cross-cultural study between Spain and the United
Kingdom” .................................................................................................................. xxxviii

10.4. Separata del trabajo titulado: “Quality of life mediates the influence of coping
on mental health and self-efficacy in patients with non-alcoholic fatty liver
disease” .......................................................................................................................... lxxv

10.5. Separata del trabajo titulado: “Quality of life and coping in nonalcoholic fatty
liver disease: Influence of diabetes and obesity” ........................................................ cvii

10.6. Separata del trabajo titulado: “Influence of psychological biomarkers on

therapeutic adherence by patients with non-alcoholic fatty liver disease: A
moderated mediation model” ..................................................................................... cxxii

10.7. Hoja de información y consentimiento informado ...................................... cxxxviii

9
10
1. MARCO LEGISLATIVO DE LA TESIS DOCTORAL

Esta Tesis Doctoral se presentará bajo la modalidad de tesis por compendio de publicaciones
en función del artículo 9 de la normativa reguladora del régimen de Tesis Doctoral (Acuerdo
9.1/CG 19-4-12) de la Universidad de Sevilla. Las publicaciones que la componen proceden
de dos líneas de trabajo cuya temática principal es el estudio del perfil biopsicosocial asociado
a la enfermedad hepática grasa no alcohólica. La primera línea de investigación parte del
contrato concedido al doctorando como parte de las Ayudas para la Formación de Profesorado
Universitario (FPU) del Programa Estatal de Promoción del Talento y su Empleabilidad, en
el marco del Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016
(Orden ECD/1721/2016, del 22 de diciembre de 2016, BOE 17-1-2017), financiado por el
Ministerio de Educación y Formación Profesional para el período 2018-2022. La segunda
línea de trabajo forma parte del proyecto I+D+i “Perfil biopsicosocial de la enfermedad
hepática grasa no alcohólica (EHGNA) asociado al trasplante hepático y prevención de los
factores de riesgo” (código PSI2017-83365-P), financiado por el Ministerio de Ciencia e
Innovación (Resolución de 8 de agosto de 2017) en la convocatoria de “Ayudas
correspondientes al Programa Estatal de Fomento de la Investigación Científica y Técnica de
Excelencia, Subprograma Estatal de Generación de Conocimiento, en el marco del Plan
Estatal de Investigación Científica y Técnica y de Innovación 2013-2016” (BOE 13-6-2017)
para el período 2018-2021. Esta Tesis Doctoral ha sido realizada desde un enfoque
multidisciplinar y multicéntrico, siendo posible gracias a la colaboración, por una parte, con
diversas unidades de gestión clínica de varios centros hospitalarios españoles. Por otra parte,
con diversos centros universitarios extranjeros.

11
2. INTRODUCCIÓN

La enfermedad hepática grasa no alcohólica (EHGNA), población clínica protagonista en la

presente Tesis Doctoral, ha pasado de ser una enfermedad prácticamente desconocida a
convertirse en el siglo XXI en un problema alarmante de salud pública, siendo definida como
una de las principales causas de hepatopatía y trasplante hepático en el mundo (Villeret et al.,
2022). La EHGNA comprende un espectro de patologías hepáticas metabólicas, sin mediar
un consumo excesivo de alcohol, que se extiende desde la esteatosis hepática simple a la
esteatohepatitis no alcohólica, cirrosis hepática, y finalmente hepatocarcinoma (Makri et al.,
2021). Se calcula que entre el 10 y el 15% de los pacientes con EHGNA presentan algún grado
de fibrosis hepática, la cual es un importante predictor del perfil clínico y psicosocial del
paciente (Dulai et al., 2017; Younossi & Henry, 2021). Es por ello que en esta Tesis
situaremos nuestro foco de atención en la fibrosis.
La prevalencia global de la EHGNA, cuya estimación oscila alrededor del 25%, está
incrementándose exponencialmente al mismo ritmo que la diabetes tipo 2 y la obesidad, como
consecuencia de un estilo de vida basado en hábitos alimentarios poco saludables y en el
sedentarismo (Younossi, 2019). De hecho, la EHGNA es considerada como la manifestación
hepática del síndrome metabólico, manteniendo una estrecha relación bidireccional con la
diabetes tipo 2 y la obesidad. Por una parte, es especialmente frecuente el diagnóstico de
EHGNA en personas diabéticas y obesas: entre las primeras se sitúa en torno al 60%, mientras
que entre las segundas las cifras pueden alcanzar incluso el 90% en personas con obesidad
mórbida sometidos a cirugía bariátrica, agravando en ambos casos las complicaciones
asociadas a la enfermedad metabólica (Dai et al., 2017; Younossi et al., 2019a). Por otra parte,
la presencia de diabetes tipo 2 u obesidad en pacientes con EHGNA favorece la progresión
del daño hepático (Polyzos et al., 2017; Radaelli et al., 2018). Todo ello convierte a estas dos
patologías metabólicas en los principales factores de riesgo asociados a la EHGNA, por lo
que ambas recibirán también una especial atención en esta Tesis Doctoral.
Respecto al tratamiento de la EHGNA, ninguna terapia farmacológica se postula aún como
definitiva (Pennisi et al., 2019). En su lugar, la medida más efectiva implica la pérdida de
peso a través de la modificación del estilo de vida (Geier & Rau, 2017). En los últimos años
han sido elaborados unos planes de intervención realizados conjuntamente por la Asociación
Europea para el Estudio del Hígado, la Asociación Europea para el Estudio de la Diabetes y
la Asociación Europea para el Estudio de la Obesidad (European Association for the Study of
the Liver, European Association for the Study of Diabetes y European Association for the

12
Study of Obesity, EASL-EASD-EASO). Estos planes recomiendan, por una parte, una pauta
de entre 150 y 200 minutos de actividad física aeróbica de intensidad moderada, o
entrenamiento de resistencia, de tres a cinco días por semana. Por otra parte, sugieren la
conveniencia de seguir un plan de dieta mediterránea que restrinja aquellos alimentos con un
alto contenido en grasas saturadas o azúcares, y promueve en su lugar alimentos ricos en
ácidos grasos monoinsaturados y omega-3 (EASL et al., 2016; Romero-Gómez et al., 2017).
El cumplimiento de estos planes es necesario para perder el 10% del peso corporal, objetivo
fundamental para conseguir mejoras significativas en la evolución de la enfermedad hepática,
como la reducción de la esteatosis, la mejora de la inflamación o la regresión de la fibrosis
hepática (Reginato et al., 2019; Vilar-Gómez et al., 2015). Sin embargo, el cumplimiento de
las pautas terapéuticas es inadecuado en más de la mitad de los pacientes con EHGNA,
quienes no consiguen perder el peso necesario, o bien vuelven a ganarlo en un corto espacio
de tiempo (Serfaty, 2018). Esto podría explicarse en parte por la falta de motivación que
suelen tener estos pacientes para cambiar (Centis et al., 2013), y por los efectos que ciertos
biomarcadores psicológicos podrían ejercer sobre la adherencia terapéutica. En efecto, el
estudio de variables psicológicas como la calidad de vida, la salud mental, las estrategias de
afrontamiento, la autoeficacia o el apoyo social, y su relevancia en el perfil biopsicosocial
asociado a la EHGNA, será el objetivo principal de la presente Tesis Doctoral.
De hecho, la fisiopatología, los marcadores bioquímicos o los mecanismos moleculares
relacionados con la EHGNA han sido ampliamente investigados hasta la fecha (Ma et al.,
2021; Negi et al., 2022; Steinman et al., 2021). Sin embargo, no existen tantas evidencias
sobre el impacto de la EHGNA directamente desde el punto de vista del paciente. Esto es
comprensible teniendo en cuenta que hasta la década de los ochenta, tras el planteamiento del
modelo biopsicosocial por parte de Engel (Engel, 1977), no comenzaron a considerarse las
contribuciones de factores psicológicos, comportamentales y sociales tanto en la aparición
como en el tratamiento de las enfermedades. Desde entonces, la salud ya no depende
exclusivamente de factores biológicos, sino que se ve también influida directamente por las
interpretaciones, emociones y respuestas dadas por la persona a las demandas del entorno.
Esta nueva concepción pasó a conferir al ser humano un rol activo y responsable en el manejo
de los factores que interfieren en su salud y, por tanto, en la enfermedad (León-Rubio et al.,
2004).
En este contexto surge el estudio de los resultados comunicados por el paciente, enfoque
basado en la percepción y experiencia particular de la persona respecto a su enfermedad y
tratamiento (Weldring & Smith, 2013). Destaca especialmente el estudio de la calidad de vida,
13
la cual es notablemente inferior en personas con EHGNA en comparación con pacientes con
otras patologías hepáticas crónicas o con la población general (Afendy et al., 2009;
Assimakopoulos et al., 2018; Sayiner et al., 2016). Este impacto suele producirse
principalmente sobre la salud física del paciente y su capacidad para realizar sus actividades
diarias (Assimakopoulos et al., 2018; Golabi et al., 2016). El principal síntoma detrás de este
deterioro es la fatiga, que ha sido reportada en hasta aproximadamente un 75% de los
pacientes con EHGNA (Cook et al., 2019). Otros problemas que también pueden contribuir a
este declive en la calidad de vida son la inactividad, malestar o dolor abdominal, somnolencia
diurna o problemas para dormir por la noche, alteraciones en el estado de ánimo, o
preocupación sobre la evolución de la enfermedad hepática (Cook et al., 2019; Newton et al.,
2008; Younossi et al., 2019b).
El nivel de gravedad del daño hepático, la comorbilidad metabólica o el perfil
sociodemográfico del paciente pueden ser también determinantes respecto al impacto
ocasionado por la enfermedad. No obstante, hay resultados contradictorios en la literatura
acerca de la influencia de estos factores sobre la calidad de vida, posiblemente debido a la
excesiva heterogeneidad en los criterios de selección de las muestras de los estudios realizados
(Assimakopoulos et al., 2018). Para empezar, en cuanto a los niveles de gravedad hepática, la
presencia de esteatohepatitis ha sido asociada a una peor calidad de vida, principalmente a
nivel físico (Huber et al., 2019; Kennedy-Martin et al., 2018; Sayiner et al., 2016), si bien no
se obtuvieron resultados significativos al respecto en los análisis multivariantes de David et
al. (2009). Estos mismos autores sí encontraron una asociación inversa entre la severidad de
la fibrosis y la calidad de vida (David et al., 2009), aunque otros estudios no han encontrado
un efecto significativo de la fibrosis sobre el funcionamiento físico y mental del paciente con
EHGNA (Huber et al., 2019; Taylor et al., 2020). Sí parece haber consenso al señalar que,
considerando todos los niveles de gravedad hepática, son los pacientes cirróticos los que peor
calidad de vida refieren (David et al., 2009; Sayiner et al., 2016).
En relación con la comorbilidad metabólica, mientras que algunas investigaciones han
sugerido un mayor deterioro en la esfera física de la calidad de vida en pacientes diabéticos u
obesos con EHGNA (Younossi & Henry, 2015; Younossi et al., 2017), otras no han detectado
diferencias significativas en función de la ausencia o presencia de diabetes u obesidad
(Sayiner et al., 2016; Tapper & Lai, 2016). En cuanto a las características sociodemográficas,
sí hay unanimidad al señalar el mayor impacto negativo en la calidad de vida física y mental
asociado al género femenino (Afendy et al., 2009; David et al., 2009; Huber et al., 2019). Por
el contrario, las evidencias respecto a la influencia de la edad, el nivel educativo o la actividad
14
laboral sobre la calidad de vida de pacientes con EHGNA son contradictorias hasta la fecha
(Afendy et al., 2009; Chawla et al., 2016; David et al., 2009; Ozawa et al., 2021; Stepanova
et al., 2017).
La salud mental del paciente con EHGNA también ha sido estudiada en los últimos años.
Así, encontramos una peor salud mental, especialmente una mayor sintomatología depresiva,
en pacientes con EHGNA en comparación con otros enfermos hepáticos crónicos y con la
población general (Huang et al., 2017; Kim et al., 2019; Weinstein et al., 2011). En un estudio
realizado con 567 personas diagnosticadas con EHGNA, se observó una prevalencia de
depresión subclínica y clínica del 53% y 14%, respectivamente, así como un 45% y un 25%
de ansiedad subclínica y clínica (Youssef et al., 2013).
Ejemplos de factores que predicen de manera independiente el desarrollo de un episodio
depresivo en pacientes con EHGNA son la presencia de hipertensión o enfermedad pulmonar,
el hábito tabáquico, o ser mujer de procedencia europea (Weinstein et al., 2011). La relevancia
de estos datos radica en los efectos perjudiciales que estos trastornos emocionales ejercen
normalmente en el curso y desarrollo de una enfermedad: incrementan la intensidad y
frecuencia de los síntomas físicos, producen alteraciones a nivel funcional, y reducen la
probabilidad de obtener una adecuada adherencia terapéutica (Corruble et al., 2011; Hauser
et al., 2004). En concreto en la EHGNA, se ha encontrado que el trastorno depresivo repercute
en una menor calidad de vida y en una mayor posibilidad de progresar hacia las fases más
avanzadas de la enfermedad hepática (Weinstein et al., 2011; Youssef et al., 2013). En este
sentido, se puede observar una asociación positiva entre la gravedad de la sintomatología
depresiva y la probabilidad de desarrollar fibrosis avanzada y un grado severo de balonización
hepatocelular (Tomeno et al., 2015).
A todo ello habría que añadir la elevada prevalencia de ansiedad y depresión que se observa
en personas con diabetes tipo 2 (Patel et al., 2017) y obesidad (Sharafi et al., 2012). Factores
como el estrés oxidativo, la ganancia de peso secundaria a la medicación, alteraciones en el
metabolismo, la inactividad o la neuroinflamación podrían contribuir a esta relación entre
patología metabólica y alteración en el estado de ánimo (McIntyre et al., 2012). Por lo tanto,
teniendo en cuenta el impacto de la EHGNA en la calidad de vida y salud mental del paciente,
esta Tesis Doctoral analizará el papel de ambos biomarcadores psicológicos en el perfil
biopsicosocial de estos pacientes.
Por otro lado, existen otros biomarcadores psicológicos sobre los que apenas existen
evidencias en pacientes con EHGNA, pero que son de potencial interés para su perfil
biopsicosocial.
15
 En primer lugar, las estrategias de afrontamiento, que hacen referencia a las acciones que
realiza un individuo para gestionar una demanda interna o externa que excede sus propios
recursos. Estas pueden ser calificadas como adaptativas o desadaptativas, en función de los
resultados obtenidos tras su puesta en práctica (Lazarus & Folkman, 1986). Las adaptativas
generalmente siguen un estilo de afrontamiento activo y consiguen reducir el nivel de estrés,
facilitando una mayor calidad de vida y bienestar a largo plazo a la persona, como suele
ocurrir con la búsqueda de información o de apoyo. Por el contrario, las estrategias
desadaptativas suelen seguir un estilo de afrontamiento pasivo o evitativo y, si bien pueden
ayudar a la persona a reducir el estrés a corto plazo, las consecuencias para su salud
generalmente acabando siendo perjudiciales (Giordano & Everly, 1986).
El efecto negativo del empleo de estrategias de afrontamiento desadaptativas ha sido
observado previamente en poblaciones con patologías crónicas (David et al., 2021;
Dollenberg et al., 2021; Grolimund et al., 2018). No hay evidencias en pacientes con EHGNA,
aunque existen motivos que justifican su estudio. Por una parte, sí ha sido explorado el efecto
del estilo de afrontamiento en la patología hepática crónica, estando relacionado el
afrontamiento desadaptativo con una inferior calidad de vida y una peor percepción de salud
en pacientes con hepatitis C (Constant et al., 2005; Gutteling et al., 2010). Por otra parte, el
afrontamiento se convierte en un predictor de la adherencia terapéutica en personas con
diabetes tipo 2, pudiendo anticipar si su evolución será más o menos favorable (Fall et al.,
2021). Además, el empleo de estrategias de afrontamiento centradas exclusivamente en la
emoción y en la evitación se asocia con una mayor probabilidad de desarrollar síntomas
ansioso-depresivos en personas diabéticas (Burns et al., 2016). En el caso de la obesidad, la
salud mental y el funcionamiento físico se ven influidos por el estilo de afrontamiento
empleado (Aarts et al., 2014). La exposición intensa a experiencias de estigmatización social
afecta a la imagen corporal y a la autoestima, asociándose con una mayor probabilidad de
desarrollar cuadros ansioso-depresivos. En este tipo de situaciones es común el empleo de
estrategias desadaptativas como la autocrítica o la evitación, que se asocian con mayor estrés
y con una peor salud mental (Puhl & Brownell, 2006). En consecuencia, la relevancia de las
estrategias de afrontamiento en la diabetes tipo 2 y la obesidad nos invita a pensar que jugarán
también un rol determinante en la EHGNA.
Otro factor potencialmente relevante para la EHGNA es la autoeficacia, término acuñado
por Bandura en su teoría cognitivo-social (Bandura, 1982), y que hace referencia a las
creencias que una persona tiene sobre su capacidad para regularse y para realizar las acciones
necesarias con las que gestionar con garantías una determinada situación. Una autoeficacia
16
satisfactoria fomenta el proceso de toma de decisiones, un sentido elevado de optimismo y un
alto compromiso con las metas establecidas. No es de extrañar por lo tanto que las personas
con altos niveles de autoeficacia suelan implicarse en objetivos personales más desafiantes,
invirtiendo un mayor esfuerzo y tolerando más adaptativamente los obstáculos y las
dificultades (Bandura, 1997).
La autoeficacia ha sido estudiada en diversas patologías crónicas como la enfermedad
pulmonar obstructiva crónica, enfermedad renal crónica, diabetes tipo 2, hipertensión arterial
o dolor crónico (Farley, 2019). Ha sido probada su importancia a la hora de confeccionar
planes de intervención exitosos, incluyendo modificaciones en el estilo de vida, ya que
permite confirmar la percepción de la persona sobre su capacidad para llevar a cabo cambios
conductuales relacionados con su salud (Bellentani et al., 2008; O’Sullivan & Strauser, 2009).
Una alta autoeficacia ejerce un efecto positivo sobre comportamientos salutogénicos como la
realización de ejercicio físico, la reducción del peso corporal, la capacidad de recuperación
tras sufrir problemas de salud o el afrontamiento de enfermedades crónicas. Todo ello se
asocia con una mayor capacidad funcional y bienestar en la persona y, en definitiva, con una
mejor calidad de vida (Klein-Hessling et al., 2005).
Con respecto a la enfermedad hepática crónica, apenas existen evidencias sobre el efecto
de la autoeficacia. Aun así, ha sido identificada una relación significativa entre una peor salud
mental y una baja percepción de autoeficacia en estos pacientes (Gutteling et al., 2010), lo
cual es relevante teniendo en cuenta la pobre autoeficacia que suele observarse en pacientes
con EHGNA en comparación con otras enfermedades hepáticas. En concreto, se suele dar una
falta de confianza con relación a la capacidad para realizar ejercicio, lo que se convierte en
un factor que puede en parte explicar la falta de motivación que refieren generalmente estos
pacientes a la hora de cumplir las pautas terapéuticas (Centis et al., 2013; Frith et al., 2010).
Mejorar la percepción de autoeficacia en el paciente debería por lo tanto conllevar un mejor
rendimiento en el seguimiento de pautas de dieta y actividad física en personas que están
realizando un plan de modificación del estilo de vida. Esto es lo que hallaron tanto Zelber-
Sagi et al. (2017) en una muestra de 146 pacientes con EHGNA, como distintos estudios sobre
diabetes tipo 2 y obesidad (Adam & Folds, 2014; Dutton et al., 2009; Leung et al., 2019;
Leung et al., 2020). En personas diabéticas, además, una alta percepción de autoeficacia puede
predecir una mayor realización de conductas de autocuidado y una menor sintomatología
depresiva (Adam & Folds, 2014). Asimismo, en personas con obesidad, considerar la
evaluación previa de la autoeficacia y su inclusión dentro de la intervención para la pérdida
de peso es especialmente necesario (Martin et al., 2004).
17
 Por último, el apoyo social puede ser definido como la percepción del individuo sobre la
ayuda instrumental, emocional e informacional que le proporciona su contexto social más
inmediato, que suele estar constituido por cónyuge, familia o amigos. Un apoyo social
satisfactorio conlleva consecuencias positivas para la salud. Por ejemplo, se asocia con
mejoras significativas en el grado de morbilidad psiquiátrica o en el proceso de recuperación
de patologías crónicas. También favorece el éxito de los cambios conductuales continuados
relacionados con la pérdida de peso, y un mejor y más eficaz afrontamiento ante situaciones
diarias estresantes (Karfopoulou et al., 2016; Larsson et al., 2017). Por el contrario, una
percepción negativa sobre el apoyo social se vincula con consecuencias negativas para la
salud, como un incremento de la presión arterial en pacientes con hipertensión, así como una
mayor actividad de marcadores inflamatorios, como el factor de necrosis tumoral o la proteína
C reactiva (Ruppar et al., 2017; Tomfohr et al., 2015).
En cuanto a la patología hepática crónica, un satisfactorio apoyo social ha sido asociado a
una mejor calidad de vida y a una disminución de la intensidad y frecuencia de síntomas
depresivos concomitantes (Blasiole et al., 2006; Poorkaveh et al., 2012). Sin embargo, aún se
desconoce el efecto del apoyo social en EHGNA.
Sí hay evidencias sobre la influencia del apoyo social en la diabetes tipo 2 y la obesidad.
Para la primera, se ha encontrado que los miembros de la red social influyen
significativamente en su manejo y afrontamiento. En este caso, la adherencia a un plan de
dieta es más elevada en personas diabéticas que perciben algún tipo de ayuda, ya sea
emocional o instrumental, por parte de su contexto social inmediato (Gallant, 2003). Los
beneficios de contar con un alto nivel de apoyo social para las personas con diabetes tipo 2
son considerables, entre los que se encuentran una tendencia a mostrar mejores resultados
clínicos, a presentar una mejor salud mental y a lograr una mayor adaptación a las actividades
de la vida diaria tras el diagnóstico de la enfermedad (Strom & Egede, 2012). Asimismo, con
relación a la obesidad, un apoyo social satisfactorio protege frente al deterioro en la calidad
de vida física que refieren generalmente las personas con obesidad (Wiczinski et al., 2009).
En resumen, en la presente Tesis Doctoral se proponen seis trabajos que tienen en común
el estudio del perfil biopsicosocial de los pacientes con EHGNA. Por un lado, un estudio
teórico en forma de capítulo de libro, publicado en una editorial académica indexada en
Scholarly Publishers Indicators (SPI) Expanded, en la que se discuten las repercusiones
psicológicas de la EHGNA, así como aquellos biomarcadores psicológicos que pueden ser
relevantes para el perfil biopsicosocial de estos pacientes. Por otro lado, cinco investigaciones
empíricas en forma de artículos científicos, tres de ellos ya publicados en revistas indexadas
18
en la Journal Citation Reports (JCR) de Web of Science, en las que se pretende a) identificar
el perfil biopsicosocial (calidad de vida, salud mental, afrontamiento, autoeficacia y apoyo
social) asociado a los distintos niveles de gravedad de la EHGNA (esteatohepatitis y fibrosis
hepática) y b) a sus principales factores de riesgo (diabetes tipo 2 y obesidad), así como c)
determinar qué biomarcadores psicológicos son relevantes para la adherencia terapéutica de
los pacientes con EHGNA. En la Tabla 1 se resumen los objetivos generales y específicos, así
como las cuestiones relativas al método (diseño, tamaño muestral y análisis estadísticos) de
los trabajos que conforman esta Tesis Doctoral.

19
Tabla 1. Objetivos y método de los trabajos que conforman la presente Tesis Doctoral

Objetivo Determinar aquellos biomarcadores psicológicos que pueden ser relevantes para el perfil biopsicosocial
general de los pacientes con EHGNA

Título del Psychological biomarker profile in NAFLD/NASH with advanced fibrosis (publicado en el libro
trabajo “NAFLD and NASH. Biomarkers in detection, diagnosis and monitoring”)

Objetivos -Examinar el impacto de la EHGNA en la calidad de vida y salud mental de los pacientes
específicos
-Explorar variables potencialmente relevantes para el perfil biopsicosocial de pacientes con EHGNA:
estrategias de afrontamiento, autoeficacia y apoyo social

-Abordar el tratamiento de la EHGNA desde un enfoque multidisciplinar

Método -Estudio teórico

Objetivo Determinar el perfil biopsicosocial asociado a los distintos niveles de gravedad de la EHGNA
general (esteatohepatitis y fibrosis hepática)

Título del Psychological biomarkers and Health-related quality of life in Quality of life mediates the
trabajo fibrosis: An innovative approach non-alcoholic fatty liver disease: influence of coping on mental
to non-alcoholic fatty liver A cross-cultural study between health and self-efficacy in patients
disease (publicado en la Revista Spain and the United Kingdom with non-alcoholic fatty liver
“Frontiers in Medicine”) (enviado a publicar en la revista disease (enviado a publicar en la
“British Journal of Psychology”) revista “Journal of Psychosomatic
Research”)

Objetivos -Comparar la calidad de vida, -Comparar la calidad de vida en -Determinar si la calidad de vida
específicos salud mental y estrategias de función del lugar de procedencia mental y el rol físico median la
afrontamiento de pacientes con (España o Reino Unido), de la asociación entre el estilo de
EHGNA en función del nivel de ausencia o presencia de afrontamiento pasivo/evitativo y
apoyo social y de la ausencia o esteatohepatitis y del nivel de la autoeficacia en pacientes con
presencia de esteatohepatitis y gravedad de la fibrosis hepática EHGNA
fibrosis significativa,
-Determinar qué marcadores -Determinar si la fibrosis hepática
considerando además los datos
histológicos y biopsicosociales ejerce un rol moderador sobre la
de la población general española
predicen la calidad de vida de relación anterior
para la calidad de vida
pacientes de España y el Reino
Unido con EHGNA

20
 -Determinar qué marcadores -Determinar qué marcadores
histológicos y psicosociales biopsicosociales ejercen un rol
predicen la calidad de vida de mediador o moderador en
pacientes con EHGNA modelos predictores de la
calidad de vida de pacientes con
EHGNA

Método -Diseño transversal -Diseño transversal -Diseño transversal

-n = 492 pacientes -n = 737 pacientes (513 de -n = 509 pacientes

-ANOVA factorial 2x2
-ANOVA de un factor
-Prueba T para muestras
independientes
-Regresión logística binaria
España y 224 del Reino Unido)
-Modelos de mediación y
-ANOVA factorial 2x2 y 2x3 mediación moderada
-Regresión logística binaria
-Modelos de mediación y
mediación moderada

Objetivo Determinar el perfil biopsicosocial asociado a los principales factores de riesgo de la EHGNA (diabetes
general tipo 2 y obesidad)

Título del Quality of life mediates the influence of coping on Quality of life and coping in nonalcoholic fatty liver
trabajo mental health and self-efficacy in patients with disease: Influence of diabetes and obesity
non-alcoholic fatty liver disease (enviado a (publicado en la revista “International Journal of
publicar en la revista “Journal of Psychosomatic Environmental Research and Public Health”)
Research”)

Objetivos -Determinar si la vitalidad media la asociación -Comparar la calidad de vida y estrategias de

específicos entre el estilo de afrontamiento activo y la afrontamiento de pacientes con EHGNA en función
sintomatología depresiva en pacientes con de la ausencia o presencia de diabetes tipo 2 y
EHGNA obesidad

-Determinar si la diabetes tipo 2 y la obesidad -Determinar qué estrategias de afrontamiento

ejercen un rol moderador sobre la relación anterior predicen la calidad de vida de pacientes diabéticos
u obesos con EHGNA

Método -Diseño transversal

-Diseño transversal
-n = 307 pacientes
-n = 509 pacientes
-ANOVA factorial 2x2
-Modelos de mediación y mediación moderada
-Regresión lineal múltiple

21
Objetivo Determinar qué biomarcadores psicológicos son relevantes para la adherencia terapéutica de los
general pacientes con EHGNA

Título del Influence of psychological biomarkers on therapeutic adherence by patients with non-alcoholic fatty
trabajo liver disease: A moderated mediation model (publicado en la revista “Journal of Clinical Medicine”)

Objetivos -Determinar si la sintomatología depresiva media la asociación entre la calidad de vida física y la
específicos realización de actividad física en pacientes con EHGNA, así como la asociación entre el apoyo social y
el seguimiento de una dieta mediterránea

-Determinar si la autoeficacia ejerce un rol moderador sobre las relaciones anteriores

Método -Diseño transversal

-n = 413 pacientes

-Modelos de mediación y mediación moderada

22
3. OBJECTIVES

1. Discuss those psychological biomarkers that could be significant for the biopsychosocial
profile associated with non-alcoholic fatty liver disease (NAFLD):
1.1. Examine the impact of NAFLD on patient quality of life and mental health.
1.2. Explore the roles of the variables of potential interest in NAFLD: coping strategies,
self-efficacy and social support.
1.3. Explore treatment of NAFLD from a multidisciplinary approach.
2. Determine the biopsychosocial profiles of NAFLD patients associated with the severity
of the disease:
2.1. Compare quality of life, mental health and coping strategies of NAFLD patients by
their level of social support and absence or presence of non-alcoholic steatohepatitis
and significant fibrosis, comparing their quality of life with data from the general
Spanish population.
2.2. Determine what histological and psychosocial variables predict the quality of life of
NAFLD patients.
2.3. Compare the quality of life of NAFLD patients by their place of origin (Spain or
United Kingdom), absence or presence of non-alcoholic steatohepatitis and the
severity of liver fibrosis.
2.4. Determine what biopsychosocial variables have a mediating or moderating role in
predictive quality of life models of NAFLD patients.
2.5. Determine whether mental quality of life and role physical mediate the association
between passive/avoidance coping and self-efficacy of NAFLD patients. Determine
whether liver fibrosis moderates this relationship.
3. Determine the biopsychosocial profile associated with the main risk factors for non-
alcoholic fatty liver disease (type 2 diabetes and obesity):
3.1. Determine whether vitality mediates the association between an active coping style
and depressive symptoms of NAFLD patients. Determine whether type 2 diabetes
and obesity moderate this relationship.
3.2. Compare quality of life and coping strategies of NAFLD patients by absence or
presence of type 2 diabetes and obesity.
3.3. Determine what coping strategies predict quality of life in diabetic or obese patients
with non-alcoholic fatty liver disease.

23
4. Determine what psychological variables influence therapeutic adherence by NAFLD
patients:
4.1. Determine whether depressive symptomatology mediates the association between
physical quality of life and physical activity of NAFLD patients, as well as the
association between social support and adherence to a Mediterranean diet. Determine
whether self-efficacy moderates these relationships.

24
4. TRABAJOS QUE CONFORMAN LA TESIS DOCTORAL

4.1. Primer trabajo titulado “Psychological biomarker profile in NAFLD/NASH with

advanced fibrosis”

Este trabajo corresponde al capítulo de libro publicado que se referencia a continuación:

Funuyet-Salas, J., Martín-Rodríguez, A., Conrad, R., & Pérez-San-Gregorio, M. Á. (2020).

Psychological biomarker profile in NAFLD/NASH with advanced fibrosis. En M. Romero-
Gómez (ed.), NAFLD and NASH. Biomarkers in detection, diagnosis and monitoring (pp.
205-223). Springer Nature.

25
Abstract

This chapter analyzes the psychological biomarkers in NAFLD, to give insight into the
biopsychosocial profile of affected patients. First, we examined the impact of the disease on
the patients’ well-being and found an inversely proportional relationship between quality of
life and NAFLD severity. The worsening in quality of life is related to the high prevalence of
anxiety/depression symptomatology, as well as fatigue and cognitive dysfunction. We also
evaluated the role of further relevant variables affecting mental health, such as coping
strategies, social support and self-efficacy. In concluding, we approach some treatment-
related questions. Lack of therapeutic adherence makes the inclusion of cognitive-behavioral
treatment in a multidisciplinary approach to NAFLD highly recommendable. Diffusion of
educational and prevention awareness programs on this new twenty-first century pandemic is
urgent. Keywords: NAFLD; quality of life; mental health; coping strategies; social support;
self-efficacy; multidisciplinary treatment.

Introduction

NAFLD appears as one of the main causes of chronic hepatic pathology, morbidity and
mortality worldwide (mainly linked to NASH with significant fibrosis), with global
prevalence estimated at around 25% (Araújo et al., 2018; Tomic et al., 2018; Younossi et al.,
2016a). Although this alone is alarming, its prevalence is foreseen to grow in coming decades,
affecting both children and adults (Braun et al., 2018; Younossi et al., 2018). In fact, it was
recently estimated that in the next 10 years, there will be a 178% increase in cases of death
related to NASH (Estes et al., 2018), so its consideration as a new twenty-first century
pandemic does not seem exaggerated (Augustin et al., 2017). Many studies have been done
on the influence of biochemical markers or molecular mechanisms on the course or evolution
of NAFLD, however, little is known about psychological risk or protection factors that could
help predict or shape the development of the disease.
In any case, the historical context in which the subject of this chapter is framed should be
recalled. Until the 80s, after the proposal of the biopsychosocial model by Engel (Engel,
1977), the contributions of psychological, behavioral and social factors to the appearance of
disease or its treatment had not been considered. However, from then on, health did not
depend exclusively on biological factors, but was also directly influenced by interpretations,
emotions and responses to demands from the setting. This new conception goes on to confer
to the human being an active and responsible role in managing the factors that interfere with
their health and therefore, disease (León-Rubio et al., 2004).

26
 For an idea of how this paradigm is applied to NAFLD, we might reflect on the following
example. It is quite understandable that a person with a long history of liver pathology, which
advances inexorably toward cirrhosis, with the social stigma (even today, the word “cirrhosis”
appears socially linked to alcoholism), develops depression. However, based on the work by
Engel, we might go on to wonder if depression or some personality traits tending to depression
associated with a certain lifestyle could facilitate the onset of NAFLD. Or whether it could
negatively affect therapeutic adherence once the disease has been diagnosed, thereby
impeding the person’s stabilization in stages of light-to-moderate severity.
Throughout this chapter, special attention will be given to Type 2 diabetes mellitus
(T2DM) and obesity as both pathologies are closely connected to the incidence of NAFLD.
There is a consensus affirming that the exponential growth observed in the incidence of cases
diagnosed with NAFLD worldwide, especially in westernized countries (Duseja & Chalasani,
2013), goes hand in hand with the growing epidemic of T2DM and obesity (Nascimbeni et
al., 2014; Younossi et al., 2016a). Epidemiological data show that NAFLD, NASH, liver
cirrhosis and hepatocellular carcinoma are continually growing among persons with T2DM
(Tilg et al., 2017), placing the prevalence of NAFLD at 50–69% of cases (Leite et al., 2009;
Portillo-Sánchez et al., 2015). In addition, the higher the body mass index is, the higher the
probability of a NAFLD diagnosis (Ruhl & Everhart, 2003). Its prevalence increases
drastically up to 65% in persons with Grade I or II obesity, while in morbid obesity it is as
high as 85% (Fabbrini et al., 2010). This figure could even surpass 90% in persons with
morbid obesity subjected to bariatric surgery (Beymer et al., 2003).
There is evidence that the presence of obesity and T2DM promote progression of NAFLD
to its final stages that is advanced fibrosis and cirrhosis triggered by NASH (Anstee et al.,
2013; Koppe, 2014). This, combined with a high likelihood of their coinciding with presence
of liver disease, makes these two pathologies the two main risk factors associated with
NAFLD (Reeves et al., 2016). Along this line we will approach psychological biomarkers that
make up the NAFLD biopsychosocial profile, specifically concentrating on the following key
questions: (1) NAFLD’s impact on the patients’ quality of life and mental health, (2) the
influence of psychological variables such as coping strategies, perceived social support and
perceived self-efficacy, and (3) treatment of the disease by a multidisciplinary approach.
Psychosocial Repercussions of NAFLD

Quality of Life

27
To understand how NAFLD affects the patients’ physical and mental condition, first the
disease’s consequences must be considered. Concerning its clinical impact, the close
relationship between cirrhosis in NASH and development of hepatocarcinoma is notorious
(Younossi et al., 2015a). There is growing evidence that non-cirrhotic NAFLD patients are
also especially vulnerable to this type of cancer (van Meer et al., 2016). This, along with its
high prevalence, makes this disease one of the main causes of liver transplantation in the
world (Wong et al., 2015), with high expectations for its leading the list in a very short time
(Patel et al., 2016). Its mortality has also increased in recent years, with advanced fibrosis as
its main predictor (Ekstedt et al., 2015; Younossi et al., 2019). Considering that around 41%
of NASH patients experience progression of fibrosis (Younossi et al., 2016a), advanced
fibrosis would be another factor to focus attention on in this chapter.
There is broad scientific evidence confirming the negative impact of NAFLD on quality of
life (Golabi et al., 2016, Sayiner et al., 2016, Younossi et al., 2016b). To begin with, it is
notably lower in persons with NAFLD than in the general population (Sayiner et al., 2016),
as well as in patients diagnosed with hepatitis B (HBV) or C (HCV) (Dan et al., 2007), or
individuals with alcoholic liver disease, autoimmune hepatitis or cholestatic liver disease
(Afendy et al., 2009). This decline in quality of life is mainly based on physical health, with
no significant differences in mental functioning (Golabi et al., 2016; Younossi et al., 2015b;
Younossi et al., 2016b). In fact, 66% of patients refer to the disease as interfering with their
ability to perform daily activities (Newton et al., 2008a).
Worsening of the physical aspects of quality of life may be explained largely by NAFLD
symptomatology. In the first place, fatigue, often considered the most important problem for
persons with NAFLD, leads to alterations of normal physical functioning (Golabi et al., 2016).
Fatigue is not clearly related to severity of liver disease, but to other symptoms weakening
the patient. One of them is daytime somnolence, which affects around 30% of NAFLD cases
(Newton et al., 2008a). Another one is autonomic dysfunction, which involves such symptoms
as vasovagal syncope or postural dizziness, and is present in both early and advanced stages
of the liver disease (Newton & Frith, 2013).
In addition to abovementioned symptoms, other manifestations associated with NAFLD
can be considered significant predictors of patients’ loss of functionality, such as cognitive
dysfunction (Elliott et al., 2013), which leads to alterations in psychomotricity or loss of
memory and concentration. Eighty-five percent of patients have slight or moderate cognitive
impairment, figures similar to individuals with primary biliary cirrhosis, which is
characterized by the greatest number of cognitive symptoms among liver diseases (Newton et
28
al., 2008b). The cognitive impairment is observed both in early and late NAFLD stages, which
discards its relationship with hepatic encephalopathy (Frith et al., 2012).
Moreover, the presence and severity of liver fibrosis is a determining factor in the diagnosis
and prognosis of NAFLD patients, and significantly influences the impact of the disease on
patients’ wellbeing. Thus, an inversely proportional relationship can be observed between
NAFLD severity and the physical aspects of quality of life: NASH and advanced fibrosis
patients mention worse physical functionality than those with NAFLD alone. At all levels of
severity, cirrhotic patients suffer from the worst quality of life (Afendy et al., 2009; David et
al., 2009; Sayiner et al., 2016).
Other determinants of quality of life in NAFLD patients may be their sociodemographic
characteristics or presence of T2DM and obesity. However, the findings on the influence of
respective characteristics on quality of life are inconsistent due to the selectivity of different
samples (Assimakopoulos et al., 2018). Concerning sociodemographic factors in NAFLD, in
some studies advanced age was related to a generalized decline in quality of life, especially
in physical functioning (Afendy et al., 2009; David et al., 2009), whereas others did not find
any correlation between the two variables (Chawla et al., 2016), or they even showed an
improvement in emotional functioning in older patients compared to younger ones (Younossi
et al., 2017). With respect to gender, empirical findings show more consistency; women with
NAFLD report worse physical and mental quality of life (Afendy et al., 2009; Tapper & Lai,
2016). Lower formal education and socio-economic level are also significantly associated
with lower mental quality of life (David et al., 2009).
The empirical inconsistencies become even more evident regarding the influence of T2DM
and obesity. Diabetics with NAFLD show a higher likelihood of a lower physical and mental
quality of life (David et al., 2009). Other studies point in the same direction, confirming,
however, only impaired physical functionality (Chawla et al., 2016; Younossi et al., 2017).
Contrary to these findings, others did not find any significant relationship between the
presence of T2DM and quality of life in liver patients (Dan et al., 2007; Sayiner et al., 2016;
Tapper & Lai, 2016).
There is some evidence with respect to comorbid obesity on the association between
morbid obesity and worse physical quality of life in NAFLD (David et al., 2009). In another
study obese patients compared to those with normal weight reported more fatigue, less activity
and more systemic symptoms (Younossi et al., 2017). However, several other studies did not
show any relationship between patients’ body mass index and their quality of life (Chawla et
al., 2016; Sayiner et al., 2016; Tapper & Lai, 2016). All abovementioned studies, however,
29
did have one point in common: comorbid obesity was not associated with significant
impairment in the mental component of quality of life. One possible interpretation attributes
the unaffected mental quality of life in these patients to a lower cognitive and emotional
involvement in issues concerning their weight. Consequently, they tend to consider the
treatment received as focused exclusively on their liver disease and not on their obesity
(Marchesini & Bianchi, 2009).

Mental Health

In research on mental health associated with NAFLD/NASH, depression and anxiety

disorders are the most widely studied (Macavei et al., 2016). The prevalence of both disorders,
especially that of depression, is higher in NAFLD patients than in the general population
(Weinstein et al., 2011). In keeping with this fact, chronic liver diseases are associated in
general with anxiety and, especially, mood alterations, particularly depressive disorders
(Huang et al., 2017). The higher prevalence of depressive disorders in liver diseases is
associated with a higher frequency of attempted suicide (Le Strat et al., 2015).
In a study with 567 NAFLD patients, the prevalence of subclinical and clinical depression
was 53% and 14%, respectively, and the prevalence of subclinical and clinical anxiety 45%
and 25%, respectively (Youssef et al., 2013). The clinical relevance of these data lies in the
negative effects of these emotional disorders on the course and development of a disease.
Thus, they increase the intensity and frequency of physical symptoms, produce functional
alterations and reduce adherence to treatment thereby worsening quality of life (Corruble et
al., 2011; Hauser et al., 2004). Another study found even higher rates of depression in NAFLD
patients (27.2%), which highly surpassed prevalence rates in HBV (3.7%) and the general
population (2–5%). Independent factors predicting the development of a depressive episode
in NAFLD were high blood pressure, lung disease, smoking and female sex of European
descent (Weinstein et al., 2011).
Comorbid depressive disorder in NAFLD has negative consequences not only for quality
of life but also a higher likelihood of progression towards more advanced stages of the liver
disease (Weinstein et al., 2011; Youssef et al., 2013). Furthermore, a close association
between the severity of depression and the likelihood of severe hepatocellular ballooning as
well as advanced fibrosis has also been observed (Tomeno et al., 2015). This coincides with
another study, which concluded that the link between resistance to insulin and depression and
anxiety, as well as the inflammatory states which these emotional disorders generate, are
determining factors in the progression of simple steatosis to NASH (Elwing et al., 2006). This

30
line of reasoning is supported by the fact that major depressive disorder and generalized
anxiety disorder become more prevalent in patients diagnosed with NASH than in individuals
with mild liver damage. Specifically, presence of generalized anxiety disorder is related to
more severe lobular inflammation and fibrosis than what is observed in patients without
respective disorder.
Additionally, the prevalence of anxiety and depression among patients with T2DM (Patel
et al., 2017) and obesity (Stewart & Levenson, 2012), which are the main comorbidities of
NAFLD, is very high. Factors such as oxidative stress, weight gain as a side effect of
medication, metabolic alterations, inactivity or neuroinflammation could contribute to the
relationship between metabolic pathology and mental disorder (McIntyre et al., 2012).
Design and implementation of effective psychotherapeutic programs in NAFLD
presupposes knowledge of abovementioned facts on its relationship with mental health. That
is, to understand on the one hand, to what extent emotional disorders predispose to NAFLD,
and on the other, the likelihood in which anxiety and/or depression develop as consequences
of the liver disease.

Variables of Potential Interest in NAFLD

Coping Strategies

When people feel that internal or external demands exceed their own resources, they make an
effort to confront them, using coping strategies which can be qualified as adaptive or
maladaptive, depending on their results after they are put into practice (Lazarus & Folkman,
1986). Adaptive strategies, such as the search for information or support, are usually able to
reduce stress and facilitate high quality of life and wellbeing in the long run. Maladaptive
strategies, although they may diminish stress in the short term, have consequences which are
harmful to the person’s health (Giordano & Everly, 1986). During the course of a liver disease,
the coping strategies used may be maladaptive. After diagnosis, the reaction is often anger.
Individuals may also deny the existence of the pathology or give up and consequently do
nothing to recover. Finally, patients may decide to take substances as a way of coping with
the disease, whether drinking, smoking or unprescribed medication (Gutteling et al., 2010).
The negative effect of maladaptive coping strategies has previously been described for
heart transplant (Burker et al., 2009), chronic pain (Samwel et al., 2006), irritable bowel
syndrome (Stanculete et al., 2015), and others. They have not been studied in NAFLD,
although there are reasons justifying their importance. Nevertheless, coping strategies have
been explored in chronic liver pathology. For example, in individuals with HCV a positive

31
association has been found between maladaptive coping and decline in quality of life
(Gutteling et al., 2010), worse perception of health (Constant et al., 2005) and longer time to
diagnosis (Kraus et al., 2000). The relevance of coping in T2DM and obesity has also been
studied. In T2DM this factor is a good predictor of therapeutic adherence, and can anticipate
whether the course of the disease will be more or less favorable (Turan et al., 2002). The use
of coping strategies concentrating exclusively on emotion is associated with a higher
likelihood of developing anxiety/depression symptoms (Burns et al., 2016). With respect to
obesity, there is strong evidence for the influence of coping on patient’s mental health and
physical functioning (Aarts et al., 2014). Obese individuals are usually exposed to social
stigmatization, and this negatively influences their body image and self-esteem, associated in
turn with alterations in mental health through anxiety/depression symptoms. Adaptive
strategies for coping with this experience would be emotional expression, search for social
support, confrontation or problem-solving efforts. However, maladaptive strategies
associated more with anxiety symptomatology, such as self-criticism or avoidance, are
common in these situations (Myers & Rosen, 1999).
It seems reasonable to argue that NAFLD patients will use coping strategies similar to
those found in T2DM and obesity, as these are their main comorbidities. This tendency might
be even stronger in more advanced cases of the liver disease, where the prevalence of T2DM
and obesity is greater.

Social Support

The concept of social support can be defined as perception of instrumental, emotional or

economic assistance provided in the individual’s most immediate environment. This usually
consists of the spouse, family and friends, if the person possesses those bonds. Satisfactory
support from this social network may lead to positive consequences for health, such as
significant improvement in psychological morbidity or recovery from chronic pathologies
(Asher, 1984). There is no clear consensus on the mechanisms by which social support has
such positive effects on the individual. One might argue that it acts as a modulating agent on
health and quality of life, facilitating the coping with daily stressful situations (de la Revilla-
Ahumada & Fleitas, 1991).
Social support in chronic illness has been found to be associated with high self-esteem as
well as significant reduction in the frequency and intensity of concomitant depressive
symptoms (Symister & Friend, 2003). With regard to our research question, there are no
published data on perceived social support in NAFLD. However, this concept has been

32
studied in other chronic liver diseases. Thus, perceiving satisfactory social support is
associated with better mental health and quality of life in HBV patients (Poorkaveh et al.,
2012). Similarly, low levels of perceived social support in HCV patients are significantly
related to dysfunctional mood, anxiety and depressive symptomatology, as well as low
subjective psychological wellbeing. At the same time, patients with low social support are
prone to report more and stronger physical symptoms related to mobility and functional
capacity (Blasiole et al., 2006). Against this backdrop it is reasonable to argue that social
support presumably also has important implications for mental and physical health in
NAFLD.
The relationship of perceived social support to T2DM and obesity throws further light on
this subject. In the first case, members of the social network significantly influence how it is
managed and coped with. Adherence to a diet is higher in diabetics who perceive some type
of help, whether emotional or instrumental, from persons belonging to their immediate social
context (Gallant, 2003). The benefits of counting on strong social support in individuals with
T2DM are considerable, including a tendency to show a better clinical outcome, less frequent
and less severe concomitant anxiety and depressive symptomatology, and adapting better to
activities in daily life (Strom & Egede, 2012).
In obesity, the perception of social support is one of the main predictors of subjective
wellbeing (Dierk et al., 2006). Positive evaluation of social support buffers the strong deficit
which is generally observed in quality of life related to physical functioning of obese
individuals (Wiczinski et al., 2009). Social support is also an element to be kept in mind in
preventing obesity, due to its relevance as a protective factor against intergenerational
transmission of this illness (Serlachius et al., 2016).

Self-Efficacy

Perceived self-efficacy, a term coined by Bandura in his social cognitive theory (Bandura,
1982), refers to personal beliefs about one’s capacity for self-regulation and for taking action
to manage and cope with a certain situation. Strong perceived self-efficacy promotes decision-
making, a high sense of optimism and strong commitment to goals set. Thus, persons with
high levels of perceived self-efficacy usually become involved in more challenging personal
goals, investing more effort and tolerating more adaptively obstacles and difficulties
(Bandura, 1997).
The self-efficacy concept has been studied in different salutogenic behaviors, some of
which are fundamental to the study of NAFLD, such as exercising, losing weight, capacity

33
for recovering from health problems or coping with chronic diseases (Forsyth & Carey, 1998).
The positive effect that high perceived self-efficacy has on these behaviors, which lead to
greater patient functional capacity and wellbeing, and in general better quality of life, has
been demonstrated (Klein-Hessling et al., 2005). People with high self-efficacy also are more
likely to take action for disease prevention and tend to be more optimistic about the idea of
the treatment proposed culminating successfully, so it is easily inferred that therapeutic
adherence is significantly greater in such cases (Grembowski et al., 1993).
Perceived self-efficacy has been studied in various pathologies, such as cancer
(Mystakidou et al., 2010), chronic obstructive pulmonary disease, cardiovascular disease
(Arnold et al., 2005) and chronic pain (Meredith et al., 2006), and its importance for planning
successful interventions, including modifying the lifestyle, has been confirmed (Bellentani et
al., 2008). Hardly any studies have been performed on this subject in chronic liver diseases.
Even so, there is evidence of a close association between the presence of anxious-depressive
symptoms and low self-efficacy in these patients, which would imply a lower quality of life
(Gutteling et al., 2010).
Study of self-efficacy in NAFLD is of special relevance with regard to its treatment, as it
enables adjustment to intervention to be measured based on the individual perception of
his/her disability and competence for participating in the behavioral change (O'Sullivan &
Strauser, 2009). It is common to find lower self-efficacy among persons diagnosed with
NAFLD than in other liver diseases. Particularly, a significant lack of confidence in the ability
to do exercise is observed, which may partly explain the low adherence they usually show in
interventions based on lifestyle changes through physical exercise. Fear of falling, a frequent
emotion among NAFLD patients, could be behind this phenomenon (Frith et al., 2010).
Among Type 2 diabetics, perceived self-efficacy also has a determining role in the choice
of coping strategies and self-care (Gharaibeh et al., 2016). Thus, high perceived self-efficacy
is associated with adequate self-care, fewer depressive symptoms and better adherence to
treatment. Specifically, it is very likely that patients will carry out their diet and physical
exercise as planned by their doctor (Adam & Folds, 2014).
With respect to obesity, several studies (Choo & Kang, 2015; Linde et al., 2006; Warziski
et al., 2008) have established that a primary goal of intervention for weight loss must be to
increase perceived self-efficacy of their ability to carry out healthy behavior enabling them to
control their weight. Another study (Martin et al., 2004) goes beyond this finding, concluding
that those patients who already have high self-efficacy before intervention tend to lose less
weight compared to those whose perceived self-efficacy increases during treatment. This may
34
be explained by the fact that high self-efficacy before the intervention is indicative of excess
self-confidence, thereby underestimating the difficulties entailed in losing weight. Therefore,
it is fundamental to consider the pre-treatment evaluation of patients’ self-efficacy and its
inclusion in therapies for weight loss a primary objective of NAFLD intervention.

NAFLD Treatment: A Multidisciplinary Approach

Changes in Lifestyle

It has become indispensable to implement an effective NAFLD/NASH treatment program for

prevention and lowering the likelihood of the disease progressing to its most advanced stages.
No medication has yet been approved for treatment of NAFLD. To date, the most effective
measure involves weight loss through changes in lifestyle (Geier & Rau, 2017).
The components determining NAFLD activity (steatosis, ballooning and lobular
inflammation) evolve positively with weight loss (Musso et al., 2012; Promrat et al., 2010).
Specifically, loss of at least 10% of body weight is necessary to achieve significant
improvements in portal inflammation or advanced fibrosis, histological parameters typical of
the last stages of the liver disease (Vilar-Gómez et al., 2015). Weight loss is also associated
with lowering abdominal obesity (Ross et al., 2015; Vissers et al., 2013) and risk of
developing T2DM (Jensen et al., 2013), as well as improvements in quality of life, especially
in patients with NASH without T2DM or advanced fibrosis (Tapper & Lai, 2016). In patients
with NASH and fibrosis, an intensive treatment for a successful change of lifestyle is vital
because of its potential somatic complications (Dyson et al., 2014). In fact, one study found
64% resolution of hepatic fibrosis in patients who had received an intensive intervention with
nutritionist support, compared to 20% in patients who had only received general
recommendations to lose weight (Wong et al., 2013). The change in lifestyle must include
diet, physical activity and exercise (Romero-Gómez et al., 2017). It is recommended to begin
with restrictive diets, avoiding saturated fats, carbohydrates and sugar-added beverages
(Gallego-Durán et al., 2013). A Mediterranean diet, in turn, is established as an effective
strategy in NAFLD, as its relationship with significant reductions in fatty liver disease and
transaminases have been proven (Abenavoli et al., 2018; Biolato et al., 2019; Khalatbari-
Soltani et al., 2019). Furthermore, as a measure against low physical activity and sedentariness
which usually predominate among these patients, it is recommended that their usual rhythm
of aerobic activity be increased by walking for at least 60 min a day, 5 days a week. This
pattern, kept up for 3 months has positive repercussions, lowering alanine and aspartate
aminotransferase concentrations by half (Sreenivasa-Baba et al., 2006). Therefore, high levels

35
of physical activity and regular exercise protect against worsening NAFLD symptoms
(Macavei et al., 2016) and are associated with improvements in hepatic steatosis,
inflammation and serum liver enzyme levels (Katsagoni et al., 2017; Promrat et al., 2010).

Adherence to Therapy

Lack of adherence is the main problem in weight loss interventions for NAFLD patients: a
large proportion of patients (over 50%) are unable to lose the necessary weight or regain it in
a short time (Promrat et al., 2010; Stewart & Levenson, 2012). This can be explained by the
patients’ lack of health awareness not thinking of themselves as being ill. The NAFLD
diagnosis is not associated with an adequate increase in health awareness in the short or long
term. Consequently, it does not lead to more use of health services by the patient, who does
not interpret the disease as a health challenge, possibly until it advances to its last stages
(Mlynarsky et al., 2016). Therefore, it is fundamental to make patients understand their illness
including risks and complications at an early stage, so that they believe in the effectiveness of
medical treatment and perceive their ability to change the course of the disease by changing
their future lifestyle. This may be particularly challenging, when their previous lifestyle was
very different and greatly unhealthy (Arora et al., 2018; Ofosu et al., 2018).
Patients’ emotional state is also a relevant element in this analysis, as depression and
disease-related emotional stress are associated with low self-efficacy, which in turn has
negative consequences for adherence to therapy and lifestyle changes (Tomeno et al., 2015;
Zelber-Sagi et al., 2017).
Another key question for understanding problems with adherence to therapy in NAFLD
patients is the lack of willingness to change resulting in little motivation to follow the health
professionals’ guidelines, in particular concerning physical activity. This is particularly
alarming considering that physical and mental symptoms following severe liver damage do
not strengthen willingness to change, quite the opposite (Centis et al., 2013; Mlynarsky et al.,
2016). There are some strategies the health professional can use for improving patients’
motivation to change their lifestyle: (1) a collaborative style which attracts, motivates and
commits the patient, (2) evaluate, along with the patient, the advantages and disadvantages of
the treatment, (3) promote self-efficacy by designing individualized plans, focusing
feasibility, (4) analyze with the patient all variables that maintain the unhealthy lifestyle, (5)
explain the treatment in detail, and (6) increase the patient’s awareness of the negative impact
of the social stigmatization of obesity (Marchesini et al., 2016; Miller & Rollnick, 2002).

36
 To further strengthen adherence, it is also recommended that health professionals
encourage a clearly structured diet, which limits the patient’s choices, so that the likelihood
of eating undesirable foods and making mistakes in calculating the daily amount of calories
is reduced (Fabricatore, 2007). The proposed diet may include planned meals, menus and
recipes (Wing et al., 1996). In contrast to the recommendations concerning diets, some studies
have noted that adherence to physical exercises increase when they are less structured. From
this viewpoint, the likelihood of successfully implementing a plan for physical activity would
be better if carried out individualized at home instead of taking part in a supervised workout
program alone or in group sessions in a gym (Dalle-Grave et al., 2011; Perri et al., 1997).

Cognitive-Behavioral Treatment

Interventions in NAFLD must provide patients with enough tools to achieve the therapeutic
goals and include them in their daily habits, maintaining the results in the long term. To
achieve this, the traditional recommendations for changes in lifestyle must be replaced,
especially in individuals at risk of advanced liver disease, by implementing a cognitive-
behavioral treatment (CBT) (Centis et al., 2010; Marchesini et al., 2005).
CBT attempts to modify maladaptive patterns of thinking and behavior to achieve
improvement in an individual’s mood and psychosocial functioning (Stewart & Levenson,
2012). In this sense, CBT techniques recommended for intervention in NAFLD are: (1)
controlling stimuli, which consists of modifying the context, eliminating signals leading to
the problem behavior and increasing those leading to the desired response. For example, by
not allowing forbidden foods to enter their home and placing those recommended in an
accessible place (Fabricatore, 2007), (2) setting realistic personal goals and commitments, for
example, “I’ll only eat when I’m at the table” or “I am going to lose half a kilo a week”
(Fabricatore, 2007), (3) writing down everything eaten, physical activity and weight using
self-report questionnaires (Cooper et al., 2003), (4) reinforcing alternative behaviors, where
the patients, for example, learn to identify signals that can lead them to eat without being
hungry, replacing this response with other options, such as showering, exercising or using
relaxation or distraction techniques (Bellentani et al., 2008), (5) problem-solving strategies to
approach obstacles to weight loss or maintenance, by planning a series of steps to be able to
cope with them successfully (Bellentani et al., 2008), and (6) cognitive restructuring which
promotes development of a more adaptive style of thinking, including interventions for
cognitive bias and unrealistic expectations related to weight and weight loss, which are
significantly linked to quitting therapy (Dalle-Grave et al., 2005; Fabricatore, 2007).

37
 Inclusion of CBT in NAFLD interventions is associated with positive changes in patients’
health. Normalization of liver enzymes, improvements in sensitivity to insulin and greater
weight loss in the short and long-term should be emphasized (Moscatiello et al., 2011). For
its assured implementation, in addition to a well-defined program with the techniques
described above, a multidisciplinary team of medical and nursing staff, psychologists,
nutritionists and experts in physical exercise is recommended, which assists the patients
during treatment sessions and can flexibly react to their needs (Arena et al., 2016; Bellentani
et al., 2008). It has been found that multidisciplinary interventions are associated with better
clinical results and higher patient satisfaction than standard care (Katon et al., 2010).
Unfortunately, lack of resources often impedes multidisciplinary approaches, so it is
essential to promote NAFLD training programs for physicians. These include pragmatic
interventions for promoting lifestyle behavior changes in problematic patients (Arora et al.,
2018; Ghevariya et al., 2014; Ofosu et al., 2018; Polanco-Briceno et al., 2016). The clinical
relevance of NAFLD often is undererstimated and knowledge of the disease is inadequate,
especially among physicians who are not hepatologists (Wieland et al., 2013; Said et al., 2013;
Bergqvist et al., 2013). Add to this the urgent need for public information and education
programs on NAFLD (Ghevariya et al., 2014; Goh et al., 2016) by increasing knowledge of
the disease through the communications media, and by strengthening physical activity in
schools and providing incentives to use parks or bicycle lanes for exercise; warning about
junk food, ultra-processed and sugar-added foods, especially regulating advertising directed
at children, and promoting access for the lower socio-economic population groups to healthy
foods (World Health Organization, 2003).
In this chapter we have reviewed the psychosocial biomarkers associated with NAFLD.
This is a subject that should be studied in greater depth in the coming years, as to date there
are only few and sometimes contradictory studies. In spite of this, we have analyzed the
quality of life of persons with NAFLD, and how it is affected by such factors as fatigue,
anxiety, depression and cognitive dysfunction. We have also examined further relevant
variables, such as coping strategies, perceived social support and perceived self-efficacy,
which are understudied in NAFLD. However, their relevance for subjective wellbeing in
obesity and T2DM, which are the main comorbidities of NAFLD, makes it highly likely that
they also play an important part in mental health and quality of life in NAFLD. Finally, we
approached matters related to treatment of NAFLD and came to the conclusion that in
hospitals multidisciplinary teams are necessary, where psychologists, nutritionists and other

38
health professionals cooperate with doctors and nurses in the design and implementation of
medical therapy, cognitive-behavioral intervention programs and awareness campaigns.
The significant impact of advanced liver disease on patients’ life as well as its massive
economic and societal implications demand every effort for the optimization of prevention as
well as treatment programs.
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4.2. Segundo trabajo titulado “Psychological biomarkers and fibrosis: An innovative
approach to nonalcoholic fatty liver disease”

Este trabajo corresponde al artículo publicado que se referencia a continuación:

Funuyet-Salas, J., Pérez-San-Gregorio, M. Á, Martín-Rodríguez, A., & Romero-Gómez, M.

(2020). Psychological biomarkers and fibrosis: An innovative approach to nonalcoholic fatty
liver disease. Frontiers in Medicine, 7, 585425. https://doi.org/10.3389/fmed.2020.585425

54
Abstract

Background: It is unknown how perceived social support and the progression of liver damage
influence the psychosocial profile of patients with non-alcoholic fatty liver disease (NAFLD).
In the present study, we therefore investigated which biomarkers influence the quality of life,
mental health, and coping strategies of NAFLD patients. Methods: Quality of life (SF-12 and
CLDQ-NAFLD), mental health (HADS and BDI-II), and coping strategies (COPE-28) were
evaluated by high or low perceived social support (MSPSS) and the presence of non-alcoholic
steatohepatitis (NASH) and significant fibrosis in 492 biopsy-proven NAFLD patients. The
results were compared with quality of life normality tables for the general Spanish population.
We also determined whether liver histology and biopsychosocial variables predicted
participants’ quality of life. Results: Interactive effects were found in vitality (p = 0.05),
activity (p = 0.005), anxiety (p = 0.04), and denial (p = 0.04), with NASH patients showing a
higher-risk biopsychosocial profile when they perceived less social support. Furthermore,
patients with low perceived social support showed lower quality of life, worse mental health,
and more maladaptive coping than those with high perceived social support, regardless of
NASH presence. Patients with significant fibrosis showed lower quality of life compared to
those without or the general Spanish population. Patients with significant fibrosis also
reported worse mental health and more maladaptive coping. Lastly, significant fibrosis,
female sex, greater anxiety and depressive symptoms, and worse physical and mental health-
related quality of life were found to be independent determinants of worse disease-specific
quality of life in these patients. Conclusions: Low perceived social support, significant
fibrosis, and female sex were independently associated with a higher-risk psychosocial profile
in NAFLD. These findings support the role of psychological biomarkers based on quality of
life, mental health, and coping strategies in the management of these patients and suggest the
potential benefits of a psychological intervention. Keywords: NAFLD; fibrosis; quality of
life; mental health; coping; perceived social support.

Introduction

Non-alcoholic fatty liver disease (NAFLD) causes a stronger negative impact on patients’
quality of life (QoL) than do viral, alcoholic, autoimmune, or cholestatic liver diseases
(Afendy et al., 2009; Dan et al., 2007), especially impairing physical functioning or the ability
to perform daily activities (Assimakopoulos et al., 2018; Golabi et al., 2016; Sayiner et al.,
2016; Younossi et al., 2016). Mental health is also affected by an increase in anxiety and
depressive symptoms (Youssef et al., 2013). Similarly, although coping strategies have not

55
been studied in NAFLD, maladaptive coping, such as denial of the disease, anger or getting
upset after the diagnosis, disengagement, or giving up (Gutteling et al., 2010), is often found
among chronic liver patients. The influence of perceived social support on these variables has
not been approached. However, in chronic liver diseases, such as hepatitis B or C, satisfactory
support implies improved patient progress and recovery (Blasiole et al., 2006; Poorkaveh et
al., 2012) and a decrease in the frequency and intensity of depressive symptoms (Symister &
Friend, 2003).
The fibrosis stage is the main predictor of mortality associated with NAFLD (Hagström et
al., 2017), although the results are contradictory. Some studies have found worse QoL in
patients with nonalcoholic steatohepatitis (NASH) and advanced fibrosis than those with
NAFLD without advanced fibrosis, with cirrhotic patients complaining of the most decline in
their QoL of all severity levels (Afendy et al., 2009; David et al., 2009; Sayiner et al., 2016).
However, Huber et al. (Huber et al., 2018) did not find any significant effect of fibrosis stage
on QoL. In addition, the relationship between fibrosis and mental health in NAFLD patients
is not clear either. Several studies have found an association between the presence of fibrosis
and anxiety and depressive symptoms (Tomeno et al., 2015; Weinstein et al., 2011; Youssef
et al., 2013), while Kim et al. (2019) found no relationship. Furthermore, female sex has been
associated with a worse physical and mental QoL than does male sex (Afendy et al., 2009;
Tapper & Lai, 2016).
In view of the shortage of psychological studies in NAFLD, we decided to analyze the
differences in QoL, mental health, and the coping strategies of patients with the absence or
presence of NASH by perceived social support (high or low). We also studied the influence
of liver disease severity levels on these variables using data from the general Spanish
population to compare QoL. Finally, we determined whether certain histological and
biopsychosocial variables predicted participants’ QoL. We hypothesized that patients would
have worse QoL, more anxiety and depressive symptoms, and more maladaptive coping when
they have low perceived social support, NASH, or significant fibrosis. Furthermore, we
hypothesized that the presence of determinants of liver damage (moderate or severe steatosis,
lobular inflammation, hepatocellular ballooning, and significant fibrosis) and a higher-risk
biopsychosocial profile (female sex, older age, presence of obesity, worse physical and mental
health-related QoL, greater anxiety and depressive symptoms, maladaptive coping strategies,
and low perceived social support) would be associated with a greater negative impact on the
disease-specific QoL of NAFLD patients.

56
Methods

Participants

This research was approved by the Ethics Committee of the Virgen del Rocío University
Hospital of Seville. All patients gave their informed consent for participation, and the research
was conducted in accordance with the 1975 Declaration of Helsinki guidelines of good
practice. As shown in Figure 1, we selected a group of 492 patients with biopsy-proven
NAFLD (290 men and 202 women) with a mean age of 54.90 ± 11.74 years. The
sociodemographic characteristics of the groups are shown in Supplementary Tables 1, 2. Data
from the general Spanish population were also considered for QoL (SF-12) (Schmidt et al.,
2012).

Figure 1. Study participant selection flowchart.

Measures

The 12-Item Short-Form Health Survey (SF-12v.2). This scale comprised 12 items with either
three- or five-point Likert-type scales (Maruish, 2012; Ware et al., 2002). It evaluates the
following eight dimensions of health-related QoL: physical functioning, role-physical, bodily
pain, general health, vitality, social functioning, role-emotional, and mental health. It also
57
calculates two summary measures using Quality Metric Health OutcomesTM Scoring
Software 5.0: physical component summary (PCS) and mental component summary (MCS).
All scores ranged from 0 (worst state of health) to 100 (best state of health). Higher scores
indicate better health-related QoL. In our sample, the Cronbach’s alpha for the dimensions
varied from 0.72 to 0.95. The Cronbach’s alpha values for the PCS and MCS were 0.92 and
0.88, respectively (Ware et al., 2002).
Chronic Liver Disease Questionnaire - Non-alcoholic Fatty Liver Disease. The Chronic
Liver Disease Questionnaire - Non-alcoholic Fatty Liver Disease (CLDQ-NAFLD)
comprised 36 items rated on either a one- or a seven-point Likert-type scale (Younossi et al.,
2017). It evaluates specific QoL for NAFLD and NASH patients. It provides information
referring to the total score on the scale and six domains: abdominal symptoms, activity,
emotional, fatigue, systemic symptoms, and worry. Higher scores indicate better disease-
specific QoL. In our sample, the Cronbach’s alpha was 0.94 for the total instrument and from
0.68 to 0.89 for the domains.
Hospital Anxiety and Depression Scale. The Hospital Anxiety and Depression Scale
(HADS) is made up of 14 items, seven on the anxiety subscale and seven on the depression
subscale, with either zero- or three-point Likert-type scales (Zigmond & Snaith, 1983). It
evaluates anxiety and depressive symptoms. The test provides two total scores, one for anxiety
and the other for depression. Scores range from 0 to 21 for each subscale. Higher scores
indicate more anxiety and depressive symptoms. We used the Spanish version of this
instrument (Caro & Ibáñez, 1992). In our sample, the Cronbach’s alpha was 0.81 for the
anxiety subscale and 0.87 for the depression subscale.
Beck Depression Inventory – II. The Beck Depression Inventory - II (BDI-II) has 21 items
answered on a four-point (0–3) scale, except for items 16 and 18, which have seven categories
(Beck et al., 1996). It evaluates the severity of depression during the past 2 weeks. A total
score of 0–63 is found. Higher scores show more severe depression. We used the Spanish
version of this instrument (Beck et al., 2011). In our sample, the Cronbach’s alpha was 0.91.
The Brief COPE. The Brief COPE (COPE-28) comprised 28 items with either zero- or
three-point Likert-type scales (Carver, 1997). It evaluates 14 coping strategies: active coping,
planning, instrumental support, emotional support, self-distraction, venting, disengagement,
positive reframing, denial, acceptance, religion, substance use, humor, and self-blame. We
used the Spanish version of this instrument (Morán et al., 2010). On all the subscales, higher
scores indicate more use of the coping strategy. In our sample, the Cronbach’s alpha was
0.80–0.99 on the different subscales, except for positive reframing which was 0.45.
58
 Multidimensional Scale of Perceived Social Support. The Multidimensional Scale of
Perceived Social Support (MSPSS) consists of 12 items with either a one- or a seven-point
Likert type scale (Zimet et al., 1988). It evaluates perceived support from three different
sources: family, friends, and partner or other significant persons. It also provides information
on the total scale. We used the Spanish version of this instrument (Landeta & Calvete, 2002).
Higher scores show more perceived social support. In our sample, the Cronbach’s alpha was
0.94 for the total instrument and was 0.95–0.99 for the various dimensions of social support.

Procedure

The 492 study patients were selected from 12 hospitals in six autonomous regions of Spain
(Andalusia, Madrid, Castile and Leon, Catalonia, Cantabria, and Valencia). The same
procedure was followed for all patients in the study. The researcher responsible at each
participating hospital was contacted, and this contact provided a list of candidate NAFLD
patients for the study. Then, these patients were phoned to make an appointment for the
evaluation. All patients were evaluated by the same psychologist using the same
psychological measures, always applied in the same order: a psychosocial interview and the
SF-12, CLDQ-NAFLD, HADS, BDI-II, COPE-28, and MSPSS instruments. The inclusion
criteria were as follows: (a) over 18 years of age; (b) informed consent; (c) no difficulties in
understanding the evaluation instruments; (d) no severe or disabling psychopathological
condition; and (e) diagnosed with biopsy-proven NAFLD. As all of the patients had
undergone liver biopsy, they could be classified into groups by the hepatologist’s criteria (G1
= absence of NASH and G2 = presence of NASH) and liver severity levels based on NASH
and significant fibrosis (F2, F3, and F4) (Ga = no-NASH without significant fibrosis, Gb =
NASH with significant fibrosis, Gc = no-NASH with significant fibrosis, and Gd = NASH
without significant fibrosis) (Figure 1). Patients were classified as NASH or not after clinical
assessment by the hepatologist, who provided a histological diagnosis by liver biopsy based
on hepatocellular ballooning and lobular inflammation levels. The two perceived social
support groups (G3 = high and G4 = low) were formed in two stages: firstly, each patient’s
total score on the MSPSS scale, which varied from 1 to 7, where higher scores show greater
social support, was taken. These scores were then arranged in ascending order and the
percentages accumulated were used to divide the sample into two groups at the 50.2 percentile
(G3 = high and G4 = low) (Figure 1). Finally, to determine how liver histology and
biopsychosocial variables predicted disease specific QoL, the following histological variables
provided by liver biopsy were analyzed: hepatic steatosis severity (a mild group of steatosis

59
patients with 6–33% and a moderate-to-severe group with steatosis equal to or more than
34%); lobular inflammation (absence or presence depending on the number of foci per HPF,
from none to more than one); hepatocellular ballooning (absence or presence based on the
existence of ballooned cells); and significant fibrosis (absence, F0–F1, or presence, F2–F4,
depending on the fibrosis stage). The biopsychosocial variables analyzed were sex (male or
female), age, obesity, physical and mental health-related QoL (PCS and MCS; SF-12), anxiety
and depressive symptoms (total anxiety and total depression; HADS, BDI-II), coping
strategies (scores for all 14 coping strategies; COPE-28), and perceived social support (total
scale score; MSPSS).

Statistical analysis

Pearson’s chi-square test was applied to the sociodemographic variables to compare

categorical variables (sex, marital status, education, and employment) and the t-test for
independent samples or a one-way ANOVA (Welch’s U) with Games–Howell post hoc
pairwise analysis to compare the age variable.
A 2 × 2 factorial ANOVA (Snedecor’s F) was performed to evaluate the influence on QoL
(SF-12 and CLDQ-NAFLD), mental health (HADS and BDI-II), and coping strategies
(COPE-28) exerted by NASH (absence or presence) and perceived social support (high or
low). And to compare these variables (QoL, mental health, and coping strategies) between the
NAFLD severity groups, a one-way ANOVA (Snedecor’s F or Welch’s U) as an omnibus test
was computed depending on whether or not they met the assumption of homoscedasticity. For
post hoc multiple comparisons, Tukey’s honestly significant difference or the Games–Howell
test was applied. The t-test for independent samples was also applied for comparison with the
general Spanish population. Cohen’s d (for continuous variables) and w (for categorical
variables) were computed as effect size indexes.
Binary logistic regression analysis was used to determine the contribution of the
histological and biopsychosocial variables to disease-specific QoL. The independent variables
in the regression model were hepatic steatosis severity, lobular inflammation, hepatocellular
ballooning, significant fibrosis, sex, age, obesity, PCS (SF-12), MCS (SF-12), total anxiety
(HADS), total depression (HADS and BDI-II), the 14 coping strategies measured with the
COPE-28, and total perceived social support (MSPSS). For categorical variables, reference
groups were formed for patients with moderate to severe steatosis, presence of lobular
inflammation, hepatocellular ballooning or significant fibrosis, female sex, and the presence
of obesity. The total score on the CLDQ-NAFLD questionnaire (total CLDQ-NAFLD) was

60
 analyzed as the dependent variable. This score was arranged in ascending order and the
cumulative percentages were used to divide the sample into two groups (better and worse
QoL) at the 50th percentile. The results for binary logistic regression were reported as odds
ratios (OR) at 95% confidence intervals. A two-sided p-value < 0.05 was considered
statistically significant. All the data were analyzed with the SPSS Statistics v.25 program.

Results

Sociodemographic Variables

There were no important between-group differences (null or small effect sizes) in NASH,
social support, or severity (Supplementary Tables 1, 2). The only difference in severity was
that age was higher in Gb (NASH with significant fibrosis) than in Gd (NASH without
significant fibrosis; p < 0.001, d = 0.557). Age was also higher in Gc (no-NASH with
significant fibrosis) than in Ga (no-NASH without significant fibrosis; p = 0.003, d = −0.725)
or Gd (NASH without significant fibrosis; p = 0.001, d = 0.778) (Supplementary Table 2).

Influence of NASH and Social Support Variables on QoL, Mental Health, and Coping
Strategies

The results are shown in Table 1 (SF-12), Table 2 (CLDQNAFLD), Table 3 (HADS and BDI-
II), and Table 4 (COPE-28). Four statistically significant interactive effects were found:
vitality (p = 0.05; Table 1), activity (p = 0.005; Table 2), anxiety (p = 0.04; Table 3), and
denial (p = 0.04; Table 4).

Table 1. Quality of life (SF-12) of non-alcoholic fatty liver disease (NAFLD) patients based on non-alcoholic
steatohepatitis (NASH; absence and presence) and social support level (high and low) variables.

61
SF-12 NASH Social support level Main effects Interaction
effects
Ma (SD) Ma (SD)
Absence Presence High Low NASH Social F(1,488)
support
(G1) (G2) F(1,488) (p)
(G3) (G4) level
n = 201 n = 291 p (db)
n = 245 n = 247 F(1,488)
p (db)
Physical 76.85 65.71 81.73 60.83 13.53 47.55 3.73
functioning
(33.03) (33.09) (33.34) (33.79) <0.001 <0.001 (0.06)
(0.337 S) (0.623 M)
Role-physical 81.53 73.21 86.67 68.08 10.17 50.76 2.97
(28.50) (28.49) (28.80) (29.07) 0.002 <0.001 (0.09)
(0.292 S) (0.642 M)
Bodily pain 79.18 70.86 81.43 68.61 11.09 26.33 1.36
(27.22) (27.29) (27.55) (27.82) 0.001 <0.001 (0.24)
(0.304 S) (0.463 S)
General health 52.06 46.72 56.77 42 5.74 43.97 1.73
(24.24) (24.22) (24.57) (24.83) 0.02 <0.001 (0.19)
(0.220 S) (0.598 M)
Vitality 62.71 52.24 66.35 48.59 19.62 56.45 3.98
(25.80) (25.76) (25.98) (26.40) <0.001 <0.001 (0.05)
(0.406 S) (0.678 M)
Social 88.85 85.57 94.43 79.99 2.63 51.01 1.80
functioning
(21.97) (22.00) (22.23) (22.47) 0.11 <0.001 (0.18)
(0.149 N) (0.646 M)
Role-emotional 83.02 78.74 89.31 72.45 3.65 56.45 1.36
(24.53) (24.39) (24.73) (24.99) 0.06 <0.001 (0.24)
(0.175 N) (0.678 M)
Mental health 73.00 68.01 77.60 63.41 6.57 53.07 2.35
(21.27) (21.15) (21.44) (21.69) 0.01 <0.001 (0.13)
(0.235 S) (0.658 M)
PCS 48.89 45.67 49.94 44.63 11.98 32.57 2.51
(10.21) (10.06) (10.17) (10.37) 0.001 <0.001 (0.11)
(0.318 S) (0.517 M)
MCS 52.26 50.57 54.61 48.21 3.86 55.44 1.64
(9.36) (9.38) (9.55) (9.59) 0.05 <0.001 (0.20)
(0.180 N) (0.669 M)
A 2 × 2 factorial ANOVA (Snedecor’s F) was applied.

62
SF-12, 12-Item Short-Form Health Survey; PCS, physical component summary; MCS, mental component summary.
a
Higher scores show better quality of life.
b
Effect sizes: N, null; S, small; M, medium.

Table 2. Quality of life (CLDQ-NAFLD) of non-alcoholic fatty liver disease (NAFLD) patients based on non-alcoholic
steatohepatitis (NASH; absence and presence) and social support level (high and low) variables.
CLDQ- NASH Social support level Main effects Interaction
NAFLD Ma (SD) Ma (SD) effects
Absence Presence High Low NASH Social F(1,488)
(G1) (G2) (G3) (G4) F(1,488) support level (p)
n = 201 n = 291 n = 245 n = 247 p (db) F(1,488)
p (db)
Abdominal 5.64 5.51 5.88 5.28 0.91 19.36 0.201
symptoms (1.42) (1.53) (1.41) (1.57) 0.34 <0.001 (0.65)
(0.088 N) (0.402 S)
Activity 5.86 5.45 5.99 5.33 13.32 33.92 7.97
(1.28) (1.19) (1.25) (1.26) <0.001 <0.001 (0.005)
(0.332 S) (0.526 M)
Emotional 5.90 5.62 6.17 5.35 9.14 82.23 3.34
(0.99) (1.02) (0.94) (0.94) 0.003 <0.001 (0.07)
(0.279 S) (0.872 L)
Fatigue 5.55 5.13 5.86 4.82 14.60 89.58 2.61
(1.13) (1.19) (1.25) (1.26) <0.001 <0.001 (0.11)
(0.362 S) (0.829 L)
Systemic 5.98 5.64 6.10 5.52 17.60 47.72 1.04
symptoms (0.85) (0.85) (0.94) (0.94) <0.001 <0.001 (0.31)
(0.400 S) (0.617 M)
Worry 6.30 6.10 6.39 6.00 5.22 19.42 0.012
(0.99) (1.02) (0.94) (0.94) 0.02 <0.001 (0.91)
(0.199 N) (0.415 S)
Total 5.87 5.58 6.06 5.38 14.54 75.10 3.04
(0.85) (0.85) (0.78) (0.78) <0.001 <0.001 (0.08)
(0.341 S) (0.872 L)
A 2 × 2 factorial ANOVA (Snedecor’s F) was applied.
a
Higher scores show better quality of life.
b
Effect sizes: N, null; S, small; M, medium; L, large.

Table 3. Mental health (HADS and BDI-II) of non-alcoholic fatty liver disease (NAFLD) patients based on non-alcoholic
steatohepatitis (NASH; absence and presence) and social support level (high and low) variables.

63
 NASH Social support level Main effects Interaction
Ma (SD) Ma (SD) effects

Absence Presence High Low NASH Social F(1,488)

(G1) (G2) (G3) (G4) F(1,488) support level (p)
n = 201 n = 291 n = 245 n = 247 p (d) F(1,488)
p (d)
HADS
Total anxiety 3.20 3.78 2.46 4.52 3.29 42.52 4.079
(3.40) (3.41) (3.44) (3.46) 0.07 <0.001 (0.04)
(-0.170 N) (-0.597 M)
Total 2.26 3.09 1.22 4.13 7.66 94.63 2.916
depression (3.26) (3.24) (3.29) (3.30) 0.006 <0.001 (0.09)
(-0.255 S) (-0.883 L)
BDI-II
Total 6.17 7.58 3.38 10.38 4.89 12.69 2.272
depression (6.95) (6.99) (7.04) (7.07) 0.03 <0.001 (0.13)
(-0.202 S) (-0.992 L)
A 2 × 2 factorial ANOVA (Snedecor’s F) was applied.
a
Higher scores show worse mental health.
b
Effect sizes: N, null; S, small; M, medium; L, large.

Table 4. Coping strategies (COPE-28) of non-alcoholic fatty liver disease (NAFLD) patients based on non-alcoholic
steatohepatitis (NASH; absence and presence) and social support level (high and low) variables.
COPE-28 NASH Social support level Main effects Interaction
Ma (SD) Ma (SD) effects

Absence Presence High Low NASH Social F(1,488)

(G1) (G2) (G3) (G4) F(1,488) support (p)
n = 201 n = 291 n = 245 n = 247 p (d) level
F(1,488)
p (d)
Active coping 1.96 1.87 2.21 1.62 1.95 74.35 0.10
(0.71) (0.68) (0.78) (0.78) 0.16 <0.001 (0.92)
(0.129 N) (0.756 M)
Planning 1.29 1.34 1.63 1.01 0.27 45.29 1.35
(0.99) (1.02) (0.94) (1.10) 0.60 <0.001 (0.25)
(-0.050 N) (0.606 M)
Instrumental 1.15 1.14 1.40 0.88 0.02 33.89 0.33
support (0.99) (1.02) (0.94) (0.94) 0.88 <0.001 (0.56)
(0.010 N) (0.553 M)
Emotional 1.03 1.10 1.33 0.79 0.56 35.66 0.10
support (0.99) (1.02) (0.94) (0.94) 0.45 <0.001 (0.75)
(-0.070 N) (0.574 M)
Self-distraction 0.67 0.82 0.68 0.80 2.53 1.83 1.23
(0.99) (1.02) (0.94) (0.94) 0.11 0.18 (0.27)
(-0.149 N) (-0.128 N)

64
 Venting 0.98 1.02 1.17 0.83 0.15 13.55 0.75
(0.99) (1.02) (1.09) (1.10) 0.70 <0.001 (0.39)
(-0.040 N) (0.310 S)
Disengagement 0.30 0.31 0.14 0.47 0.11 50.74 0.19
(0.57) (0.51) (0.47) (0.47) 0.74 <0.001 (0.66)
(-0.018 N) (-0.702 M)
Positive 1.35 1.16 1.58 0.93 4.33 52.02 0.47
reframing (0.99) (1.02) (0.94) (0.94) 0.04 <0.001 (0.49)
(0.189 N) (0.691 M)
Denial 0.18 0.24 0.12 0.30 2.63 21.32 4.14
(0.42) (0.34) (0.47) (0.47) 0.10 <0.001 (0.04)
(-0.157 N) (-0.383 S)
Acceptance 2.04 1.99 2.29 1.75 0.64 61.92 1.44
(0.71) (0.68) (0.78) (0.78) 0.42 <0.001 (0.23)
(0.072 N) (0.692 M)
Religion 0.84 0.99 0.90 0.94 2.00 0.117 0.01
(1.13) (1.19) (1.25) (1.26) 0.16 0.73 (0.94)
(-0.129 N) (-0.032 N)
Humor 1.11 1.00 1.29 0.82 1.45 24.21 0.02
(0.99) (1.02) (1.09) (0.94) 0.23 <0.001 (0.89)
(0.109 N) (0.462 S)
Self-blame 0.55 0.50 0.39 0.66 0.43 18.35 1.94
(0.71) (0.68) (0.78) (0.78) 0.51 <0.001 (0.16)
(0.072 N) (-0.346 S)
A 2 × 2 factorial ANOVA (Snedecor’s F) was applied.
a
Higher scores show more use of the coping strategy.
b
Effect sizes: N, null; S, small; M, medium.

As observed in Table 5 and Figure 2, the simple effects showed that NASH patients had
less vitality (p < 0.001, d = 0.873), less activity (p < 0.001, d = 0.805), more anxiety (p <
0.001, d = −0.786), and more denial (p < 0.001, d = −0.638) when they perceived less social
support. However, in patients without NASH, there were no differences depending on
perceived social support, except in the vitality variable (p < 0.001, d = 0.505), which was
lower in patients with low social support. Moreover, when social support was high, there were
no differences between patients with and without NASH, but when social support was low,
patients with NASH had lower scores in vitality (p < 0.001, d = 0.590) and activity (p < 0.001,
d = 0.600).
Table 5. Simple effects in vitality (SF-12), activity (CLDQ-NAFLD), anxiety (HADS), and denial (COPE-28).
Vitality Activity Anxiety Denial
(SF-12) (CLDQ-NAFLD) (HADS) (COPE-28)
p Cohen’s p Cohen’s p Cohen’s p Cohen’s
da da da da
Social support level High–low Absence NASH (G1): n = 201

65
 <0.001 0.505 M 0.05 0.283 S 0.004 -0.410 S 0.09 -0.250 S
Presence NASH (G2): n = 291
<0.001 0.873 L <0.001 0.805 L <0.001 -0.786 M <0.001 -0.638 M
NASH Absence–presence High social support (G3): n = 245
0.08 0.223 S 0.56 0.075 N 0.88 0.020 N 0.77 0.045 N
Low social support (G4): n = 247
<0.001 0.590 M <0.001 0.600 M 0.007 -0.352 S 0.01 -0.395 S
SF-12, 12-Item Short-Form Health Survey; CLDQ-NAFLD, Chronic Liver Disease Questionnaire - Non-alcoholic Fatty Liver
Disease; HADS, Hospital Anxiety and Depression Scale; COPE-28, Brief COPE.
a
Cohen’s d: N, null effect size; S, small effect size; M, medium effect size; L, large effect size.

Figure 2. Interactive effects of non-alcoholic steatohepatitis (NASH; absence or presence)

and level of social support (high or low) factors.

Note. Analysis of the influence of NASH and social support on the quality of life, mental
health, and coping strategies of non-alcoholic fatty liver disease (NAFLD) patients showing
interactive effects in vitality (p = 0.05), activity (p = 0.005), anxiety (p = 0.04), and denial
(p = 0.04).

The main effects by relevant effect sizes (medium and large) were that, regardless of
whether NASH was present or not, patients with low social support had worse QoL (SF-12

66
and CLDQ-NAFLD) than those with high social support on most of the variables, except
bodily pain, abdominal symptoms, and worry, in which there were no differences between the
two groups (Tables 1, 2). In mental health (HADS and BDI-II), patients with low social
support had higher scores in anxiety (p < 0.001, d = −0.597) and depressive symptoms
measured with both HADS (p < 0.001, d = −0.883) and BDI-II (p < 0.001, d = −0.992) (Table
3). And in coping strategies (COPE-28), by relevant effect sizes (medium), patients with low
social support scored higher in disengagement (p < 0.001, d = −0.702) and lower in active
coping (p < 0.001, d = 0.756), planning (p < 0.001, d = 0.606), instrumental support (p <
0.001, d = 0.553), emotional support (p < 0.001, d = 0.574), positive reframing (p < 0.001, d
= 0.691), and acceptance (p < 0.001, d = 0.692) (Table 4).

Influence of Liver Disease Severity on QoL, Mental Health, and Coping Strategies

In QoL (SF-12 and CLDQ-NAFLD), there were statistically significant differences between
the severity levels in physical functioning (p < 0.001), role-physical (p < 0.001), bodily pain
(p < 0.001), general health (p < 0.001), vitality (p < 0.001), social functioning (p = 0.01), role-
emotional (p = 0.01), mental health (p = 0.001), PCS (p < 0.001), MCS (p = 0.03), abdominal
symptoms (p < 0.001), activity (p < 0.001), emotional (p < 0.001), fatigue (p < 0.001),
systemic symptoms (p < 0.001), worry (p < 0.001), and total CLDQ-NAFLD (p < 0.001).
Specifically, by relevant effect sizes (medium and large), as shown in Tables 6, 7 and Figures
3, 4, Ga (no-NASH without significant fibrosis) scored higher in physical functioning (p <
0.001, d = 0.660), role-physical (p < 0.001, d = 0.603), bodily pain (p < 0.001, d = 0.566),
vitality (p < 0.001, d = 0.638), PCS (p < 0.001, d = 0.647), activity (p < 0.001, d = 0.679),
emotional (p < 0.001, d = 0.517), fatigue (p < 0.001, d = 0.736), systemic symptoms (p <
0.001, d = 0.750), worry (p < 0.001, d = 0.573), and total CLDQ-NAFLD (p < 0.001, d =
0.769) than Gb (NASH with significant fibrosis). Ga (no-NASH without significant fibrosis)
also scored higher in physical functioning (p = 0.04, d = 0.610), PCS (p = 0.06, d = 0.574),
activity (p = 0.06, d = 0.575), fatigue (p = 0.03, d = 0.671), systemic symptoms (p = 0.15, d
= 0.514), worry (p = 0.14, d = 0.537), and total CLDQ-NAFLD (p = 0.11, d = 0.546) than Gc
(no-NASH with significant fibrosis). Gb (NASH with significant fibrosis) scored lower in
physical functioning (p < 0.001, d = −0.547), role-physical (p < 0.001, d = –0.579), PCS (p <
0.001, d = −0.542), abdominal symptoms (p < 0.001, d = −0.559), activity (p < 0.001, d =
−0.633), emotional (p < 0.001, d = −0.521), fatigue (p < 0.001, d = −0.651), systemic
symptoms (p < 0.001, d = −0.638), worry (p < 0.001, d = −0.633), and total CLDQ-NAFLD
(p < 0.001, d = −0.804) than Gd (NASH without significant fibrosis). Gc (no-NASH with

67
 significant fibrosis) also scored lower in activity (p = 0.12, d = −0.523), fatigue (p = 0.06, d
= −0.586), worry (p = 0.10, d = −0.594), and total CLDQ-NAFLD (p = 0.12, d = −0.570) than
Gd (NASH without significant fibrosis). Similarly, the Gb (NASH with significant fibrosis)
and Gc (no-NASH with significant fibrosis) groups differed considerably from the general
Spanish population (GSP) in some dimensions of QoL measured with the SF-12 (Figure 3).

Table 6. Comparison of quality of life (SF-12) in non-alcoholic fatty liver disease (NAFLD) severity
groups: non-alcoholic steatohepatitis (NASH; with and without significant fibrosis) and no-NASH (with
and without significant fibrosis.
SF-12 Ga-Gb Ga-Gc Ga-Gd Gb-Gc Gb-Gd Gc-Gd
p (da) p (da) p (da) p (da) p (da) p (da)
<0.001 0.04 0.69 0.98 <0.001 0.14
Physical functioning
(0.660 M) (0.610 M) (0.127 N) (-0.082 N) (-0.547 M) (-0.489 S)
<0.001 0.26 0.99 0.79 <0.001 0.33
Role-physical
(0.603 M) (0.422 S) (0.034 N) (-0.189 N) (-0.579 M) (-0.395 S)
<0.001 0.57 0.79 0.68 0.001 0.83
Bodily pain
(0.566 M) (0.297 S) (0.108 N) (-0.238 S) (-0.447 S) (-0.190 N)
<0.001 0.32 0.99 0.94 0.001 0.43
General health
(0.480 S) (0.373 S) (0.036 N) (-0.124 N) (-0.439 S) (-0.332 S)
<0.001 0.26 0.14 0.65 0.007 0.92
Vitality
(0.638 M) (0.362 S) (0.257 S) (-0.220 S) (-0.375 S) (-0.125 N)
0.01 0.43 0.98 1.00 0.05 0.54
Social functioning
(0.335 S) (0.143 N) (0.012 N) (0.013 N) (-0.296 S) (-0.314 S)
0.01 0.97 1.00 0.58 0.02 0.98
Role-emotional
(0.336 S) (0.093 N) (0.010 N) (-0.255 S) (-0.346 S) (-0.088 N)
0.001 0.98 0.96 0.38 0.01 1.00
Mental health
(0.410 S) (0.085 N) (0.058 N) (-0.220 S) (-0.360 S) (-0.026 N)
<0.001 0.06 0.81 0.97 <0.001 0.17
PCS
(0.647 M) (0.574 M) (0.102 N) (-0.094 N) (-0.542 M) (-0.465 S)
0.03 1.00 0.95 0.55 0.16 1.00
MCS
(0.299 S) (0.029 N) (0.066 N) (-0.267 S) (-0.239 S) (0.035 N)
Tukey’s honestly significant difference or Games–Howell was applied depending on whether or not they
met the assumption of homoscedasticity.
Ga, no-NASH without significant fibrosis; Gb, NASH with significant fibrosis; Gc, no-NASH with
significant fibrosis; Gd, NASH without significant fibrosis; PCS, physical component summary; MCS,
mental component summary; SF-12, 12-Item Short-Form Health Survey.
a
Effect sizes: N, null; S, small; M, medium.

Table 7. Comparison of quality of life (CLDQ-NAFLD) between non-alcoholic fatty liver disease (NAFLD)
severity groups: non-alcoholic steatohepatitis (NASH; with and without significant fibrosis) and no-NASH
(with and without significant fibrosis).

CLDQ-NAFLD Ga-Gb Ga-Gc Ga-Gd Gb-Gc Gb-Gd Gc-Gd

p (da) p (da) p (da) p (da) p (da) p (da)

68
Abdominal 0.006 0.73 0.37 0.93 <0.001 0.30
symptoms (0.358) S (0.229) S (-0.186) N (-0.134) N (-0.559) M (-0.412) S

<0.001 0.06 0.91 0.91 <0.001 0.12

Activity
(0.679) M (0.575) M (0.083) N (-0.138) N (-0.633) M (-0.523) M

<0.001 0.94 1.00 0.15 <0.001 0.96

Emotional
(0.517) M (0.111) N (0.010) N (-0.428) S (-0.521) M (-0.104) N

<0.001 0.03 0.85 0.99 <0.001 0.06

Fatigue
(0.736) M (0.671) M (0.095) N (-0.056) N (-0.651) M (-0.586) M

<0.001 0.15 0.67 0.86 <0.001 0.33

Systemic symptoms
(0.750) M (0.514) M (0.131) N (-0.166) N (-0.638) M (-0.409) S

<0.001 0.14 0.94 1.00 <0.001 0.10

Worry
(0.573) M (0.537) M (-0.066) N (-0.008) N (-0.633) M (-0.594) M

<0.001 0.11 1.00 0.85 <0.001 0.12

Total
(0.769) M (0.546) M (0.000) N (-0.178) N (-0.804) L (-0.570) M

Games–Howell post hoc pairwise analysis was applied.

Ga, no-NASH without significant fibrosis; Gb, NASH with significant fibrosis; Gc, no-NASH with
significant fibrosis; Gd, NASH without significant fibrosis; CLDQ-NAFLD, Chronic Liver Disease
Questionnaire - Non-alcoholic Fatty Liver Disease.
a
Effect sizes: N, null; S, small; M, medium; L, large.

Figure 3. Comparison of quality of life (SF-12) in the non-alcoholic fatty liver disease (NAFLD)
severity groups and the general Spanish population (GSP).

69
Note. Cohen’s d: N, null effect size; S, small effect size; M, medium effect size; L, large effect
size. Ga, no-NASH without significant fibrosis; Gb, NASH with significant fibrosis; Gc, no-
NASH with significant fibrosis; Gd, NASH without significant fibrosis; GSP, general Spanish
population; PCS, physical component summary; MCS, mental component summary; SF-12,
12-Item Short-Form Health Survey.

Figure 4. Comparison of quality of life (CLDQ-NAFLD) in non-alcoholic fatty

liver disease (NAFLD) severity groups.

Note. Ga, no-NASH without significant fibrosis; Gb, NASH with significant
fibrosis; Gc, no-NASH with significant fibrosis; Gd, NASH without significant

70
 fibrosis; NASH, non-alcoholic steatohepatitis; CLDQ-NAFLD, Chronic Liver
Disease Questionnaire - Non-alcoholic Fatty Liver Disease.

More precisely, Gb (NASH with significant fibrosis) scored lower in physical functioning
(p < 0.001, d = −0.838), role-physical (p < 0.001, d = −0.610), general health (p < 0.001, d =
−0.661), vitality (p < 0.001, d = −0.752), role-emotional (p < 0.001, d = −0.578), mental health
(p < 0.001, d = −0.518), and PCS (p < 0.001, d = −0.664) than the GSP. Gc (no-NASH with
significant fibrosis) also scored lower in physical functioning (p < 0.001, d = −0.799), general
health (p < 0.009, d = −0.569), and PCS (p < 0.001, d = −0.593) than the GSP.
As shown in Table 8, differences in mental health (HADS and BDI-II) were found in total
anxiety (p = 0.01) and total depression in the HADS (p < 0.001) and BDI-II (p < 0.001).
Specifically, by relevant effect sizes (medium), Gb (NASH with significant fibrosis) showed
higher scores in total depression than groups Ga (no-NASH without significant fibrosis)
(HADS: p < 0.001, d = −0.531; BDI-II: p < 0.001, d = −0.501) or Gd (NASH without
significant fibrosis) (HADS: p < 0.001, d = 0.573; BDI-II: p < 0.001, d = 0.628).

Table 8. Comparison of mental health (HADS and BDI-II) between non-alcoholic fatty liver disease (NAFLD) severity
groups: non-alcoholic steatohepatitis (NASH; with and without significant fibrosis) and no-NASH (with and without
significant fibrosis).

No-NASH NASH No-NASH NASH Statistic p

without with significa with without
significant nt fibrosis significant significant
fibrosis (Gb) n=159 fibrosis fibrosis
(Ga) n=175 (Gc) n=26 (Gd) n=132

Ma (SD) Ma (SD) Ma (SD) Ma (SD)

HADS

Total anxiety 3.19 4.39 3.12 3.14 U(3,108.869) = 0.01

(3.37) (3.95) (3.94) (3.41) 3.72

Total depression 2.09 4.09 3.08 2.00 U(3,106.161) = <0.001

(2.94) (4.44) (4.49) (2.62) 9.46

BDI-II

Total depression 5.75 9.89 8.19 5.08 U(3,108.396) = <0.001

(7.11) (9.28) (8.26) (5.57) 10.73

71
 POST-HOC Ga-Gb Ga-Gc Ga-Gd Gb-Gc Gb-Gd Gc-Gd
COMPARISONS
p (db) p (db) p (db) p (db) p (db) p (db)

HADS

Total anxiety 0.02 1.00 1.00 0.43 0.02 1.00

(-0.327) S (0.019) N (0.015) N (0.322) S (0.339) S (-0.005) N

Total depression <0.001 0.70 0.99 1.71 <0.001 0.64

(-0.531) M (-0.261) S (0.032) N (0.226) S (0.573) M (0.284) S

BDI-II

Total depression <0.001 0.49 0.78 0.77 <0.001 0.27

(-0.501) M (-0.317) S (0.105) N (0.193) N (0.628) M (0.441) S

A one-way ANOVA (Welch’s U) with Games–Howell post hoc pairwise analysis were applied.
HADS, Hospital Anxiety and Depression Scale; BDI-II, Beck Depression Inventory—II.
a
Higher scores show worse mental health.
b
Effect sizes: N, null; S, small; M, medium.

In coping strategies (COPE-28), shown in Table 9, differences were found in active coping
(p < 0.001), planning (p = 0.03), disengagement (p < 0.001), positive reframing (p = 0.001),
denial (p = 0.004), acceptance (p < 0.001), and humor (p = 0.02). By relevant effect sizes
(medium), group Gd (NASH without significant fibrosis) scored lower in disengagement than
groups Gc (no-NASH with significant fibrosis; p = 0.21, d = 0.511) or Gb (NASH with
significant fibrosis; p < 0.001, d = 0.589). Gd (NASH without significant fibrosis) also scored
higher than Gb (NASH with significant fibrosis) in active coping (p < 0.001, d = −0.567) and
acceptance (p < 0.001, d = −0.586) (Table 10).

Table 9. Comparison of coping strategies (COPE-28) between non-alcoholic fatty liver disease (NAFLD) severity groups: non-
alcoholic steatohepatitis (NASH; with and without significant fibrosis) and no-NASH (with and without significant fibrosis).

72
COPE-28 No-NASH NASH No-NASH NASH Statistic p
without with with without
significant significant significant significant
fibrosis fibrosis fibrosis fibrosis

(Ga) (Gb) (Gc) (Gd)

n = 175 n = 159 n = 26 n = 132

Ma (SD) Ma (SD) Ma (SD) Ma (SD)

Active coping 1.99 1.66 1.88 2.10 U(3,110.482) = 7.99 <0.001

(0.77) (0.87) (0.78) (0.67)

Planning 1.27 1.17 1.50 1.52 F(3,488) = 3.02 0.03

(1.10) (1.05) (1.00) (0.99)

Instrumental 1.20 1.03 0.88 1.25 F(3,488) = 1.93 0.12

support
(0.99) (0.99) (0.96) (1.05)

Emotional 1.05 0.98 0.94 1.22 F(3,488) = 1.53 0.21

support
(1.01) (0.99) (0.93) (1.04)

Self-distraction 0.68 0.75 0.58 0.90 U(3,120.760) = 1.88 0.14

(0.98) (1.02) (0.66) (0.97)

Venting 1.01 1.06 0.86 0.96 F(3,488) = 0.37 0.77

(1.02) (1.06) (0.98) (1.00)

Disengagement 0.27 0.45 0.42 0.15 U(3,106.617) = 9.24 <0.001

(0.51) (0.63) (0.66) (0.35)

Positive 1.38 0.97 1.17 1.36 F(3,488) = 5.35 0.001

reframing
(1.01) (1.06) (1.17) (1.00)

Denial 0.17 0.34 0.23 0.14 U(3,107.139) = 4.74 0.004

(0.37) (0.54) (0.51) (0.36)

Acceptance 2.07 1.77 1.90 2.23 U(3,109.615) = 9.05 <0.001

(0.75) (0.90) (0.81) (0.65)

Religion 0.82 1.01 0.96 0.98 F(3,488) = 0.79 0.50

73
 (1.13) (1.19) (1.08) (1.23)

Substance use 0.00 0.00 0.00 0.00 F(3,488) = 0.35 0.78

(0.07) (0.04) (0.00) (0.00)

Humor 1.14 0.83 0.96 1.18 F(3,488) = 3.42 0.02

(1.10) (1.01) (1.02) (1.03)

Self-blame 0.54 0.63 0.54 0.36 U(3,120.760) = 1.88 0.14

(0.65) (0.76) (0.56) (0.63)

A one-way ANOVA (Snedecor’s F or Welch’s U) was applied depending on whether or not they met the assumption of
homoscedasticity.
COPE-28, Brief COPE.
a
Higher scores show more use of the coping strategy.

Table 10. Post hoc comparison of coping strategies (COPE-28) between non-alcoholic fatty liver disease
(NAFLD) severity groups: non-alcoholic steatohepatitis (NASH; with and without significant fibrosis) and no-
NASH (with and without significant fibrosis).
COPE-28 Ga-Gb Ga-Gc Ga-Gd Gb-Gc Gb-Gd Gc-Gd

p (da) p (da) p (da) p (da) p (da) p (da)

Active coping 0.002 0.92 0.54 0.56 <0.001 0.56

(0.402) S (0.142) N (-0.152) N (-0.266) S (-0.567) M (-0.303) S

Planning 0.82 0.74 0.17 0.46 0.03 1.00

(0.093) N (-0.219) S (-0.239) S (-0.322) S (-0.343) S (-0.020) N

Instrumental support 0.41 0.45 0.97 0.91 0.24 0.33

(0.172) N (0.328) S (-0.049) N (0.154) N (-0.216) S (-0.368) S

Emotional support 0.91 0.95 0.49 1.00 0.19 0.58

(0.060) N (0.113) N (-0.166) N (0.042) N (-0.236) S (-0.284) S

Self-distraction 0.93 0.89 0.22 0.68 0.58 0.17

(-0.070) N (0.120) N (-0.226) S (0.198) N (-0.151) N (-0.386) S

Venting 0.97 0.91 0.98 0.81 0.87 0.97

(-0.048) N (0.150) N (0.049) N (0.196) N (0.097) N (-0.101) N

74
 Disengagement 0.02 0.68 0.08 1.00 <0.001 0.21

(-0.314) S (-0.254) S (0.274) S (0.046) N (0.589) M (0.511) M

Positive reframing 0.002 0.76 1.00 0.79 0.008 0.83

(0.396) S (0.192) N (0.020) N (-0.179) N (-0.378) S (-0.175) N

Denial 0.008 0.94 0.91 0.77 0.002 0.84

(-0.367) S (-0.135) N (0.082) N (0.209) S (0.436) S (0.204) S

Acceptance 0.005 0.75 0.19 0.86 <0.001 0.22

(0.362) S (0.218) S (-0.228) S (-0.152) N (-0.586) M (-0.449) S

Religion 0.49 0.94 0.65 1.00 1.00 1.00

(-0.164) N (-0.127) N (-0.135) N (0.044) N (0.025) N (-0.017) N

Substance use 0.97 0.95 0.76 0.99 0.95 1.00

(0.000) N (0.000) N (0.000) N (0.000) N (0.000) N (0.000) N

Humor 0.04 0.84 0.99 0.94 0.03 0.77

(0.294) S (0.170) N (-0.037) N (-0.128) N (-0.343) S (-0.215) S

Self-blame 0.07 1.00 0.09 0.88 0.005 0.48

(-0.127) N (0.000) N (0.281) S (0.135) N (0.387) S (0.302) S

Tukey’s honestly significant difference or Games–Howell for post hoc multiple comparisons was applied
depending on whether or not they met the assumption of homoscedasticity.
Ga, no-NASH without significant fibrosis; Gb, NASH with significant fibrosis; Gc, no-NASH with significant
fibrosis; Gd, NASH without significant fibrosis; COPE-28, Brief COPE.
a
Effect sizes: N, null; S, small; M, medium.

Histological and Biopsychosocial Predictors of QoL in NAFLD Patients

A binary logistic regression was performed to evaluate the effect of the histological (steatosis,
lobular inflammation, hepatocellular ballooning, and fibrosis) and biopsychosocial (sex, age,
obesity, physical and mental health-related QoL, anxiety and depressive symptoms, coping
strategies, and perceived social support) variables on the disease-specific QoL of NAFLD
patients. The logistic regression model was statistically significant (χ2 = 367.256, p < 0.001).
The model explained 70.1% (Nagelkerke’s R2) of the variance in QoL, with an accuracy index
of 0.852. Sensitivity was 86.6% and specificity was 83.7%, while the positive and negative

75
 predictive values were 0.841 and 0.861, respectively. Of all predictor variables, only fibrosis,
sex, total depression (BDI-II), PCS (SF-12), total anxiety (HADS), and MCS (SF-12) were
independently associated with total CLDQNAFLD. On the one hand, a significant inverse
association was found between significant fibrosis (OR = 0.500, 95% CI = 0.253–0.987, p =
0.04), female sex (OR = 0.500, 95% CI = 0.254–0.981, p = 0.04), total depression (OR =
0.758, 95% CI = 0.661–0.869, p < 0.001), and total anxiety (OR=0.858, 95% CI=0.758–0.971,
p = 0.01) and QoL (Table 11). On the other hand, a significant direct association was found
between PCS (OR = 1.174, 95% CI = 1.123–1.227, p < 0.001) and MCS (OR = 1.073, 95%
CI = 1.022–1.125, p = 0.004) and QoL (Table 11).

Table 11. Binary logistic regression analysis with total CLDQ-NAFLD as the dependent variable.
Variables Total CLDQ-NAFLD

Coefficient SE AUC (CI) P OR 95% CI

Lower Upper

Significant fibrosis -0.693 0.347 0.616 (0.566-0.666) 0.04 0.500 0.253 0.987

Sex -0.694 0.344 0.614 (0.564-0.664) 0.04 0.500 0.254 0.981

Total depression BDI-II -0.277 0.070 0.887 (0.858-0.916) <0.001 0.758 0.661 0.869

PCS 0.160 0.023 0.789 (0.747-0.831) <0.001 1.174 1.123 1.227

Total anxiety HADS -0.154 0.063 0.785 (0.745-0.825) 0.01 0.858 0.758 0.971

MCS 0.070 0.02 0.768 (0.724-0.811) 0.004 1.073 1.022 1.125

SE, standard error; AUC, area under the ROC curve; OR, odds ratio; CI, confidence interval; PCS, physical component
summary; MCS, mental component summary; CLDQ-NAFLD, Chronic Liver Disease Questionnaire - Non-alcoholic
Fatty Liver Disease; BDI-II, Beck Depression Inventory - II; HADS, Hospital Anxiety and Depression Scale.

Discussion

This study analyzed the differences in QoL, mental health, and coping strategies in NAFLD
patients based on factors such as social support and the severity of liver damage (NASH and
fibrosis). We also analyzed whether histological and biopsychosocial variables could predict
the QoL of these patients. There were no important sociodemographic differences between
the groups compared, except in the age, which was higher in patients with significant fibrosis
than in those without significant fibrosis. This finding coincides with other studies (Gómez-

76
de-la-Cuesta et al., 2018; Klisic et al., 2019) which had already noted the relationship between
older age and the presence of significant or advanced fibrosis.
An interaction between NASH and social support was found in vitality, activity, anxiety,
and denial. Among patients with NASH, those who reported low perceived social support
showed less vitality and activity, greater anxiety, and more use of denial. This coincides with
the results of a previous study done in patients with hepatitis C, which found a relationship
between low levels of social support and more anxiety symptoms, as well as worse physical
QoL (Blasiole et al. 2006). However, there were hardly any differences depending on social
support in patients without NASH, except in vitality, which was higher in participants with
high perceived social support.
When patients with low and high social support were compared, regardless of whether they
had NASH or not, the first had poorer QoL and higher scores in anxiety and depressive
symptoms, and more maladaptive coping, due to less use of strategies such as active coping,
planning, using support, positive reframing, or acceptance. This ratifies the role of social
support as a modulating agent of QoL, mental health, and coping strategies (De la Revilla &
Fleitas, 1991). Furthermore, low social support could be considered a major risk factor in
NAFLD, especially when the disease progresses toward NASH and fibrosis. Therefore, it is
fundamental to promote the creation of support networks like self-help groups because of
their positive results in patient health, as already demonstrated in cancer (Payne et al., 2019),
multiple sclerosis (Kasser et al., 2018), or liver transplant candidate groups (Swanson et al.,
2018).
Moreover, patients with significant fibrosis had worse QoL in comparison with those
without significant fibrosis and with the Spanish general population. This finding coincides
with the study by David et al. (2009), as it confirms the significant effect of fibrosis on QoL.
In agreement with previous studies, the impact on QoL was mainly physical (Assimakopoulos
et al., 2018; Golabi et al., 2016; Sayiner et al., 2016; Younossi et al., 2016). Patients with
significant fibrosis had particularly more impairment in physical functioning, role-physical,
PCS, activity, emotional, fatigue, systemic symptoms, worry, and total CLDQ-NAFLD. This
may be partially explained by the symptomatology associated with NAFLD, as problems
affecting the patient’s functionality, such as fatigue (Golabi et al., 2016), daytime somnolence
(Newton et al., 2008), and cognitive dysfunction (Elliott et al., 2013), especially in the more
advanced stages. These results agree with other studies comparing the QoL of NAFLD
patients with that of the healthy population (David et al., 2009; Golabi et al., 2016; Sayiner et
al., 2016). We therefore suggest fibrosis as a determining factor in these differences, a
77
conclusion confirmed by the results of the binary logistic regression analysis. Of all the
variables analyzed for liver histology, fibrosis was the only one independently associated with
QoL.
The relevance of sex in the QoL of NAFLD patients was also analyzed, with the results
showing that female sex, along with the presence of significant fibrosis, was the main
independent predictor of a worse QoL in these patients. Therefore, our study coincides with
previous research, highlighting the greater vulnerability of the female sex to the impact caused
by NAFLD (Afendy et al., 2009; Tapper & Lai, 2016). Binary logistic regression analysis
also revealed that the severity of anxiety and depressive symptoms predicted the QoL of the
participants, in line with Huang et al. (Huang et al., 2017), who found that worse mental health
was associated with a reduced QoL in chronic liver disease patients. Physical and mental
health-related QoL, measured with the generic SF-12, also predicted disease-specific QoL
measured with CLDQ-NAFLD, an instrument specific to NAFLD patients. As quality of life
is one of the core goals of intervention in these patients, the model’s predictive variables
should be given special consideration in the future. Female patients with significant fibrosis,
stronger anxiety and depressive symptoms, and worse physical and mental health-related QoL
are more likely to have a greater impact on their health and well-being. These patients would
therefore require closer attention in the design of multidisciplinary NAFLD management
strategies. Lastly, fibrosis was also associated with worse mental health and more maladaptive
coping strategies. NASH patients with significant fibrosis scored higher in depression than
patients without significant fibrosis, whether or not they had NASH. Patients with significant
fibrosis also employed maladaptive strategies, such as disengagement, to a greater extent in
comparison with NASH patients without significant fibrosis, and fewer adaptive strategies
such as active coping or acceptance. The results for mental health confirm the relationship
between fibrosis and depression already noted previously by Weinstein et al. (2011), Youssef
et al. (2013), and Tomeno et al. (2015) and therefore contradict the conclusion of Kim et al.
(2019).
In brief, the main findings of this study verified that there are differences in the QoL,
mental health, and coping strategies of NAFLD patients depending on the perceived social
support and histological fibrosis and confirm that the relevant variables predicting a worse
disease-specific QoL in these patients are significant fibrosis, female sex, greater anxiety and
depressive symptoms, and worse physical and mental health-related QoL. These results are
relevant because such patients need to follow certain interventions based on lifestyle changes
including diet, physical activity, and exercise to promote NASH resolution and fibrosis
78
regression when losing weight. However, the probability of successful adherence to these
guidelines is certainly low (Serfaty, 2018). Indeed, in the study by Vilar-Gómez et al. (2015),
just 10% of patients lost 10% of body weight in spite of including behavioral meeting
bimonthly. Keeping in mind the influence that variables such as QoL (Silavanich et al., 2019),
mental health (Dos Santos et al., 2019), coping strategies (Corallo et al., 2019), or perceived
social support (Belaiche et al., 2017) exert on therapeutic adherence, the biopsychosocial risk
factors found in this study could be associated with a negative impact on adherence to
intervention guidelines in NAFLD patients.
A structured psychological intervention could therefore improve therapeutic adherence
and, as a consequence, the patient’s clinical evolution (Moscatiello et al., 2011), requiring
special attention those patients with a low social support, significant fibrosis, or of the female
sex due to their greater tendency to show a higher-risk biopsychosocial profile. We therefore
recommend the inclusion of cognitive–behavioral treatment in NAFLD interventions
(Funuyet-Salas et al., 2020) with techniques such as: psychoeducation focusing on NAFLD
and how it progresses, as patients are generally unaware of their disease and the long-term
consequences to their health (Cook et al., 2019); cognitive restructuring to intervene on
unrealistic expectations related to weight loss, significantly linked to quitting therapy
(Fabricatore, 2007); problem-solving strategies to cope with obstacles to weight loss or
maintenance (Bellentani et al., 2008); reinforcing alternative behaviors to eating without
being hungry, for instance using relaxation or distraction techniques (Bellentani et al., 2008);
using self-report questionnaires about weight, physical activity, and diet (Cooper et al., 2003);
setting commitments and realistic personal goals about weight loss or physical activity
(Fabricatore, 2007); and controlling stimuli, for example, keeping high-fat foods out of reach
and placing those recommended in an accessible place at home (Fabricatore, 2007).
Our study showed several limitations. Firstly, the possible collinearity of fibrosis and age.
Secondly, the cross-sectional design of the current study did not allow us to analyze changes
in histological features over time and their impact on the psychological profile. Thirdly, we
did not analyze how self-efficacy, an important variable in chronic liver diseases, could
influence the QoL and mental health of NAFLD patients (Gutteling et al., 2010). Lastly,
analysis of the impact of other pathologies such as type 2 diabetes, arterial hypertension,
hypercholesterolemia, hypertriglyceridemia, cardiovascular disease, thyroid disease, or
obstructive sleep apnea syndrome on the biopsychosocial profile of NAFLD patients would
be of interest for future research. Nevertheless, the large sample of consecutive patients from
real clinical practice in Spain may be considered a major strength of this study.
79
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4.3. Tercer trabajo titulado “Health-related quality of life in non-alcoholic fatty liver
disease: A cross-cultural study between Spain and the United Kingdom”

Abstract

It is unclear what biopsychosocial factors influence the impact of NAFLD on health-related

quality of life (HRQoL), and if these factors are equally important predictors between
different nationalities. Therefore, HRQoL (CLDQ) was measure in both Southern European
(Spain, n = 513) and Northern European (United Kingdom -UK-, n = 224) cohorts of patients
with NAFLD. For each cohort participant data were recorded on histological grade of
steatohepatitis, stage of fibrosis and biopsychosocial variables. Regression analysis was used
to explore which of these variables predicted HRQoL. Moderated mediation models were
conducted using SPSS PROCESS v3.5 macro. Participants with severe fibrosis reported more
fatigue, systemic symptoms and worry, and lower HRQoL than those with none/mild fibrosis,
regardless of place of origin. In addition, body mass index (BMI) and gender were found to
be significant predictors of HRQoL in both Spanish and UK participants. Female gender was
associated with worse emotional function, higher BMI and more fatigue, which predicted
lower participants' HRQoL. Lastly, UK participants showed more systemic symptoms and
worry than Spanish participants, regardless of liver severity. In general, the negative impact
of moderators on HRQoL was reported to a greater degree in UK than in Spanish participants.
In conclusion, UK participants showed a greater impairment in HRQoL than Spanish
participants. Higher fibrosis stage predicted lower HRQoL, mainly in the Spanish cohort.
Factors such as female gender or higher BMI contributed to the impact on HRQoL in both
cohorts of patients and should be considered in future multinational intervention studies in
NAFLD. Keywords: NAFLD; quality of life; liver fibrosis; NASH.

Introduction

The number of people diagnosed with chronic non-communicable diseases around the world
continues to rise (Wang & Wang, 2020). Among these is non-alcoholic fatty liver disease
(NAFLD), which in the 21st century has become one of the world’s main causes of liver
disease and liver transplant. NAFLD includes a spectrum of metabolic liver pathologies which
go from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH), accumulating
fibrosis, cirrhosis and hepatocarcinoma. NAFLD is considered the liver manifestation of

86
metabolic syndrome with obesity identified as its main and most common risk factor, with a
close two-way relationship between the two pathologies (Anstee et al., 2019).
With respect to the clinical impact of NAFLD, fibrosis has been established as an important
predictor of patient mortality (Taylor et al., 2020). Predictive models for prognosis and
survival, such as the MELD (Model for End-Stage Liver Disease) score, have been developed.
This scale, based on International Normalized Ratio (INR) for prothrombin time and serum
bilirubin and creatinine levels, is a reliable measure of mortality risk in patients with end-
stage liver disease. Its use as a measure of liver function is generalizable to patient populations
of diverse etiologies and wide ranges of severity (Kamath et al., 2001).
However, until recently the impact of NAFLD from the patient’s viewpoint had not been
assessed. The increasing use of patient-reported outcomes (PROs) allows attention not just on
the prevention and treatment of disease symptoms, but on the individual’s physical, mental
and social functioning and well-being - this is referred to as health-related quality of life
(HRQoL) (Afendy et al., 2009). Several PRO measures have been used to assess the impact
of NAFLD from a patient's point of view on their HRQoL and illness experience, most notably
the Chronic Liver Disease Questionnaire (CLDQ). CLDQ is a liver disease-specific
instrument which evaluates changes in physical and mental HRQoL due to liver disease. It
addresses problems commonly reported by these patients such as fatigue or physical
symptoms, as well as the mental or emotional impact of the disease. Higher scores indicate
better HRQoL (Younossi et al., 1999). In fact, it has been shown that NAFLD impacts
HRQOL mainly through physical health and activities of daily living (Afendy et al., 2009).
Some issues contributing to reduced HRQoL are fatigue or lack of energy, daytime
somnolence, abdominal pain or general pain (McSweeney et al., 2020). NAFLD is also
associated with significant mood disturbance, especially an increase in depression symptoms,
which may also explain the impairment of the patient's well-being (Weinstein et al., 2011).
The evidence to date on the effect of NASH and fibrosis on the HRQoL of NAFLD patients
is inconsistent (David et al., 2009; Funuyet-Salas et al., 2020a; Huber et al., 2019; Sayiner et
al., 2016; Taylor et al., 2020). NASH has been associated with worse HRQoL, primarily in
physical aspects of patients’ well-being (Younossi et al., 2019). NASH has even been linked
to an overall impairment in HRQoL in a recent study using symptom elicitation and cognitive
debriefing interviews (Doward et al., 2021). Although when controlling for other factors there
was no evidence of an association (David et al., 2009; Funuyet-Salas et al., 2020a). The
evidence for fibrosis being a predictor of HRQoL in NAFLD is mixed. Some researchers have
reported evidence of an inverse relationship between the severity of fibrosis and HRQoL
87
(David et al., 2009; Funuyet-Salas et al., 2020a) whilst others have found no evidence of an
association (Huber et al., 2019; Taylor et al., 2020). Obesity has likewise been reported as
reducing HRQoL (Funuyet-Salas et al., 2021; Huber et al., 2019; Ozawa et al., 2021;
Younossi et al., 2017). Although other studies have not provided any evidence of such a
relationship (Chawla et al., 2016; Sayiner et al., 2016). There is more consistency with respect
to impact of gender on HRQoL for those with NAFLD with females with NAFLD reporting
a greater decrement on physical and mental functioning compared with males (Afendy et al.,
2009; David et al., 2009; Funuyet-Salas et al., 2020a; Huber et al., 2019). Lastly, the influence
on HRQoL of other sociodemographic factors such as age (Afendy et al., 2009; Chawla et al.,
2016; David et al., 2009), education (David et al., 2009; Funuyet-Salas et al., 2020a; Ozawa
et al., 2021) or employment status (David et al., 2009; Funuyet-Salas et al., 2020a; Stepanova
et al., 2017) have also been investigated, but there is no conclusive evidence of an impact to
date.
Cross-cultural research has been widely recommended in the field of health care, since the
illness experience may vary according to the socio-cultural context in which the person has
developed (Guitart, 2008). It would be important to understand how the impact of NAFLD on
patients' HRQoL varies according to their place of origin, especially in order to consider these
differences in future multinational intervention and treatment-effectiveness studies in
NAFLD. Only one study has compared the HRQoL of NAFLD patients in different European
countries (Huber et al., 2019). This study compared the United Kingdom (UK) and Germany
and found a substantial burden of symptoms in patients, especially in UK, with variables such
as age, sex or lobular inflammation correlating with lower HRQoL. Given the limited data
currently available, and that biopsychosocial factors influencing and predicting HRQoL in
NAFLD patients remain unclear, the current study seeks to further explore whether there are
geographic variations in how NAFLD affects HRQoL. This paper therefore compares two
patient cohorts: one from Spain and one from the UK. Specifically, we addressed three
primary objectives: 1) to compare HRQoL of NAFLD patients based on place of origin (Spain
or UK) and liver severity (absence or presence of NASH, and fibrosis stage); 2) to identify
what histological and biopsychosocial variables predict HRQoL in Spanish and UK patient
cohorts; and 3) to analyse what biopsychosocial variables mediated or moderated in HRQoL
predictive models.
Methods

Participants and Study Sample

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The sample comprised 737 biopsy-proven NAFLD patients. 513 participants were from Spain
(HEPAmet Registry) and 224 from UK (the LITMUS Study Cohort of the European NAFLD
Registry) (Hardy et al., 2020). Full details of participant sociodemographic characteristics
may be seen in Tables S1 and S2.
All participants gave informed consent for participation in the study, which was approved
by the Ethics Committee of the Virgen del Rocío University Hospital of Seville for the
Spanish cohort and NHS HRA North East –Tyne & Wear South Research Ethics Committee
for the UK cohort (see Hardy et al, 2020). The study was carried out in compliance with the
Helsinki Declaration of 1975.
The 737 participants were consecutive prospectively recruited from 12 Spanish hospitals
and 11 UK hospitals. All the participants spoke the local language (Spanish or English) as
their native tongue, and were evaluated with a psychosocial interview and the CLDQ. To be
included in the study the participants had to be 18 years of age, give their informed consent
for participating, have been diagnosed by liver biopsy as having NAFLD, show adequate
understanding of the study evaluation instrument and not have a severe or disabling
psychopathological condition.
The participants were classified by place of origin (G1 = Spain, G2 = UK), and by
descriptors of severity of disease: NASH (G3 = absence, G4 = presence) and fibrosis (G5 =
none/mild, G6 = moderate, G7 = severe) (Fig. 1). NASH was determined by a value of activity
greater than or equal to 2 as the SAF (Steatosis, Activity and Fibrosis) score (Bedossa et al.,
2012). Fibrosis was categorized as none/mild (stages F0 and F1), moderate (F2 and F3) or
severe (F4, cirrhosis). The MELD score for each participant was calculated as a marker of
hepatic function. This score was calculated as a measure of severity of liver impairment based
on three laboratory parameters: INR for prothrombin time and serum bilirubin and creatinine
(Kamath et al., 2001). Other factors used to describe the participants were age, body mass
index (BMI), gender (male or female), education (primary, secondary or higher education)
and employment status (actively employed or not actively employed).

Table S1. Comparison of sociodemogaphic and clinic variables by place of origin (Spain and
UK).

89
 Place of origin Intergroup Effect sizes
comparisons
Spain UK
(G1) (G2)
n=513 n=224
M (SD) M (SD) t (p) Cohen’s d
Age 55.04 55.31 t(1,735) = -0.281 -0.022 N
(11.83) (12.34) (0.779)
BMI 30.62 34.85 t(1,405.762) = -9.681 -0.793 M
(5.12) (5.54) (<0.001)
MELD score 7.11 6.93 t(1,563) = 1.239 0.110 N
(1.81) (1.45) (0.216)
% % χ2 (p) Cohen’s w
Gender χ (1)=2.246
2
-0.055 N
- Male 58.9 64.7 (0.134)
- Female 41.1 35.3
Education χ2(1)=26.876 0.194 S
- Primary/Secondary 73.5 53.3 (<0.001)
- Higher 26.5 46.7
Employment χ2(1)=7.510 -0.102 S
- Actively employed 47.6 58.8 (0.006)
- Not actively employed 52.4 41.2
Effect sizes: N, null; S, small; M, medium. The t-test for independent samples was applied for
continuous variables. Pearson’s Chi-square was applied for categorical variables.

Table S2. Comparison of sociodemogaphic and clinic variables by NASH (absence and presence) and
fibrosis (none/mild, moderate and severe).
NASH Intergroup Effect sizes
comparisons
Absence Presence
(G3) (G4)
n=331 n=406
M (SD) M (SD) t (p) Cohen’s d
Age 54.30 55.80 t(1,375) = -1.692 -0.125 N
(12.38) (11.61) (0.091)
BMI 30.69 32.98 t(1,704) = -5.515 -0.417 S
(5.50) (5.49) (<0.001)
MELD score 7.06 7.02 t(1,563) = 0.288 0.023 N
(1.79) (1.60) (0.773)
% % χ2 (p) Cohen’s w
Gender χ (1)=0.116
2
0.013 N
- Male 61.3 60.1 (0.734)
- Female 38.7 39.9
Education χ2(2)=15.399 0.147 S
- Primary/Secondary 71.6 64.7 (<0.001)
- Higher 28.4 35.3
Employment χ2(1)=1.530 0.046 N
- Actively employed 53.4 48.7 (0.216)
- Not actively employed 46.6 51.3
Fibrosis Intergroup Effect sizes
comparisons

90
 None/mild Moderate Severe
(G5) (G6) (G7)
n=370 n=286 n=81
M (SD) M (SD) M (SD) U/F (p) Cohen’s d
Age 52.60 56.63 61.35 U(2,245.602) =
(12.48) (11.08) (9.39) 26.975 (<0.001)
G5-Gb6 (<0.001) -0.341 S
G5-Gb7 (<0.001) -0.792 M
G6-Gb7 (0.001) -0.459 S
BMI 30.72 33.33 32.80 F(2,703) =
(5.27) (5.64) (5.83) 18.622 (<0.001)
G5-Gb6 (<0.001) -0.478 S
G5-Gb7 (0.007) -0.374 S
G6-Gb7 (0.729) 0.092 N
MELD score 6.89 6.96 7.78 U(2,182.761) =
(1.72) (1.37) (2.23) 5.011 (0.008)
G5-Gb6 (0.883) -0.045 N
G5-Gb7 (0.006) -0.447 S
G6-Gb7 (0.010) -0.443 S
% % % χ2 (p) Cohen’s w
Gender χ2(2)=2.437 0.058 N
- Male 62.4 60.5 53.1 (0.296)
- Female 37.6 39.5 46.9
Education χ2(4)=5.063 0.084 N
- Primary/Secondary 67.9 66.5 72.2 (0.281)
- Higher 32.1 33.5 27.8
Employment χ2(2)=21.036 0.170 S
- Actively employed 59.0 43.9 36.8 (<0.001)
- Not actively employed 41.0 56.1 63.2
Effect sizes: N, null; S, small; M, medium. The t-test for independent samples or one-way ANOVA (Welch´s
U / Snedecor's F) with Games-Howell / Tukey HSD post-hoc pairwise analysis were applied for continuous
variables. Pearson’s Chi-square was applied for categorical variables.

Figure 1. Participant selection for the study.

91
Health-related Quality of Life Assessment

HRQoL was measured using the CLDQ (Younossi et al., 1999). This instrument includes 29
items with seven-point Likert-type scales on the following HRQoL dimensions: abdominal
symptoms, activity, emotional function, fatigue, systemic symptoms, and worry. It also
provides a total score corresponding to the mean of the scores on each of the dimensions. All
scores range from 0 (worst HRQoL) to 7 (best HRQoL). As for the internal consistency of the
scale used, in the total sample, the Cronbach’s alpha (Cronbach, 1951) was 0.95 for the total
score and ranged from 0.65 to 0.89 for the different dimensions. Within the Spanish cohort
the alpha was 0.92 for the total score and ranged from 0.78 to 0.93 for the different
dimensions. Within the UK cohort it was 0.96 for the total score and ranged from 0.78 and
0.93 for the different dimensions.

Statistical Analysis

The following were used for between-group comparisons of the sociodemographic and
clinical variables: an independent samples t-test or one-way ANOVA (Welch´s U or
Snedecor's F) with Games-Howell or Tukey HSD post hoc pairwise analysis for continuous
variables (age, body mass index and MELD score), and Pearson’s chi-square test for
categorical variables (gender, education and employment status). Categorical variables were
dichotomised into: male or female gender, primary/secondary or higher education, and active
or non-active employment status. Cohen’s d (for continuous variables) and w (for categorical

92
variables) were computed as effect size indexes. Effect sizes are defined as: null (d < 0.2; w
< 0.1), small (d > 0.2; w > 0.1), medium (d > 0.5; w > 0.3) or large (d > 0.8; w > 0.5) (Cohen,
1988).
Missing values were imputed with SPSS Statistics v.25. Missing values were found for
MELD score, education and employment status, but were less than 5% of the total data (1.1,
3.4 and 1.8%, respectively). Therefore, these values were assumed to be missing at random.
A 2x2 factorial ANOVA (Snedecor’s F) was used to analyse the influence of place of
origin (Spain or UK) and NASH (absence or presence) on HRQoL. To explore the influence
of place of origin (Spain or UK) and fibrosis (none/mild, moderate or severe), a 2x3 factorial
ANOVA (Snedecor’s F) was applied.
A binary logistic regression analysis was used to determine the contribution of histological
and biopsychosocial factors to HRQoL in both Spanish and UK participants separately.
Nagelkerke’s R2/AIC/BIC was calculated as a goodness-of-fit measure. The accuracy index
was calculated to check the percentage of cases correctly classified by the model. The
independent variables in both regression models were NASH (absence or presence, which
implied an activity score higher than or equal to 2 on the SAF score), fibrosis (none/mild
fibrosis vs. moderate or severe fibrosis), MELD score, BMI, gender (male or female), age,
education (primary/secondary education only vs. higher education), and employment status
(actively employed vs not actively employed). The reference categories for each variable were
NASH, moderate or severe fibrosis, females, primary/secondary education, and not actively
employed.
The dependent variable in both models was the total score on the CLDQ questionnaire
(HRQoL). This score was arranged in ascending order and the cumulative percentages were
used to divide both samples at the 50th percentile, forming two groups, one with better and the
other with a worse HRQoL. The results of the binary logistic regression were presented as
odds ratios (OR) with 95% confidence intervals. Those with a p-value below 0.05 were
considered statistically significant. All data were analysed with SPSS Statistics v.25.
In order to identify what biopsychosocial variables mediated or moderated in HRQoL in
both patient cohorts, mediation and moderated mediation models were applied using the SPSS
PROCESS macro v3.5 (Hayes & Rockwood, 2017). The CLDQ emotional function
dimension was analysed to determine the role of mood in participants' perceived HRQoL.
Fatigue was included as it is the main symptom associated with NAFLD (Cook et al., 2019)
and because of its determinant role in our study, as demonstrated by the interactive effects
found in the first objective. BMI and gender were also included as predictors of HRQoL,
93
according to the results of our second objective. Thus, emotional function, BMI and fatigue
were used as the mediators in the relationship between gender and HRQoL, applying Model
6. This is a mediation model in which the mediation effect of three variables on the
relationship between the independent variable and the dependent one can be analysed (Hayes,
2018). Bootstrapping with 5000 resamples was used to test the estimated indirect effects.
Mediation was considered significant if the 95% confidence interval (CI) of the indirect
effects did not include 0. In continuation, Model 87 was applied. This is a moderated
mediation model in which the moderating effect of one variable on a model with three
mediating variables can be analysed (Hayes, 2018). 5000 bootstrap resamples were used to
analyse the effect of moderated mediation, that is, whether the place of origin moderated the
indirect effects of gender on the HRQoL through emotional function, BMI and fatigue.
Moderation significance was tested and the conditional effect of the predictor on the criterion
variable was calculated for each value of the moderator by generating its confidence interval
(Hayes & Matthes, 2009). Those with a p-value below 0.05 were considered statistically
significant.

Results

Sociodemographic and Clinic Variables

There were no important between-group differences (null or small effect sizes) in most of the
sociodemographic and clinical variables (age, gender, education, employment status, BMI
and MELD score), except that UK participants (G2, M = 34.85, SD = 5.54) had a higher BMI
than Spanish participants (G1, M = 30.62, SD = 5.12) (p < 0.001, d = -0.793) (Table S1).
Participants with severe fibrosis (G7, M = 61.35, SD = 9.39) were older than those with
none/mild fibrosis (G5, M = 52.60, SD = 12.48) (p < 0.001, d = -0.792) (Table S2).

Objective 1. Influence of Place of Origin, NASH and Fibrosis on Health-related Quality of

Life

Interactive Effects

Table 1 shows HRQoL results by place of origin and NASH, while Table 2 shows HRQoL
results by place of origin and fibrosis. The analyses provided evidence for two interactive
effects: fatigue (p = 0.003, Table 2) and HRQoL (p = 0.039, Table 2). Simple effects showed
important effect sizes (medium or large) in Spanish participants (G1) (Table 3 and Fig. 2). In
this respect, Spanish participants had more fatigue and lower HRQoL when they had severe
fibrosis compared to those with moderate (fatigue, p = 0.001, d = 0.568; HRQoL, p = 0.001,

94
 d = 0.612) or none/mild fibrosis (fatigue, p < 0.001, d = 1.095; HRQoL, p < 0.001, d = 1.077).
Spanish participants with moderate fibrosis also suffered more fatigue than those with
none/mild fibrosis (p < 0.001, d = 0.552).
Simple effects also showed important effect sizes (medium or large) in participants with
none/mild fibrosis (G5) (Table 3 and Fig. 2). In this sense, participants with none/mild fibrosis
suffered more fatigue (p < 0.001, d = 0.566) and lower HRQoL (p < 0.001, d = 0.550) if they
were from the UK compared to Spanish participants.

Table 1. Health-related quality of life of NAFLD patients by place of origin (Spain and UK) and NASH
(absence and presence).

CLDQ Place of origin NASH Main effects Interaction

M1 (SD) M1 (SD) effects

Spain UK Absence Presence Place of NASH F(1,733)

(G1) (G2) (G3) (G4) origin F(1,733) p
n=513 n=224 n=331 n=406 F(1,733) p (d)
p (d)
Abdominal 5.58 5.42 5.59 5.41 1.36 1.50 0.00
symptoms (1.58) (1.80) (2.18) (1.61) 0.243 0.221 (0.967)
(0.094 N) (0.094 N)
Activity 5.69 5.60 5.78 5.52 0.55 4.27 0.18
(1.36) (1.65) (1.82) (1.41) 0.460 0.039 (0.675)
(-0.007 N) (0.160 N)
Emotional 5.71 5.12 5.50 5.33 29.74 2.46 0.01
function (1.13) (1.50) (1.64) (1.21) <0.001 0.117 (0.907)
(0.444 S) (0.118 N)
Fatigue 5.31 4.87 5.27 4.92 10.75 7.05 0.00
(1.36) (1.80) (2.00) (1.41) 0.001 0.008 (0.964)
(0.276 S) (0.202 S)
Systemic 5.88 5.28 5.71 5.45 37.85 7.43 0.10
symptoms (1.13) (1.20) (1.45) (1.01) <0.001 0.007 (0.753)
(0.515 M) (0.208 S)
Worry 6.11 5.07 5.64 5.54 91.54 0.72 1.66
(1.13) (1.35) (1.64) (1.21) <0.001 0.397 (0.198)
(0.835 L) (0.069 N)
HRQoL 5.71 5.23 5.58 5.36 26.76 5.36 0.00
(1.13) (1.20) (1.45) (1.01) <0.001 0.021 (0.958)
(0.412 S) (0.176 N)
1
Higher scores show more health-related quality of life. Effect sizes: N, null; S, small; M, medium; L, large.
A 2×2 factorial ANOVA (Snedecor’s F) was applied.

95
Table 2. Health-related quality of life of NAFLD patients by place of origin (Spain and UK) and fibrosis (none/mild,
moderate and severe).
CLDQ Place of origin Fibrosis Main effects Interacti
M1 (SD) M1 (SD) on
effects
Spain UK None/mild Moderate Severe Place of Fibrosis F(1,733)
(G1) (G2) (G5) (G6) (G7) origin F(2,731) p
n=513 n=224 n=370 n=286 n=81 F(1,731) p (d)
p (d)
Abdominal 5.26 5.36 5.68 5.37 4.88 0.39 7.66 2.16
symptoms (2.04) (1.80) (2.11) (1.52) (1.53) 0.531 0.001 (0.116)
(-0.052 N) G5-Gb6
0.002 (0.168 N)
G5-Gb7
<0.001 (0.434 S)
G6-Gb7
0.028 (0.321 S)
Activity 5.42 5.55 5.89 5.45 5.12 1.01 10.93 1.35
(1.81) (1.50) (1.92) (1.35) (1.35) 0.315 <0.001 (0.260)
(-0.078 N) G5-Gb6
<0.001 (0.265 S)
G5-Gb7
<0.001 (0.464 S)
G6-Gb7
0.112 (0.244 S)
Emotional 5.49 5.12 5.64 5.26 5.01 10.03 9.33 1.89
function (1.58) (1.35) (1.73) (1.18) (1.17) 0.002 <0.001 (0.152)
(0.252 S) G5-Gb6
<0.001 (0.257 S)
G5-Gb7
<0.001 (0.427 S)
G6-Gb7
0.186 (0.213 S)
Fatigue 4.90 4.73 5.28 4.87 4.31 1.58 13.43 5.84
(2.04) (1.65) (2.11) (1.35) (1.44) 0.209 <0.001 (0.003)
(0.092 N) G5-Gb6
<0.001 (0.231 S)
G5-Gb7
<0.001 (0.537 M)
G6-Gb7
0.004 (0.401 S)
Systemic 5.65 5.18 5.74 5.42 5.08 20.72 12.05 1.61
symptoms (1.36) (1.20) (1.54) (1.01) (1.08) <0.001 <0.001 (0.201)
(0.366 S) G5-Gb6
<0.001 (0.246 S)
G5-Gb7
<0.001 (0.496 S)
G6-Gb7
0.018 (0.325 S)
Worry 5.84 5.06 5.82 5.48 5.06 46.85 12.27 1.51
(1.58) (1.35) (1.73) (1.18) (1.17) <0.001 <0.001 (0.221)
(0.531 M) G5-Gb6
<0.001 (0.230 S)

96
 G5-Gb7
<0.001 (0.515 M)
G6-Gb7
0.010 (0.357 S)
HRQoL 5.43 5.17 5.67 5.31 4.91 7.09 17.32 3.25
(1.36) (1.20) (1.35) (1.01) (0.99) 0.008 <0.001 (0.039)
(0.203 S) G5-Gb6
<0.001 (0.302 S)
G5-Gb7
<0.001 (0.642 M)
G6-Gb7
0.004 (0.400 S)
1
Higher scores show more health-related quality of life. Effect sizes: N, null; S, small; M, medium. A 2×3 factorial
ANOVA (Snedecor’s F) was applied.

Table 3. Simple effects in fatigue and total health-related quality of life.

Spain UK
Fibrosis (G1) (G2)
n=513 n=224
p Cohen’s d p Cohen’s d
Fatigue
None/mild – Moderate <0.001 0.552 M 0.833 0.035 N
None/mild – Severe <0.001 1.095 L 0.204 0.265 S
Moderate – Severe 0.001 0.568 M 0.196 0.233 S
HRQoL
None/mild – Moderate <0.001 0.485 S 0.146 0.235 S
None/mild – Severe <0.001 1.077 L 0.046 0.430 S
Moderate – Severe 0.001 0.612 M 0.309 0.186 N
None/mild Moderate Severe
Place of origin (G5) (G6) (G7)
n=370 n=286 n=81
p Cohen’s d p Cohen’s d p Cohen’s
d
Fatigue
Spain - UK <0.001 0.566 M 0.617 0.065 N 0.241 -0.259 S
HRQoL
Spain - UK <0.001 0.550 M 0.008 0.305 S 0.631 -0.101 N
Effect sizes: N, null; S, small; M, medium; L, large.

Figure 2. Interactive effects of place of origin (Spain or UK) and fibrosis

(none/mild, moderate or severe) factors.

97
 Note. Analysis of the influence of place of origin and fibrosis on the health-related
quality of life of NAFLD patients showing interactive effects in fatigue (p = 0.003)
and HRQoL (p = 0.039). Scores vary from 1 to 7, higher scores showing better
health-related quality of life.

Health-related Quality of Life by Place of Origin

Concerning the main effects, considered those with important effect sizes (medium or large),
UK participants (G2) had more systemic symptoms (p < 0.001, d = 0.515) and worry (p <
0.001, d = 0.835) than Spanish participants (G1), regardless of absence or presence of NASH
(Table 1). UK participants (G2) were more worried (p < 0.001, d = 0.531) than Spanish
participants (G1), no matter what the level of fibrosis was.

Health-related Quality of Life by Liver Severity

Concerning the main effects, considered those with important effect sizes (medium or large),
participants with severe fibrosis (G7) were more fatigued (p < 0.001, d = 0.537), had more
systemic symptoms (p < 0.001, d = 0.496), more worry (p < 0.001, d = 0.515), and lower
HRQoL (p < 0.001, d = 0.642) than those with none/mild fibrosis (G5), regardless of place of
origin (Table 2).

Objective 2. Histological and Biopsychosocial Predictors of Health-related Quality of Life

A binary logistic regression was used to evaluate the effect of the histological (NASH, fibrosis
98
 and MELD score) and biopsychosocial (BMI, gender, age, education and employment status)
variables on HRQoL, both in Spanish (G1) and UK (G2) participants separately.

Spanish Cohort

For Spanish participants, HRQoL reduced as fibrosis (OR = 0.290, 95% CI = 0.165-0.507, p
< 0.001), MELD score (OR = 0.855, 95% CI = 0.744-0.982, p = 0.027) and BMI (OR = 0.921,
95% CI = 0.875-0.970, p = 0.002) increased. Lower HRQoL was also independently
associated with female gender (OR = 0.297, 95% CI = 0.176-0.501, p < 0.001) (Table 4).

UK Cohort

For UK participants, HRQoL reduced as BMI (OR = 0.942, 95% CI = 0.889-0.999, p = 0.047)
increased. Lower HRQoL was also independently associated with female gender (OR = 0.448,
95% CI = 0.219-0.915, p = 0.028), non-active employment status (OR = 0.336, 95% CI =
0.152-0.745, p = 0.007) and younger age (OR = 1.065, 95% CI = 1.029-1.102, p < 0.001)
(Table 4).

Table 4. Binary logistic regression analysis with health-related quality of life as the dependent variable.
Spain Coefficient SE AUC (CI) p OR 95% CI
Lower Upper
NASH 0.342 0.268 0.464 (0.414-0.514) 0.202 1.408 0.833 2.381
Fibrosis -1.239 0.286 0.639 (0.578-0.699) <0.001 0.290 0.165 0.507
MELD score -0.157 0.071 0.566 (0.504-0.628) 0.027 0.855 0.744 0.982
BMI -0.082 0.026 0.601 (0.540-0.663) 0.002 0.921 0.875 0.970
Gender -1.215 0.268 0.620 (0.559-0.681) <0.001 0.297 0.176 0.501
Age 0.014 0.013 0.450 (0.400-0.500) 0.251 1.015 0.990 1.040
Education 0.104 0.295 0.485 (0.435-0.535) 0.725 1.109 0.622 1.979
Employment -0.224 0.287 0.573 (0.511-0.635) 0.435 0.799 0.455 1.403
UK Coefficient SE AUC (CI) p OR 95% CI
Lower Upper
NASH -0.045 0.415 0.519 (0.436-0.601) 0.914 0.956 0.424 2.155
Fibrosis -0.403 0.426 0.524 (0.442-0.607) 0.344 0.668 0.290 1.541
MELD score -0.154 0.130 0.482 (0.399-0.564) 0.235 0.857 0.665 1.006
BMI -0.059 0.030 0.621 (0.541-0.701) 0.047 0.942 0.889 0.999
Gender -0.803 0.364 0.583 (0.501-0.665) 0.028 0.448 0.219 0.915
Age 0.063 0.017 0.614 (0.536-0.693) <0.001 1.065 1.029 1.102
Education 0.267 1.229 0.510 (0.430-0.591) 0.828 1.307 0.117 1.537
Employment -1.089 0.405 0.563 (0.481-0.645) 0.007 0.336 0.152 0.745
SE, standard error; AUC, area under the ROC curve; OR, odds ratio; CI, confidence interval.
The logistic regression model was statistically significant for both Spanish (χ2 = 63.453, p < 0.001) and UK (χ2 =
32.500, p < 0.001) participants.
Nagelkerke’s R2 was calculated as a goodness-of-fit measure. The model explained 23.6% of the variance in QoL
for the Spanish cohort, and 21.2% for the UK cohort.
For Spanish participants, the accuracy index was 0.702., therefore the model correctly classifies 70.2% of cases

99
overall. Sensitivity was 75.3% and specificity 64.7%, while positive and negative predictive values were 0.699
and 0.706, respectively. For UK participants, the accuracy index was 0.681, therefore the model correctly
classifies 68.1% of cases overall. Sensitivity was 69.5% and specificity 66.7%, while positive and negative
predictive values were 0.680 and 0.681, respectively.

Objective 3. Mediation and Moderated Mediation Analysis

Mediation Model

Fig. 3 and Table S3 show the relationships between the independent variable, the mediating
variables and the dependent variable in the mediation model. In this way, the indirect effects
of the emotional function, BMI and fatigue when mediating the relationship between gender
and HRQoL can be tested. There was evidence for the following relationships: emotional
function (effect = -0.200, p < 0.001); emotional function – BMI (effect = -0.007, p = 0.002);
emotional function – fatigue (effect = -0.165, p < 0.001); and emotional function – BMI –
fatigue (effect = -0.006, p < 0.001). Female gender therefore predicted worse emotional
function, which was associated with higher BMI, and this in turn with greater fatigue. All
these variables predicted a lower HRQoL in the participants, which was confirmed as the
bootstrapped 95% CI did not include 0. Mediation was partial, as the direct effect of gender
on HRQoL was significant after mediation analysis (effect = -0.079, p = 0.020).

Figure 3. Emotional function, body mass index and fatigue

mediate the relationship between gender and health-related
quality of life.

Note. The coefficients represent the indirect and direct effects

estimated. *p < 0.05; ***p < 0.001.

Table S3. Indirect effects of emotional function, body mass index and fatigue mediating
in the association between gender and health-related quality of life.
Indirect effect key Effect (BootSE) p Bootstrapped 95% CI
100
 Lower Upper
G–E–Q -0.200 (0.038) <0.001 -0.276 -0.125
G–B–Q 0.002 (0.005) 0.633 -0.008 0.013
G–F–Q -0.059 (0.032) 0.055 -0.120 0.002
G–E–B–Q -0.007 (0.002) 0.002 -0.012 -0.002
G–E–F–Q -0.165 (0.032) <0.001 -0.230 -0.104
G–B–F–Q 0.002 (0.004) 0.630 -0.006 0.011
G–E–B–F –Q -0.006 (0.002) <0.001 -0.010 -0.002
G, gender; E, emotional function; Q, health-related quality of life; B, body mass index;
F, fatigue; BootSE, bootstrap standard error; CI, confidence interval.

Mediation Moderated Model

Moderated mediation analyses determined whether place of origin moderated the effects of
gender on HRQoL through emotional function, BMI and fatigue. The results revealed that
place of origin (β = 0.103, p < 0.001) moderated the relationship between fatigue and HRQoL
(Fig. 4). The negative effects of fatigue on HRQoL were greater in UK than Spanish
participants (Spain, effect = 0.349, p < 0.001; UK, effect = 0.452, p < 0.001) (Table S4). Table
S5 shows the conditional indirect effects of gender on HRQoL through emotional function,
BMI and fatigue, for the two cohorts. The results showed stronger conditional indirect effects
for UK than Spanish participants, with the following significant relationships: emotional
function – fatigue (Spain, effect = -0.151, 95% CI = -0.212 to -0.096; UK, effect = -0.196,
95% CI = -0.276 to -0.124); and emotional function – BMI – fatigue (Spain, effect = -0.005,
95% CI = -0.009 to -0.002; UK, effect = -0.007, 95% CI = -0.012 to -0.002). In the pairwise
comparisons of conditional indirect effects, the bootstrapped 95% CI did not include 0,
confirming mediation moderated by place of origin.

Figure 4. The moderating effect of place of origin on the

relationship between gender and health-related quality of life
through emotional function, body mass index and fatigue.

101
 Note. The coefficients represent the moderating, indirect and
direct effects estimated. *p < 0.05; **p < 0.01; ***p < 0.001.

Table S4. Effects of moderation by place of origin (Spain or UK) on the relationship
between fatigue and health-related quality of life.
Place of origin Effect (SE) t (p) Bootstrapped 95% CI
Lower Upper
Spain 0.349 (0.017) 20.536 (<0.001) 0.315 0.382
UK 0.452 (0.022) 20.650 (<0.001) 0.409 0.495
SE, standard error; CI, confidence interval.

Table S5. Conditional indirect effect of gender (male and female) on health-related quality of
life through emotional function, body mass index and fatigue.
Place of origin Effect (BootSE) Bootstrapped 95% CI
Lower Upper
G–F–Q
- Effect 1 Spain -0.054 (0.029) -0.112 0.001
- Effect 2 UK -0.070 (0.038) -0.147 0.002
- Effect 2 – Effect 1 -0.016 (0.010) -0.038 0.000
G–E–F–Q
- Effect 1 Spain -0.151 (0.030) -0.212 -0.096
- Effect 2 UK -0.196 (0.039) -0.276 -0.124
- Effect 2 – Effect 1 -0.045 (0.014) -0.075 -0.020
G–B–F–Q
- Effect 1 Spain -0.002 (0.004) -0.005 0.010
- Effect 2 UK -0.002 (0.005) -0.007 0.013
- Effect 2 – Effect 1 -0.000 (0.001) -0.002 0.003
G–E–B–F–Q
- Effect 1 Spain -0.005 (0.002) -0.009 -0.002
- Effect 2 UK -0.007 (0.003) -0.012 -0.002
- Effect 2 – Effect 1 -0.001 (0.001) -0.003 -0.001
G, gender; F, fatigue; Q, health-related quality of life; E, emotional function; B, body mass
index; BootSE, bootstrap standard error; CI, confidence interval. Bootstrapping was employed
to analyse the conditional indirect effect.

102
Discussion

This study analysed the differences in HRQoL for people with NAFLD from two distinct
geographical cohorts. The analysis considered the impacts of both cohort and severity of liver
damage. Histological and biopsychosocial predictors of HRQoL were also analysed in both
cohorts separately. Our analysis also explored whether emotional function, BMI and fatigue
mediated the relationship between gender and HRQoL and whether place of origin moderated
that relationship.
There were no important sociodemographic differences between the cohorts, except in
BMI, which was higher in UK participants as compared to Spanish participants. These
differences were expected, considering that the UK leads current estimates of obesity in
Europe (Janssen et al., 2020). Participants with severe fibrosis were older than those with
none/mild fibrosis. This result has been reported elsewhere, and is intuitive given it may take
time for severe fibrosis to develop (Funuyet-Salas et al., 2020a).
Comparing the two cohorts showed that regardless of their liver severity, the UK
participants had lower physical and mental HRQoL, especially with respect to systemic
symptoms and worry. This coincides with Huber et al. (2019) in emphasizing more
deterioration in HRQoL in UK participants, who referred to more physical symptoms, such
as body pain or muscular cramps. UK participants reported more nervousness and worry about
the evolution of their disease than Spanish participants. It is unclear why this might be the
case, although Lazarus et al. (2021), concluded that the United Kingdom is the European
country with the highest level of awareness of NAFLD from a public health policy
perspective, whereas Spain had fewer civil society or government strategies for approaching
NAFLD. This suggests that our findings may in part be dictated by the relative provision of
information and public health messaging between the two countries.
Concerning liver impairment levels, there was no evidence of major differences in HRQoL
by absence or presence of NASH regardless whether participants were in the UK or Spanish
cohorts; similar to the findings of David et al. (2009) and Funuyet-Salas et al. (2020a), but
contrary to Huber et al. (2009), who suggested that NASH negatively affected HRQOL.
However, there were differences in HRQOL in the various levels of fibrosis, where the most
important were in the comparison of cirrhotic participants with the none/mild fibrosis group:
people with cirrhosis reported more fatigue, systemic symptoms and worry, and a lower
HRQoL compared with those with no or mild fibrosis. The decline in HRQoL as symptoms
of cirrhosis occur is consistent with previous studies (David et al., 2009; Sayiner et al., 2016)

103
including the recent systematic review by McSweeney et al. (2020) on HRQoL and PRO
measures in NASH-related cirrhosis.
Furthermore, an interaction was found between place of origin and fibrosis for fatigue and
HRQoL. Further analysis revealed that UK participants with none/mild fibrosis were more
fatigued and had lower HRQoL than Spanish participants. Of the Spanish participants, those
who had severe fibrosis showed more fatigue and lower HRQoL than the rest. Spanish
participants with moderate fibrosis were also more fatigued than those with none/mild
fibrosis. Our study builds on the body of evidence that fibrosis is a predictor of HRQoL of
NAFLD participants (David et al., 2009; Funuyet-Salas et al., 2020a). Having found evidence
of differences between levels of none/mild and moderate fibrosis, our analyses demonstrate
that the predictive capacity of fibrosis is not due exclusively to damage associated with
cirrhosis.
Similar to the reported relationship between mortality and NAFLD (Taylor et al., 2020),
the progression and accumulation of fibrosis is a key determinant of the decline in HRQoL
observed in these participants. Our work focused on fatigue, which is a recognized persistent
dysfunctional problem of NAFLD participants (Newton et al., 2008). Fatigue has been
associated with neuroinflammation and with altered neurophysiological mechanisms (Austin
et al., 2015; Swain et al., 2006). In fact, the level of cytokeratin 18 (CK18) has been found to
correlate positively with patient fatigue (Alt et al., 2016). At the same time, higher CK18
serum levels have been found in NAFLD participants than in other chronic liver patients, with
a positive association between the levels of this protein and the stage of liver fibrosis (Alt et
al., 2016; Darweesh et al., 2019). Therefore, the action of this type of biomarker could help
understand the relationship between HRQoL and fibrosis in NAFLD.
Based on our results, it can also be concluded that fibrosis functioned as a predictor of
HRQoL exclusively in the Spanish sample, in which decline in HRQoL increased as
participants advanced toward a cirrhotic state. However, for UK participants, impact on
HRQoL remained without variation over the liver severity levels, with regard to both NASH
and liver fibrosis. These results could be interpreted from the perspective of the awareness
mentioned above. Greater preparation concerning NAFLD in the UK, with better performance
in campaigns for undertaking the disease (Lazarus et al., 2021), could be contributing to UK
participants identifying their characteristic symptoms better and worrying more about the
effect of NAFLD on their health from the first stages of the disease. According to Lazarus et
al. (2021), the UK is the only European country with multidisciplinary teams and coordination
of health professionals in NAFLD management. This could be facilitating better physical and
104
psychological adjustment to the progress of the disease by UK participants than their Spanish
counterparts. This would also help explain the differences in how the MELD score predicted
HRQoL in Spanish and UK participants, evidence of which has been inconsistent to date
(Rodrigue et al., 2011; Saab et al., 2005). A higher MELD score predicted lower HRQoL in
Spanish participants for whom severity of liver damage, and specifically, fibrosis, predicts
their HRQoL. However, the MELD score was not independently associated with HRQoL in
UK participants.
Our results also revealed that the BMI and gender predict HRQoL in both Spanish and UK
participants. In line with previous studies (Funuyet-Salas et al., 2021; Huber et al., 2019;
Ozawa et al., 2021; Younossi et al., 2017), and contradicting the conclusions of Chawla et al.
(2016) and Sayiner et al. (2016), a higher BMI was associated with worse participant HRQoL.
Furthermore, female gender was associated with worse HRQoL, a finding reported by others
(Afendy et al., 2009; David et al., 2009; Funuyet-Salas et al., 2020a; Huber et al., 2019). As
suggested by Huber et al. (2019), the CLDQ could show more sensitivity in detecting the
negative impact of the disease on women’s HRQoL than men’s.
The inconsistency in the literature on the importance of sociodemographic factors on the
HRQoL of NAFLD patients (Afendy et al., 2009; Chawla et al., 2016; David et al., 2009;
Funuyet-Salas et al., 2020a; Ozawa et al., 2021; Stepanova et al., 2017) led us to analyse
whether age, education and employment status predicted HRQoL of Spanish and UK
participants. Age was positively associated with HRQoL in UK participants, as found in a
previous study with NAFLD patients (Younossi et al., 2017). Keeping in mind that in our
study older age was related to higher level of fibrosis, this result would also back the fact that
UK participants had better emotional adjustment to the evolution of the disease. On the
contrary, education did not predict HRQoL in either Spanish or UK participants, contradicting
the results of David et al. (2009) and Ozawa et al. (2021). Employment status, on the other
hand, was associated with HRQoL in UK participants, where actively employed participants
reported better HRQoL than those who were not actively employed, which had already been
identified previously in a study on chronic liver pathology (Stepanova et al., 2017). However,
employment status did not predict HRQoL in Spanish participants. This could be partly due
to the characteristics of the welfare state model in Spain. This model gives an eminent role to
the family and formal and informal support networks in the social protection system, which
would act as a protective factor for health perception in a non-active or unemployed
employment status (Acemoglu et al., 2015).

105
 Finally, the results of the moderated mediation analysis showed that emotional function,
BMI and fatigue partially mediated the relationship between gender and HRQoL. First, female
gender predicted worse emotional function, showing female gender to be a major factor
contributing to decline in NAFLD patient mental functioning, as previously found by Afendy
et al. (2009). Reduced emotional function was associated with higher participant BMI. Worse
mental HRQoL has been related to less physical activity and poorer quality diet in terms of
less adherence to healthy dietary guidelines in patients with a diversity of chronic pathologies
(Evers et al., 2021; Guicciardi et al., 2019; Rey et al., 2021). This, in turn, predicts more
obesity (Assari et al., 2016). Excess fat tends to accumulate mainly in peripheral regions such
as the hips or thighs, or in the abdominal cavity, known as central obesity (Aras et al., 2015).
Patients with central obesity are commonly resistant to insulin, a metabolic condition closely
associated with NAFLD and reduced HRQoL, functional capacity and energy (Angulo, 2007).
Therefore, higher BMI predicted greater fatigue in our study, which in turn was associated
with lower HRQoL. The close relationship between fatigue and HRQoL in NAFLD patients,
already identified by Cook et al. (2019), was thus confirmed. Place of origin, in turn,
moderated this relationship, as the indirect effects of gender on HRQoL through emotional
function, BMI and fatigue were higher in UK participants. Therefore, this study found a
biopsychosocial risk profile for HRQoL in NAFLD participants, especially those from the
UK cohort, based on female gender, poor emotional function, high BMI and greater
perception of fatigue.
Intervention to prevent the decline in physical and mental health of patients with an at-risk
biopsychosocial profile is especially necessary, considering the decline in HRQoL. NAFLD
should therefore be undertaken from a multidisciplinary patient-centered approach (Funuyet-
Salas et al., 2020b). This may prevent some of the greater use of healthcare system resources,
lower job productivity and higher mortality these people experience (David et al., 2009).
NAFLD and its impacts should be considered in national and international healthcare policies
and be included along with guidelines on clinical management of diabetes, obesity and
cardiovascular disease (Lazarus et al., 2021).
Our study had some limitations. For example, its cross-sectional design did not enable us
to establish causal relationships nor clarify the long-term evolution of the impact of NAFLD
on HRQoL. Moreover, other potential effect modifiers such as lifestyle were not considered
and would form a focus for research. Finally, the size differences between the two cohorts,
with the UK cohort being approximately one third the size of the Spanish cohort, could limit
our ability to detect effects of NASH and liver fibrosis on HRQoL among UK participants.
106
This may also be linked to the lack of statistical significance for certain predictors of HRQoL
in the UK cohort, such as the MELD score, whose results showed a similar trend to those of
the Spanish cohort. Further studies with larger samples could clarify the clinical and statistical
significance of these HRQoL predictors for the UK cohort. However, the large size of the
study sample, which was comprised of biopsy-proven patients from real clinical practice in
Spanish and UK hospitals, constitutes the main strength of this research.
The results of this study showed that HRQoL was mainly lower in UK than Spanish
participants, especially they had more physical symptoms and worry about the liver disease.
Higher fibrosis stage predicted lower HRQoL, mainly in the Spanish cohort. Gender and BMI
were found to be independently associated with HRQoL in both Spanish and UK participants.
Female gender was associated with worse emotional function, higher BMI and more fatigue,
which predicted lower participants' HRQoL. Specifically, the negative impact on NAFLD
patients' HRQoL was greater in UK than in Spanish participants. Our results confirm and
extend knowledge of the impact of NAFLD from the individual’s perspective. This cross-
cultural study will enable healthcare professionals to better understand the biopsychosocial
factors that predict and contribute to the impact of NAFLD on patient HRQoL, as well as
identify important differences in HRQoL of Spanish and UK patients with this liver disease.

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4.4. Cuarto trabajo titulado “Quality of life mediates the influence of coping on mental
health and self-efficacy in patients with non-alcoholic fatty liver disease”

Abstract

Objective: Our aim was to determine whether the association between active coping and
depressive symptoms in patients with non-alcoholic fatty liver disease (NAFLD) was
mediated by vitality, and whether diabetes and obesity could impact on this relationship.
Moreover, if mental quality of life (QoL) and role-physical modulated the relationship
between passive/avoidance coping and self-efficacy, and the role of liver fibrosis stage.
Methods: Depressive symptoms (BDI-II), self-efficacy (GSE), coping (COPE-28) and QoL
(SF-12) were evaluated in 509 biopsy-proven NAFLD patients. Mediation and moderated
mediation models were conducted using the SPSS PROCESS v3.5 macro. Results: Vitality
mediated the relationship between active coping and depressive symptoms (-2.254, CI = -
2.792 to -1.765), with diabetes (-0.043, p = 0.017) and body mass index (BMI) (-0.005, p =
0.009) moderating the association. In addition, mental QoL (-6.435, CI = -8.399 to -4.542)
and role-physical (-1.137, CI = -2.141 to -0.315) mediated the relationship between
passive/avoidance coping and self-efficacy, with fibrosis stage (0.367, p < 0.001) moderating
this association. Specifically, the presence of diabetes and significant fibrosis, and a higher
BMI, were associated with greater negative impact on participant mental health or self-
efficacy. Conclusion: A maladaptive coping style was associated with poorer physical and
mental quality of life in NAFLD patients, which along with the presence of metabolic
comorbidity (diabetes and obesity) and significant fibrosis predicted poorer mental health or
self-efficacy in these patients. These results suggested incorporating emotional and cognitive
evaluation and treatment in patients with NAFLD. Keywords: Depression; fibrosis; metabolic
disease; NAFLD; quality of life; self-efficacy.

Introduction

Nonalcoholic fatty liver disease (NAFLD) represents a wide clinical spectrum of chronic liver
pathologies, from liver steatosis to nonalcaholic steatohepatitis (NASH), liver cirrhosis and
hepatocellular carcinoma, finally requiring liver transplantation (Makri et al., 2021). It is
estimated that from 10 to 15% of patients with NAFLD have some amount of liver fibrosis,
which is an important predictor of the patient’s clinical and psychosocial profile (Dulai et al.,
2017; Funuyet-Salas et al., 2020; Younossi & Henry, 2021).

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 In recent years, there has been growing interest in study of patient-reported outcomes
(PROs), to find out the patient’s perspective of his health condition and wellbeing (Weldring
& Smith, 2013). NAFLD is associated with a worse quality of life, mainly related to physical
functioning, with patients who often refer to problems such as fatigue or lack of vitality
(Assimakopoulos et al., 2018; Younossi et al., 2017). NAFLD patients have also been found
to have worse mental health than other chronic liver pathologies, especially more depressive
symptoms (Kim et al., 2019). Similarly, a passive/avoidance coping style based on the
predominant use of coping strategies such as denial, self-blame, self-distraction or behavioral
disengagement, predict worse quality of life of NAFLD patients (Funuyet-Salas et al., 2021a).
On the contrary, active coping and focusing on action and acceptance predict satisfactory
perception of their state of health and wellbeing.
NAFLD is closely associated with metabolic syndrome components, especially type 2
diabetes mellitus (T2DM) and obesity, such that when both pathologies coexist, they usually
interact with each other worsening the patient’s prognosis and clinical evolution (Polyzos et
al., 2019; Younossi et al., 2018). In fact, the presence of T2DM or obesity has been related to
a worse quality of life and/or more maladaptive coping by those diagnosed with NAFLD
(Funuyet-Salas et al., 2021a; Younossi et al., 2019). However, the influence metabolic
comorbidity could have on the mental health of these patients is unknown.
Furthermore, intervention in NAFLD focuses on weight loss through changes in life style,
including diet, exercise and physical activity (Romero-Gómez et al., 2017). However, the
rates of therapeutic adherence by these patients are quite low (Serfaty, 2018). In this respect,
mental health and self-efficacy have recently been identified as determining factors for
therapeutic adherence in NAFLD. On one hand, greater presence of depressive symptoms
mediates the negative effects of low social support and poor physical quality of life on
following instructions on diet and physical activity, respectively (Funuyet-Salas et al., 2021b).
On the other, high perceived self-efficacy has been found to exert a protective role in
therapeutic adherence by NAFLD patients with an at-risk psychosocial profile (Funuyet-Salas
et al., 2021b), and is a fundamental condition for maintaining long-term weight loss through
diet and physical activity (Palmeira et al., 2007). Therefore, understanding the mechanisms
that determine mental health and self-efficacy of these patients would provide added value in
improving therapeutic adherence rates in this population.
In this context, we proposed exploring how depressive symptoms, self-efficacy, active
coping, passive/avoidance coping, vitality, mental quality of life, role-physical and BMI are
interrelated in NAFLD patients. We also wanted to know on one hand, whether there were
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 statistically significant differences in depressive symptoms, active coping and vitality based
on presence or absence of T2DM, and on the other, if there were statistically significant
differences in self-efficacy, passive/avoidance coping, mental quality of life and role-physical
based on presence or absence of significant fibrosis. We further examined whether vitality
mediates the relationship between active coping and depressive symptomatology, and whether
T2DM and BMI moderate that relationship. And finally, we analyzed whether the mental
quality of life and role-physical mediate the relationship between passive/avoidance coping
and self-efficacy, and whether significant fibrosis has a moderating effect on this relationship.

Methods

Participants

Our sample consisted of 509 patients with biopsy-proven NAFLD (300 men and 209 women)
with a mean age of 55 ± 12 years. This cross-sectional study was approved by the Ethics
Committee of the Virgen del Rocío University Hospital of Seville. All the patients, whose
sociodemographic characteristics are provided in Table 1, gave their informed consent to
participate. This study met the Helsinki Declaration 1964 guidelines of good practice.

Table 1. Univariate analyses of the differences in depressive symptoms and self-efficacy by sociodemographic variables.
M (SD) Depressive symptoms r (p) Self-efficacy r (p)

M (SD) M (SD)

Age 55.07 (11.85) 7.02 (7.89) 0.157 (<0.001) 65.07 (18.31) -0.163 (<0.001)

Total N (%) Depressive symptoms t / U (p) Self-efficacy t / F (p)

M (SD) M (SD)

Gender t(1,350.952) = -4.978 t(1,396.966) = 4.843

- Male 300 (58.94) 5.52 (6.51) (<0.001) 68.37 (16.55) (<0.001)

- Female 209 (41.06) 9.18 (9.13) 60.33 (19.65)

Marital status t(1,507) = 0.476 t(1,151.305) = -1.191

- With partner 401 (78.78) 6.94 (7.70) (0.634) 65.62 (17.60) (0.236)

- Without partner 108 (21.22) 7.34 (8.59) 63.03 (20.68)

Education U(2,314.092) = 10.017 F(2,506) = 18.218

- Low 226 (44.40) 8.46 (8.26) (<0.001) 60.18 (18.25) (<0.001)

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 - Medium 148 (29.08) 6.76 (7.94) 66.63 (17.77)

- High 135 (26.52) 4.90 (6.66) 71.55 (16.72)

Employment t(1,486.042) = -6.654 t(1,495.918) = 7.335

- Working 242 (47.54) 4.71 (6.29) (<0.001) 70.95 (15.06) (<0.001)

- Not working 267 (52.46) 9.12 (8.59) 59.73 (19.35)

The Pearson’s correlation (age), t-test for independent samples (gender, marital status, employment), and analysis of variance
(education) were applied.

Measurements

The Beck Depression Inventory-II (BDI-II) measures severity of depressive symptoms in the
past two weeks (Beck et al., 1996). The instrument, comprised of 21 items rated on a four-
point Likert-type scale (except Items 16 and 18, which have seven points), provides a total
score corresponding to the sum of scores on each of the items, which may vary from 0 to 63.
The higher the score, the more severe the depressive symptoms are. We used the Spanish
version of the instrument (Beck et al., 2011), which had a Cronbach’s alpha of 0.91.
The General Self-Efficacy Scale (GSE) measures how a person perceives their own ability
to manage and face stressful everyday situations (Baessler & Schwarcer, 1996). The
instrument, comprised of 10 items answered on a ten-point Likert-type scale provides a total
score from the sum of scores on each item, which can vary from 10 to 100. The higher the
score, the greater self-efficacy is. We used the Spanish version of the instrumentnto (Sanjuán-
Suárez et al., 2000), which had a Cronbach’s alpha of 0.94.
The Brief COPE (COPE-28) evaluates coping strategies usually used by a person to face
problems or difficult situations (Carver, 1997). In this study, seven of these strategies were
selected to establish two dimensions according to participant coping style. Based on the
results of a previous study (Funuyet-Salas et al., 2021a), active coping, positive reframing and
acceptance made up an active, or adaptive, coping style, while self-distraction,
disengagement, denial and self-blame constituted a passive/avoidance or maladaptive coping
style. The instrument, made up of 28 items with four-point Likert-type scales, provide a score
for each one of the coping strategies, which can vary from 0 to 3. The higher the score, the
more the coping strategy is used. We used the Spanish version of the instrument (Morán et
al., 2010), which had a Cronbach’s alpha of 0.82-0.96 for the different subscales used.
The 12-Item Short Form Health Survey (SF-12v.2) measures health-related quality of life

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(Maruish, 2012; Ware et al., 2002). The instrument is composed of 12 items with three or
five-point Likert-type scales, providing a score for each of the following dimensions of health-
related quality of life: physical functioning, general health, social functioning, bodily pain,
role-physical, role-emotional, vitality, and mental health. The last dimension was analyzed as
a measure of participant mental quality of life. Their scores vary from 0 to 100, from a worse
to a better state of health, respectively. The higher the score, the better the health-related
quality of life. In our sample, the Cronbach’s Alpha for the various dimensions employed was
0.72-0.94.

Procedure

Starting from an original sample of 755 NAFLD patients from 12 Spanish hospitals, 509 were
finally selected (102 were excluded because they did not want to participate in the study and
81 because they had undergone bariatric surgery either before or after the liver pathology
diagnosis, 35 due to incomplete data on the biopsy report, and 28 for multimor0bidity).
Sample inclusion requirements were to be of legal age, have given their informed consent to
participate in the study, understand the study evaluation instruments, have been diagnosed
with NAFLD by liver biopsy, and not have any severe or disabling psychopathology. The
whole evaluation was carried out by the same psychologist who employed the same evaluation
instruments in the same order for all participants: psychosocial interview, SF-12, BDI-II,
COPE-28 and GSE.

Statistical Analysis

The independent samples t-test and analysis of variance (ANOVA) were applied to examine
the differences in depressive symptoms and self-efficacy of the participants by their
sociodemogaphic characteristics (gender, age, marital status, education, employment).
Pearson’s correlations were employed to analyze the associations between depressive
symptoms, self-efficacy, active coping, passive/avoidance coping, vitality, mental quality of
life, role-physical and body mass index. To analyze the differences in these variables by
absence or presence of T2DM and significant fibrosis, the independent sample t-test was
applied. Cohen’s d was calculated as the effect size index.
Mediation and moderated mediation models were estimated using the SPSS PROCESS
macro v3.5 (Hayes & Rockwood, 2017). First, vitality was analyzed as a mediator in the
relationship between active coping and depressive symptoms, using Model 4 (Hayes, 2018).
Then Model 6 was applied to test whether the mental quality of life and role-physical mediated

117
the relationship between passive/avoidance coping and self-efficacy. In both cases
bootstrapping with 5000 resamples was employed to test the indirect effects estimated. The
mediation effect was considered significant when the confidence interval (CI) of 95% of the
indirect effects did not include 0. In continuation, Model 16 (Hayes, 2018) was used, again
with bootstrapping with 5000 resamples, to analyze the moderated mediation effect, that is,
whether T2DM and the BMI moderated the indirect effects of active coping, through vitality,
on depressive symptoms. Model 91 was applied to test whether significant fibrosis moderated
the indirect effects of passive/avoidance coping, through mental quality of life and role-
physical, on self-efficacy.
Pick-a-point with the PROCESS macro was used to test the significance of the moderation
effect. This technique provides three quantitative moderator groups, classifying participants
as low, medium or high in that variable. Finally, for each of those values, the conditional
effect of the predictor variable on the criterion variable was calculated, generating a
confidence interval for it (Hayes & Matthes, 2009). A two-sided p-value < 0.05 was
considered statistically significant.

Results

Sociodemographic and Clinical Variables

The 509 participants had a mean age of 55.07 (SD = 11.85), 58.94% were men and 41.06%
women. Of these, 78.78% had a partner, 44.40% low education, and 47.54% were actively
employed. The mean score for depressive symptoms was 7.02 (SD = 7.89), while for self-
efficacy it was 65.07 (SD = 18.31). The results of the independent samples t-test and ANOVA
showed that the scores on depressive symptoms and self-efficacy were significantly different
(p < 0.001) by gender, education and employment. There was also a significant correlation (p
< 0.001) between age and scores in depressive symptomatology and self-efficacy (Table 1).

Correlation Analysis

The most important results revealed by the Pearson correlation analysis were that depressive
symptoms were negatively associated with active coping (r = -0.603) and vitality (r = -0.637)
and positively associated with BMI (r = 0.219), while self-efficacy was negatively associated
with passive/avoidance coping (r = -0.472) and positively associated with mental quality of
life (r = 0.551) and role-physical (r = 0.481). Furthermore, active coping was positively
associated with vitality (r = 0.507) and negatively associated with BMI (r = -0.193), while
passive/avoidance coping was negatively associated with mental quality of life (r = -0.521)

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and role-physical (r = -0.352). Vitality was negatively associated with BMI (r = -0.218), while
mental quality of life was positively associated with role-physical (r = 0.486). All of these
correlations were statistically significant (p < 0.001).
In addition, the independent samples t-test revealed statistically significant differences
based on absence or presence of T2DM (Table 2). Thus, diabetic participants had worse
depressive symptoms (p < 0.001, d = -0.45), and less active coping (p = 0.014, d = 0.23) and
vitality (p < 0.001, d = 0.38). There were also statistically significant differences by absence
or presence of significant fibrosis (Table 3). So, participants with significant fibrosis referred
to lower self-efficacy (p < 0.001, d = 0.51), mental quality of life (p < 0.001, d = 0.34) and
role-physical (p < 0.001, d = 0.58), and more passive/avoidance coping (p = 0.002, d = -0.29).

Table 2. Differences in depressive symptoms, active coping and vitality as a function of type 2
diabetes mellitus (absence or presence).
General T2DM Intergroup Effect

comparisons sizes

Absence Presence

n = 509 n = 345 n = 164

Variables M M M t Cohen’s

(SD) (SD) (SD) (p) d

1. Depressive 7.02 5.84 9.51 t(1,249.219) = -4.512 -0.45 S

symptoms (7.89) (6.82) (9.31) (<0.001)

2. Active 1.71 1.77 1.59 t(1,279.944) = 2.468 0.23 S

coping (0.75) (0.71) (0.83) (0.014)

3. Vitality 56.39 59.86 49.09 t(1,268.235) = 3.845 0.38 S

(27.86) (25.37) (31.32) (<0.001)

S small effect size.

The independent sample t-test was applied.
Table 3. Differences in self-efficacy, passive/avoidance coping, mental quality of life and role-
physical as a function of significant fibrosis (absence or presence).
General Significant fibrosis Intergroup Effect

comparisons sizes

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 Absence Presence

n = 509 n = 317 n = 192

Variables M M M t Cohen’s

(SD) (SD) (SD) (p) d

1. Self-efficacy 65.07 68.58 59.28 t(1,331.142) = 5.396 0.51 M

(18.31) (15.95) (20.40) (<0.001)

2. Passive/avoidance 0.46 0.41 0.54 t(1,349.360) = -3.085 -0.29 S

coping (0.43) (0.40) (0.48) (0.002)

3. Mental quality 70.09 72.95 65.36 t(1.507) = 3.724 0.34 S

of life (22.55) (21.76) (23.09) (<0.001)

4. Role-physical 76.20 82.89 65.17 t(1,317.294) = 6.161 0.58 M

(30.46) (25.53) (34.54) (<0.001)

S small effect size, M medium effect size.

The independent sample t-test was applied.

Mediation Analysis

Figure 1 shows the significant indirect effect of vitality when it mediates in the association
between active coping and depressive symptoms (-2.254, p < 0.001). The bootstrap 95% CI
did not include 0 (-2.792 to -1.765), confirming the significant indirect effect of active coping
on depressive symptoms through vitality. The direct effect of active coping on depressive
symptoms was significant after mediation analysis (-3.665, p < 0.001), showing partial
mediation of vitality.

Figure 1. Vitality mediates the relationship between active coping and

depressive symptoms. In addition, mental quality of life and role-physical
mediate the relationship between passive/avoidance coping and self-efficacy.

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 Note. Gender, age, education and employment were entered in the
analysis as covariates. The coefficients represent the indirect and direct
effects estimated. ***p < 0.001.

Figure 1 also shows the significant indirect effects of mental quality of life and role-
physical when mediating in the association between passive/avoidance coping and self-
efficacy (mental quality of life, -6.435, p < 0.001; role-physical, -1.137, p = 0.006; both, -
1.435, p < 0.001). The bootstrap 95% CI did not include 0 in any of the cases (mental quality
of life, -8.399 to -4.542; role-physical, -2.141 to -0.315; both, -2.356 to -0.661), confirming
the significant indirect effect of passive/avoidance coping on self-efficacy through mental
quality of life and role-physical. The direct effect of passive/avoidance coping on self-efficacy
was significant after mediation analysis (-9.625, p < 0.001), showing partial mediation of
mental quality of life and role-physical.

Analysis of Moderated Mediation

The moderated mediation analyses determined whether T2DM and BMI moderated the effects
of active coping on depressive symptoms through vitality on one hand, and on the other,
whether significant fibrosis moderated the effects of passive/avoidance coping on self-
efficacy through mental quality of life and role-physical.
Figure 2 shows the results of the moderated mediation model for depressive symptoms.
The results revealed that T2DM (β = -0.043, p = 0.017) and BMI (β = -0.005, p = 0.009)

121
 moderated the relationship between vitality and depressive symptoms. The pick-a-point
technique (Table 4) showed that the negative effects of vitality on depressive symptoms were
higher in diabetic patients than in those who were not. They also increased the higher the
patient’s BMI as measured on three levels: a low BMI, equivalent to a standard deviation
below the mean (absence T2DM, effect = -0.073, p < 0.001; presence T2DM, effect = -0.116,
p < 0.001); medium BMI, equivalent to the mean (absence of T2DM, effect = -0.097, p <
0.001; presence of T2DM, effect = -0.140, p < 0.001); and high level of BI, equivalent to one
standard deviation above the mean (absence of T2DM, effect = -0.120, p < 0.001; presence
of T2DM, effect = -0.164, p < 0.001).

Figure 2. The moderating effect of T2DM and BMI on the

relationship between active coping and depressive symptoms
through vitality.

Note. Gender, age, education and employment were entered

in the analysis as covariates. The coefficients represent the
moderating, indirect and direct effects estimated. *p < 0.05;
**p < 0.01, ***p < 0.001.

Table 4. Moderating effects of type 2 diabetes mellitus (absence or presence) and body mass index on the
relationship between vitality and depressive symptoms.
T2DM BMI Effect (SE) t (p) Bootstrapped 95% CI

Lower Upper

Absence 25.499 (M – 1 SD) -0.073 (0.015) -4.828 (<0.001) -0.103 -0.043

Absence 30.636 (M) -0.097 (0.013) -7.483 (<0.001) -0.122 -0.071

Absence 35.772 (M + 1 SD) -0.120 (0.016) -7.389 (<0.001) -0.152 -0.088

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 Presence 25.499 (M – 1 SD) -0.116 (0.017) -6.699 (<0.001) -0.151 -0.082

Presence 30.636 (M) -0.140 (0.015) -9.541 (<0.001) -0.169 -0.111

Presence 35.772 (M + 1 SD) -0.164 (0.017) -9.612 (<0.001) -0.197 -0.130

T2DM type 2 diabetes mellitus, BMI body mass index, M mean, SD standard deviation, SE standard error, CI
confidence interval.
The pick-a-point technique was applied to test the significance of the moderating effects.

Table 5 shows the conditional indirect effects of active coping on depressive symptoms
through vitality on the levels established for T2DM and BMI. The results showed a larger
conditional indirect effect on diabetic participants than on those who were not. There was also
a significant increase in the conditional indirect effect as the BMI increased: low BMI
(absence T2DM, effect = -1.381, 95% CI = -2.028 to -0.771; presence of T2DM, effect = -
2.194, 95% CI = -2.991 to -1.475); medium BMI (absence T2DM, effect = -1.825, 95% CI =
-2.512 to -1.233; presence of T2DM, effect = -2.637, 95% CI = -3.410 to -1.952); and high
BMI (absence of T2DM, effect = -2.268, 95% CI = -3.250 to -1.470; presence of T2DM,
effect = -3.081, 95% CI = -4.058 to -2.211). In the pairwise comparisons between the
conditional indirect effects, a strong majority did not include 0 in the bootstrapped 95% CI,
confirming that the mediation effect was moderated by T2DM and BMI.

Table 5. The conditional indirect effect of active coping on depressive symptoms through vitality.
T2DM BMI Effect (BootSE) Bootstrapped 95% CI

Lower Upper

Effect 1 Absence 25.499 (M – 1 SD) -1.381 (0.320) -2.028 -0.771

Effect 2 Absence 30.636 (M) -1.825 (0.323) -2.512 -1.233

Effect 3 Absence 35.772 (M + 1 SD) -2.268 (0.450) -3.250 -1.470

Effect 4 Presence 25.499 (M – 1 SD) -2.194 (0.384) -2.991 -1.475

Effect 5 Presence 30.636 (M) -2.637 (0.370) -3.410 -1.952

Effect 6 Presence 35.772 (M + 1 SD) -3.081 (0.472) -4.058 -2.211

Effect 2 – Effect 1 -0.443 (0.219) -0.884 -0.030

Effect 3 – Effect 1 -0.887 (0.438) -1.769 -0.060

Effect 4 – Effect 1 -0.813 (0.400) -1.613 -0.045

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Effect 5 – Effect 1 -1.256 (0.442) -2.149 -0.413

Effect 6 – Effect 1 -1.700 (0.572) -2.859 -0.608

Effect 3 – Effect 2 -0.443 (0.219) -0.884 -0.030

Effect 4 – Effect 2 -0.369 (0.469) -1.286 0.568

Effect 5 – Effect 2 -0.813 (0.400) -1.613 -0.045

Effect 6 – Effect 2 -1.256 (0.442) -2.149 -0.413

Effect 4 – Effect 3 0.074 (0.617) -1.097 1.320

Effect 5 – Effect 3 -0.369 (0.469) -1.286 0.568

Effect 6 – Effect 3 -0.813 (0.400) -1.613 -0.045

Effect 5 – Effect 4 -0.443 (0.219) -0.884 -0.030

Effect 6 – Effect 4 -0.887 (0.438) -1.769 -0.060

Effect 6 – Effect 5 -0.443 (0.219) -0.884 -0.030

M mean, SD standard deviation, BootSE bootstrap standard error, CI confidence interval.

Bootstrapping was employed to analyze the conditional indirect effect.

Figure 3 shows the results of the moderated mediation model for self-efficacy, where
significant fibrosis (β = 0.367, p < 0.001) moderated the relationship between mental quality
of life and role-physical. The pick-a-point technique (Table 6) showed that the negative
effects of mental quality of life on role-physical were higher in patients who had significant
fibrosis than in those who did not (absence of significant fibrosis, effect = 0.374, p < 0.001;
presence of significant fibrosis, effect = 0.742, p < 0.001).

Figure 3. The moderating effect of significant fibrosis on the relationship between

passive/avoidance coping and self-efficacy through mental quality of life and role-
physical.

124
 Note. Gender, age, education and employment were entered in the analysis as
covariates. The coefficients represent the moderating, indirect and direct effects
estimated. **p < 0.01, ***p < 0.001.

Table 6. The moderating effects of significant fibrosis (presence or absence) on the

relationship between mental quality of life and role-physical.
Significant fibrosis Effect (SE) t (p) Bootstrapped 95% CI

Lower Upper

Absence 0.374 (0.070) 5.323 (<0.001) 0.236 0.512

Presence 0.742 (0.084) 8.822 (<0.001) 0.576 0.907

SE standard error, CI confidence interval.

The pick-a-point technique was applied to test the significance of the moderating
effects.

Table 7 presents the conditional indirect effects of passive/avoidance coping on self-

efficacy through mental quality of life and role-physical for the different levels of fibrosis.
The results showed a larger conditional indirect effect on participants who had significant
fibrosis than those who did not (absence of significant fibrosis, effect = -0.996, 95% CI = -
1.675 to -0.445; presence of significant fibrosis, effect = -1.974, 95% CI = -3.257 to -0.895).
In the pairwise comparisons between the conditional indirect effects, the bootstrapped 95%
CI did not include 0, confirming that the mediation effect was moderated by fibrosis.

Table 7. The conditional indirect effect of passive/avoidance coping on self-efficacy through

mental quality of life and role-physical.

125
 Significant fibrosis Effect (BootSE) Bootstrapped 95% CI

Lower Upper

Effect 1 Absence -0.996 (0.316) -1.675 -0.445

Effect 2 Presence -1.974 (0.611) -3.257 -0.895

Effect 2 – Effect 1 -0.978 (0.420) -1.927 -0.281

BootSE bootstrap standard error, CI confidence interval.

Bootstrapping was employed to analyze the conditional indirect effect.

Discussion

To date, it is not known what psychological, liver and metabolic biomarkers could predict
depressive symptoms and self-efficacy of NAFLD patients, which are relevant variables for
therapeutic adherence by these patients, as recently demonstrated (Funuyet-Salas et al.,
2021b). We therefore studied whether both variables were significantly associated with active
coping, passive/avoidance coping, vitality, mental quality of life, role-physical and BMI of
the participants. We also wanted to find out whether there were any statistically significant
differences in participants’ depressive symptoms, active coping and vitality by absence or
presence of T2DM, and also, whether there would be statistically significant differences in
self-efficacy, passive/avoidance coping, mental quality of life and role-physical by absence
or presence of significant fibrosis. We examined whether vitality mediated the relationship
between active coping and depressive symptoms, and whether there was a moderating effect
of T2DM and BMI on this relationship. Finally, we analyzed whether the mental quality of
life and role-physical mediated the relationship between passive/avoidance coping and self-
efficacy, and whether significant fibrosis moderated that relationship.
The results of the univariate analysis showed significant differences in depressive
symptoms and self-efficacy of participants by age, gender, education and employment. Older
participants, women, and participants with a low level of education and not actively employed
reported greater depression and less self-efficacy. Thus, the results of previous studies that
have associated these sociodemographic characteristics with poorer mental health and
perceived self-efficacy in patients with chronic or metabolic liver pathologies (Bohanny et
al., 2013; Cherrington et al., 2010; Dehghan et al., 2017; Duan et al., 2012; Kim et al., 2019;
Weng et al., 2014; Xing et al., 2015) are confirmed.

126
 As expected, the results showed that active coping, vitality, T2DM and BMI were
significantly associated with depressive symptoms, while passive/avoidance coping, mental
quality of life, role-physical and significant fibrosis were with self-efficacy. Vitality partially
mediated the relationship between active coping and depressive symptoms. First, low active
coping predicted less vitality, confirming the positive association between adaptive coping
and quality of life in NAFLD (Funuyet-Salas et al., 2021a). The choice of coping strategies
by the patient depends on how they construct their own experience with the disease (Coelho
et al., 2003). Thus, less use of active coping strategies, such as positive reappraisal or
acceptance of the problematic situation, would be determined in large part by the patient’s
concept of the disease as an uncontrollable process that is beyond his/her own resources. This
style of coping would be associated with lower self-esteem and less energy and vitality
(Vosvick et al., 2003), which is relevant considering that fatigue is one of the main problems
referred to by NAFLD patients (Younossi et al., 2017).
Less vitality, in turn, predicted worse depressive symptoms, which activation of
immunological-inflammatory pathways could be contributing to (Maes et al., 2012). The
relevance of this has been demonstrated in the fatigue experienced both by the general
population and patients with a diversity of chronic diseases (Collado-Hidalgo et al., 2008;
Lasselin et al, 2012; Rohleder et al., 2012). Thus, high serum levels of proinflammatory
cytokines, such as interleukin (IL-6), have been associated with worse quality of life and more
fatigue or lack of vitality through their effect on the central nervous system (Dantzer et al.,
2014; Younossi et al., 2018). And at the same time, IL-6 has been found to correlate positively
with depressive symptoms referred to by the patient (Bossola et al., 2015). Therefore, the
action of inflammatory markers such as IL-6 could help understand the close relationship
between vitality and depressive symptoms in NAFLD patients.
Furthermore, the moderated mediation analyses revealed that T2DM and BMI moderated
the relationship between active coping and depression through vitality. The indirect effects of
vitality on depressive symptoms increased in patients with T2DM and higher BMI. That is,
T2DM and obesity were risk factors for patient mental health, increasing the negative impact
of low vitality on depressive symptoms. Both metabolic pathologies, like NAFLD, are
associated with decreased vitality (Feyisa et al., 2020; Svenningsson et al., 2011). Therefore,
it would be expected for metabolic comorbidity in NAFLD to strengthen the negative impact
on vitality perceived by the patient. Less perceived energy or vitality also implies less physical
activity by these patients (Thiel et al., 2016; Tous-Espelosín et al., 2020), which in turn, is
related to more body weight (Aguirre-Urdaneta et al., 2012). Inactivity, worse self-efficacy
127
related to physical exercise, or fear and self-blame for weight gain could contribute to worse
mental health of these patients (Beaulieu et al., 2012; Levinson et al., 2020; McAuley et al.,
2010).
In another area, the mental quality of life and role-physical mediated partially in the
relationship between passive/avoidance coping and self-efficacy. First, high
passive/avoidance coping predicted worse mental quality of life, which in turn, was associated
with worse role-physical. Therefore, the relevance of coping in physical and mental quality
of life of the patient was confirmed (Ben-Zur, 2009). Those patients who cope with their
disease from a passive/avoidance style, employing strategies such as self-blame, self-
distraction, behavioral disengagement or negation, usually show worse psychological
adjustment and greater presence of maladaptive health behaviors, anxiety and depressive
symptoms, which end up diminishing their quality of life (Terrazas-Romero et al., 2018). This
impact would be mainly on the mental sphere (Funuyet-Salas et al., 2021a), which in turn
would deteriorate the patient’s role-physical, that is, perception of autonomy and ability to
performing daily activities.
This link between state of mental and physical health, which had already been previously
proven in patients with metabolic syndrome (Danhauer et al., 2019), predicted participant
self-efficacy, such that worse mental quality of life and worse role-physical were associated
with lower self-efficacy. Therefore, this study identified an at-risk psychological profile for
self-efficacy in NAFLD, which is relevant considering that these patients refer to less
confidence in managing their disease and making changes in health-related behavior than
other chronic liver disease patients (Frith et al., 2010). To date, there has been consensus in
conceiving self-efficacy as a predictor of quality of life in a diversity of chronic pathologies
(Chin et al., 2021; Peters et al., 2019; Thomson et al., 2019). However, the results of this study
point out that this could be a two-way relationship, since those patients who reported a worse
mental and physical quality of life showed lower perception of self-efficacy.
Finally, moderated mediation analyses revealed that fibrosis moderated the relationship
between passive/avoidance coping and self-efficacy through mental quality of life and role-
physical. The indirect effects of mental quality of life on role-physical and consequently, on
self-efficacy, was higher in patients with significant fibrosis. Therefore, this study identified
for the first time, the presence of significant fibrosis as a risk factor for self-efficacy of
NAFLD patients. Significant fibrosis has previously been associated with worse physical and
mental health in NAFLD (Funuyet-Salas et al., 2020). This could be due to fatigue, which has
been found in a higher proportion of patients with significant fibrosis, and its associated
128
symptoms: alterations in mood, including depression, as well as daytime somnolence or
cognitive dysfunction (Swain & Jones, 2019; Yamamura et al., 2021). Thus, the presence of
an at-risk psychological profile based on more maladaptive coping and worse mental quality
of life would imply lower perceived productivity and functioning in daily activities, especially
in patients with significant fibrosis, which would lead to worse self-efficacy. Consequently,
the determinant role of liver fibrosis in the biopsychosocial profile of NAFLD patients is
confirmed (Funuyet-Salas et al., 2020; Younossi et al., 2019).
In conclusion, this study demonstrated which psychological, liver and metabolic
biomarkers can predict depressive symptoms and self-efficacy in NAFLD patients. First,
vitality mediates the relationship between active coping and depressive symptomatology, with
T2DM and obesity as moderators: the presence of metabolic comorbidity intensifies the
negative effects of less active coping and less vitality on depression. Second, the mental
quality of life and role-physical mediate the relationship between passive/avoidance coping
and self-efficacy, moderated by fibrosis: the presence of significant fibrosis intensifies the
negative effects that more maladaptive coping and worse mental quality of life exert on the
patient’s role-physical, and thereby, self-efficacy. Therefore, the results of this study
emphasize the importance of incorporating emotional and cognitive aspects in NAFLD
evaluation and treatment, including cognitive/behavioral strategies, such as decision-making,
problem-solving, cognitive restructuring or time management (Bellentani et al., 2008). These
strategies would help those patients with an at-risk psychological profile to analyze, interpret
and approach obstacles derived from their disease and treatment in a more adaptive manner,
with the consequent improvements associated with quality of life, mental health and self-
efficacy. This would probably involve an improvement in the low rates of therapeutic
adherence usually observed in these patients, which is important considering the growing
clinical and economic impact of this disease around the world (Serfaty, 2018; Terai et al.,
2021).
Our study had some limitations. For example, different liver or metabolic markers could
have been included as moderators, such as lobulillar inflammation, hepatocellular ballooning
or hypertension. Instead, we chose the variables in the literature which have been
demonstrated to have more weight in the NAFLD biopsychosocial profile (Alrasheed et al.,
2022; Dulai et al., 2017; Funuyet-Salas et al., 2021a; Funuyet-Salas et al., 2020; Mantovani
et al., 2020). Moreover, due to the cross-sectional study design, it was not possible to
determine the long-term evolution of the results. However, the large size of the study sample,

129
comprised of biopsied patients from real clinical practice in several Spanish hospitals, is the
study’s main strength.

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4.5. Quinto trabajo titulado “Quality of life and coping in nonalcoholic fatty liver
disease: Influence of diabetes and obesity”

Este trabajo corresponde al artículo publicado que se referencia a continuación:

Funuyet-Salas, J., Pérez-San-Gregorio, M. Á., Martín-Rodríguez, A., & Romero-Gómez, M.

(2021). Quality of life and coping in nonalcoholic fatty liver disease: Influence of diabetes
and obesity. International Journal of Environmental Research and Public Health, 18(7),
3503. https://doi.org/10.3390/ijerph18073503

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Abstract

Our aim was to analyze how type 2 diabetes and obesity influence quality of life (QoL) and
coping in patients with nonalcoholic fatty liver disease (NAFLD), and which coping strategies
predict diabetic or obese participants’ QoL. QoL (SF-12, CLDQ-NAFLD) and coping
strategies (COPE-28) were evaluated in 307 biopsy-proven NAFLD patients with absence or
presence of diabetes or obesity. QoL was compared with normality tables for the general
Spanish population. Interactive effects were found in physical functioning (p = 0.008), role-
physical (p = 0.016) and activity (p = 0.014). Diabetic patients reported worse scores when
they were also obese and vice versa, that is, obese patients scored worse when they were also
diabetic. Both diabetic and obese patients had lower QoL than those without metabolic
pathology or the general population, and obese patients also reported more passive/avoidance
coping. Active coping, positive reframing and acceptance predicted better QoL, while denial,
self-blame, self-distraction, disengagement and religion predicted lower QoL. In conclusion,
diabetes and obesity were associated with lower QoL in patients with NAFLD. Obesity was
also associated with more passive/avoidance coping. Furthermore, passive/avoidance coping
strategies predicted lower QoL than active, recommending modification of maladaptive
coping strategies in future multidisciplinary NAFLD treatments. Keywords: NAFLD; quality
of life; coping strategies; type 2 diabetes mellitus; obesity.

Introduction

Nonalcoholic fatty liver disease (NAFLD) is a wide clinical spectrum spanning from hepatic
steatosis to nonalcoholic steatohepatitis, and can progress to different degrees of hepatic
fibrosis, cirrhosis and hepatocellular carcinoma (Sharma & Arora, 2020). In recent years,
NAFLD has become an alarming public health problem as the most common world-wide
cause of chronic hepatopathy (Marjot et al., 2020). Its prevalence is exponentially increasing
at the same rate as type 2 diabetes mellitus (T2DM) and obesity, as a consequence of a life
style based on unhealthy eating habits and sedentarism (Younossi, 2019). In fact, NAFLD,
considered as the hepatic manifestation of metabolic syndrome, has a close two-way
relationship with T2DM and obesity. On one hand, NAFLD is highly prevalent among
diabetics and the obese, and worsens the complications derived from these pathologies (Dai
et al., 2017; Li et al., 2016). On the other, the presence of T2DM and obesity in patients with
NAFLD favors the progression of liver damage (Polyzos et al., 2017; Radaelli et al., 2018).
NAFLD is associated with worse quality of life (QoL) than other alcoholic, viral, self-
immune or cholestatic hepatopathies (Afendy et al., 2009), or the general population (Sayiner

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et al., 2016). The impact is mainly felt in physical functioning, which patients often refer to
as fatigue or lack of vitality (Younossi et al., 2017). Evidence of the influence of T2DM and
obesity on QoL is contradictory. While some studies have suggested greater deterioration in
QoL, mainly physical, associated with the presence of T2DM or obesity along with NAFLD
(Younossi & Henry, 2015; Younossi et al., 2017), others have found no significant difference
in absence or presence of either metabolic pathology (Sayiner et al., 2016; Tapper & Lai,
2016).
T2DM and obesity usually impact negatively on patient psychosocial adjustment, and
therefore, the most frequent and appropriate coping strategies for stress associated with the
disease should be determined (Tuncay et al., 2008). Studies disagree about whether these
metabolic pathologies are associated with more use of active coping strategies (Féki et al.,
2019; Terrazas-Romero et al., 2018), or passive/avoidance (Coelho et al., 2003; Fettich &
Chen, 2012). The relevance of this issue stems from active coping usually predicting better
global QoL in both diabetics and obese than avoidance coping (Karimi et al., 2016; Terrazas-
Romero et al., 2018). The same trend is observed in chronic hepatic patients (Jurado et al.,
2011), although for the moment there are no results available for NAFLD.
In this context, we analyzed the differences in QoL and coping strategies of patients with
NAFLD by assessing whether T2DM and obesity were present or not, employing data from
the general Spanish population to compare QoL. We also determined what coping strategies
predicted QoL in both diabetics and obese. We hypothesized that patients would have worse
QoL and more passive/avoidance coping when they had T2DM or obesity, and
passive/avoidance coping strategies would predict worse QoL than active coping in these
patients.

Methods

Participants

The sample of this cross-sectional study consisted of 307 patients with biopsy-proven NAFLD
(192 men and 115 women) with a mean age of 52.6 ± 12.2. Access to patient records was
acquired in 2018 to conduct the study. All patients gave their informed consent for
participation. This research was approved by the Ethics Committee of the Virgen del Rocío
University Hospital of Seville and was conducted in accordance with the 1975 Declaration of
Helsinki. Four groups were formed based on the T2DM (G1 = absence, G2 = presence) and
obesity (G3 = absence, G4 = presence) variables. The sociodemographic characteristics of the
groups are shown in Table 1. Data from the general Spanish population (n = 4261) for QoL

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(SF-12) (Schmidt et al., 2012) were also considered.

Table 1. Intergroup comparison of sociodemographic variables: Type 2 diabetes mellitus (T2DM)

(absence and presence) and obesity (absence and presence).
Intergroup
T2DM Effect Sizes
Comparisons
Absence (G1) Presence (G2)
n = 250 n = 57
M (SD) M (SD) t (p) Cohen’s d
51.3 58.3 t(1, 305) = −4.04
Age −0.60 M
(12.0) (11.5) (<0.001)
% % χ2 (p) Cohen’s w
Gender
χ2(1) = 0.64
Male 63.6 57.9 0.05 N
(0.422)
Female 36.4 42.1
Marital status
χ2(1) = 0.75
With partner 77.2 82.5 0.05 N
(0.386)
Without partner 22.8 17.5
Education
Low 37.6 47.4 χ2(2) = 1.92
0.08 N
Medium 31.6 28.1 (0.383)
High 30.8 24.6
Employment
χ2(1) = 4.39
Working 60.8 45.6 0.12 S
(0.036)
Not working 39.2 54.4
Intergroup
Obesity Effect Sizes
Comparisons
Absence (G3) Presence (G4)
n = 165 n =142
M (SD) M (SD) t (p) Cohen’s d
52.0 53.2 t(1, 305) = −0.86
Age −0.10 N
(12.4) (11.9) (0.391)
% % χ2 (p) Cohen’s w
Gender
χ2(1) = 0.04
Male 63.0 62.0 0.01 N
(0.848)
Female 37.0 38.0
Marital status
χ2(1) = 0.08
With partner 78.8 77.5 −0.02 N
(0.780)
Without partner 21.2 22.5
Education
Low 43.0 35.2 χ2(2) = 2.73
0.09 N
Medium 30.9 31.0 (0.256)
High 26.1 33.8
Employment
χ2(1) = 2.16
Working 61.8 53.5 0.08 N
(0.142)
Not working 38.2 46.5
N: null effect size; S: small effect size; M: medium effect size.
Independent sample t-test (age), and Pearson’s Chi-square (categorical variables) were applied.
Instruments

12-Item Short Form Health Survey (SF-12v.2) (Maruish, 2012; Ware et al., 2002). This scale

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evaluates the following health-related QoL dimensions: physical functioning, role-physical,
bodily pain, general health, vitality, social functioning, role-emotional and mental health.
Using the Quality Metric Health OutcomesTM Scoring Software 5.0. (QualityMetric
Incorporated LLC, Johnston, RI, United States), two summary components may be found, the
physical component summary (PCS) and mental component summary (MCS). Scores vary
from 0 (worst state of health) to 100 (best state of health), where higher scores show better
QoL. The Cronbach’s alpha varied from 0.70 to 0.93 for the various dimensions and was 0.92
and 0.88 for the PCS and MCS, respectively (Maruish, 2012).
Chronic Liver Disease Questionnaire-Non-Alcoholic Fatty Liver Disease (CLDQ-
NAFLD) (Younossi et al., 2017). This measure evaluates the following NAFLD-related QoL
dimensions: abdominal symptoms, activity, emotional, fatigue, systemic symptoms and
worry, as well as a total score for the scale. Scores vary from 1 to 7, higher scores showing
better QoL. The Cronbach’s alpha varied from 0.65 to 0.86 for the different dimensions, and
was 0.92 for the total score.
The Brief COPE (COPE-28) (Carver, 1997; Morán et al., 2010). This evaluates the
following coping strategies: active coping, planning, instrumental support, emotional support,
self-distraction, venting, disengagement, positive reframing, denial, acceptance, religion,
substance use, humor and self-blame. Scores can vary from 0 to 3. Higher scores show more
use of the coping strategy. The Cronbach’s alpha varied from 0.74 to 1.00 for the various
subscales.

Procedure

As shown in Figure 1, 307 patients with NAFLD were selected from 12 Spanish hospitals.
Inclusion criteria were: (a) over 18 years old, (b) diagnosis of biopsy-proven NAFLD without
significant fibrosis, (c) informed consent, (d) no severe or disabling psychopathological
condition and (e) being able to understand the evaluation instruments. Furthermore, keeping
in mind the transcendence of significant fibrosis in the biopsychosocial profile of the NAFLD
patient, as independently associated with worse QoL and more passive/avoidance coping
(Funuyet-Salas et al., 2020), the presence of significant fibrosis was considered an exclusion
criterion in this study. Cancelling out the potential effect of fibrosis on the results enabled a
more precise analysis of the influence of the metabolic pathology on the biopsychosocial
profile associated with NAFLD. The participants were classified by absence or presence of
T2DM and obesity, and evaluated using a psychosocial interview and the SF-12 (Maruish,
2012; Ware et al., 2002), CLDQ-NAFLD (Younossi et al., 2017) and COPE-28 (Carver, 1997;

141
Morán et al., 2010). Recruited patients answered the questionnaires prospectively. The
questionnaires were filled in by the participants on paper forms, and their data transferred to
a common database.

Figure 1. Participant selection for the study.

Statistical Analysis

To compare the sociodemographic variables, the Pearson’s Chi-square was applied to the
categorical variables (gender, marital status, education and employment), and the independent
sample t-test for age. A 2 × 2 factorial ANOVA (Snedecor’s F) was done to analyze the
influence of absence or presence of T2DM and obesity on QoL (SF-12, CLDQ-NAFLD) and
coping strategies (COPE-28). Cohen’s d (for continuous variables) and w (for categorical
variables) were computed as effect size indexes. According to Cohen (Cohen, 1988), effect
sizes can be null (d, < 0.2; w, < 0.1), small (d, > 0.2; w, > 0.1), medium (d, > 0.5; w, > 0.3) or
large (d, > 0.8; w, > 0.5). A stepwise multiple linear regression analysis was performed to
analyze what coping strategies predicted QoL (criterion or dependent variable; PCS, MCS,
and total CLDQ-NAFLD) in both diabetic and obese patients with NAFLD. A series of
statistical parameters were calculated for this: to begin with, the unstandardized (B) and
standardized (β) partial regression coefficients, and their standard error (SE). This coefficient
reports the relationship between the dependent and the independent variables, so the farther
from 0, the stronger the intensity of the relationship. The sign of the coefficient suggests the
direction of the relationship: when positive, that the higher the value of the coping strategy is,

142
 the higher the quality of life, while if it is negative, it shows that the quality of life decreases
with higher value of coping strategy. Furthermore, t-test significance was estimated such that
a p below 0.05 confirmed a statistically significant relationship between the independent
variable and the criteria variable. Finally, the coefficient of determination (R2), which refers
to the proportion of variability in the dependent variable explained by the set of independent
variables, was found. This coefficient varies from 0 to 1, and the higher it is, the more
explanatory the model proposed is. R2 can be overestimated depending on the number of
independent variables in the model, and therefore, it is usually corrected by the number of
degrees of freedom, which yields the corrected coefficient of determination (∆R2). Statistical
requirements for the implementation of linear regression analysis (linearity, independence of
residuals, homoscedasticity, and no-multicollinearity) were fulfilled.

Results

Sociodemographic Variables

In most of the sociodemographic variables (age, gender, marital status, education and
employment) there were no important between-groups differences (null or small effect sizes)
(Table 1), except diabetic patients (G2) were older than nondiabetics (G1) (p < 0.001, d =
−0.60, Table 1).

Influence of T2DM and Obesity on QoL and Coping Strategies

The results are shown in Tables 2 (SF-12), 3 (CLDQ-NAFLD) and 4 (COPE-28). Three
statistically significant interactive effects were found: physical functioning (p = 0.008, Table
2), role-physical (p = 0.016, Table 2) and activity (p = 0.014, Table 3).

Table 2. Quality of life (SF-12) of patients with nonalcoholic fatty liver disease (NAFLD) by T2DM (absence and
presence) and obesity (absence and presence) variables.
T2DM Obesity Interaction
Main Effects
Ma (SD) Ma (SD) Effects
SF-12 Absence Presence Absence Presence T2DM Obesity
F(1, 303)
(G1) (G2) (G3) (G4) F(1, 303) F(1, 303)
(p)
n = 250 n = 57 n = 165 n = 142 p (d) p (d)
5.53 15.03
Physical 80.4 69.7 83.8 66.2 7.03
0.019 <0.001
functioning (30.4) (31.1) (45.0) (34.4) (0.008)
(0.35 S) (0.44 S)
5.03 11.97
84.8 76.4 87.1 74.1 5.89
Role-physical 0.026 0.001
(25.1) (25.8) (37.4) (28.6) (0.016)
(0.33 S) (0.39 S)
80.7 72.6 78.5 74.8 4.46 0.90 0.10
Bodily pain
(25.8) (26.3) (38.1) (29.2) 0.036 0.343 (0.756)

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 (0.31 S) (0.11 N)
1.28 8.26
53.8 49.6 57.0 46.3 1.15
General health 0.259 0.004
(24.8) (25.4) (36.9) (28.2) (0.284)
(0.17 N) (0.32 S)
2.08 10.95
62.5 56.9 66.1 53.3 2.93
Vitality 0.150 0.001
(25.9) (26.5) (38.4) (29.4) (0.088)
(0.21 S) (0.37 S)
3.99 6.79
91.0 85.1 91.9 84.2 3.33
Social functioning 0.047 0.010
(19.9) (20.4) (29.5) (22.6) (0.069)
(0.29 S) (0.29 S)
0.16 0.72
84.0 82.6 84.8 81.7 1.47
Role-emotional 0.693 0.398
(24.2) (24.8) (36.0) (27.5) (0.225)
(0.06 N) (0.10 N)
0.00 0.78
73.3 73.4 74.8 71.9 3.62
Mental health 0.987 0.379
(22.1) (22.6) (32.7) (25.1) (0.058)
(−0.00 N) (0.10 N)
7.32 13.05
50.0 46.3 50.6 45.6 2.80
PCS 0.007 <0.001
(9.2) (9.4) (13.6) (10.4) (0.095)
(0.40 S) (0.41 S)
0.01 0.62
52.24 52.3 52.8 51.7 2.00
MCS 0.941 0.433
(9.5) (9.7) (14.1) (10.8) (0.159)
(−0.01 N) (0.09 N)
N: null effect size; S: small effect size; PCS: Physical component summary; MCS: Mental component summary.
2 × 2 factorial ANOVA was applied.
a
Higher scores show more quality of life.

Table 3. Quality of life (CLDQ-NAFLD) of patients with nonalcoholic fatty liver disease (NAFLD) by T2DM
(absence and presence) and obesity (absence and presence) variables.
T2DM Obesity Interaction
Main Effects
Ma (SD) Ma (SD) Effects
CLDQ-NAFLD Absence Presence Absence Presence T2DM Obesity
F(1, 303)
(G1) (G2) (G3) (G4) F(1, 303) F(1, 303)
(p)
n = 250 n = 57 n = 165 n = 142 p (d) p (d)
0.27 2.78
Abdominal 5.8 5.7 5.9 5.6 0.02
0.601 0.096
symptoms (1.4) (1.4) (2.0) (1.5) (0.880)
(0.08 N) (0.19 N)
7.10 17.76
6.0 5.6 6.1 5.5 6.07
Activity 0.008 <0.001
(1.1) (1.1) (1.5) (1.2) (0.014)
(0.39 S) (0.49 S)
0.63 0.07
5.9 5.8 5.9 5.9 0.07
Emotional 0.428 0.795
(0.9) (1.1) (1.5) (1.2) (0.797)
(0.12 N) (0.03 N)
4.50 4.85
5.7 5.3 5.7 5.3 1.81
Fatigue 0.035 0.028
(1.1) (1.2) (1.7) (1.3) (0.179)
(0.32 S) (0.25 S)
11.37 3.72
Systemic 6.1 5.7 6.0 5.8 0.14
0.001 0.055
symptoms (0.8) (0.8) (1.3) (0.9) (0.710)
(0.52 M) (0.21 S)
6.4 6.2 6.4 6.3 2.86 0.98 0.01
Worry
(0.8) (0.7) (1.2) (0.8) 0.092 0.323 (0.925)

144
 (0.25 S) (0.11 N)
6.00 7.17
6.0 5.7 6.0 5.7 1.07
Total 0.015 0.008
(0.8) (0.7) (1.0) (0.8) (0.303)
(0.35 S) (0.32 S)
N: null effect size; S: small effect size; M: medium effect.
2 × 2 factorial ANOVA was applied.
a
Higher scores show more quality of life.

Table 4. Simple effects in physical functioning (SF-12), role-physical (SF-12) and activity (CLDQ-
NAFLD).
Absence T2DM Presence T2DM
Obesity
(G1) n = 250 (G2) n = 57
p Cohen’s d p Cohen’s d
Physical Functioning (SF-12)
Absence-presence 0.148 0.19 N <0.001 0.99 L
Role-Physical (SF-12)
Absence-presence 0.222 0.16 N 0.001 0.89 L
Activity (CLDQ-NAFLD)
Absence-presence 0.039 0.26 S <0.001 1.01 L
T2DM Absence Obesity Presence Obesity
(G3) n = 165 (G4) n = 142
p Cohen’s d p Cohen’s d
Physical Functioning (SF-12)
Absence-presence 0.846 −0.04 N <0.001 0.76 M
Role-Physical (SF-12)
Absence-presence 0.905 −0.03 N <0.001 0.71 M
Activity (CLDQ-NAFLD)
Absence-presence 0.897 0.04 N <0.001 0.79 M
N: null effect size; S: small effect size; M: medium effect size; L: large effect size.

As observed in Table 4 and in Figure 2, the simple effects showed statistically significant
differences, with relevant effect sizes (medium or large), in the groups with T2DM (G2) or
obesity (G4). In particular, diabetic patients showed less physical functioning (d = 0.99), role-
physical (d = 0.89) and activity (d = 1.01) if they were obese. Similarly, obese patients had
less physical functioning (d = 0.76), role-physical (d = 0.71) and activity (d = 0.79) if they
were diabetic.

Figure 2. Interactive effects regarding physical functioning, role-physical and

activity dimensions in patients with NAFLD.

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 Concerning the main effects, QoL (SF-12, CLDQ-NAFLD) was worse for diabetic (G2)
than nondiabetic (G1) patients, regardless of absence or presence of obesity. Their scores were
lower in physical functioning (d = 0.35), role-physical (d = 0.33), bodily pain (d = 0.31),
social functioning (d = 0.29), PCS (d = 0.40), activity (d = 0.39), fatigue (d = 0.32), systemic
symptoms (d = 0.52) and total CLDQ-NAFLD (d = 0.35) (Tables 2 and 3, Figure 3). It was
also worse for obese patients (G4) than those who were not (G3), whether they had T2DM or
not, with worse scores in physical functioning (d = 0.44), role-physical (d = 0.39), general
health (d = 0.32), vitality (d = 0.37), social functioning (d = 0.29), PCS (d = 0.41), activity
(d = 0.49), fatigue (d = 0.25) and total CLDQ-NAFLD (d = 0.32) (Tables 2 and 3, Figure 3).
The main differences from the general Spanish population (GSP) were in the comparison with
diabetic (G2) and obese (G4) patients, who had worse QoL in physical functioning (T2DM, d
= −0.52; obesity, d = −0.60), role-physical (T2DM, d = −0.29; obesity, d = −0.36), general
health (T2DM, d = −0.37; obesity, d = −0.46), vitality (T2DM, d = −0.44; obesity, d = −0.54),
role-emotional (T2DM, d = −0.29; obesity, d = −0.31) and PCS (T2DM, d = −0.39; obesity,
d = −0.44) (Figure 3). Nevertheless, no statistically significant differences were found in the
main effects of coping strategies (COPE-28) between diabetic patients (G2) and nondiabetic
(G1). However, obese patients (G4), whether or not they had T2DM, had lower scores in active
coping (d = 0.25) and acceptance (d = 0.25), and higher in disengagement (d = −0.30), than those
who were not obese (G3) (Table 5).

146
 Figure 3. Comparison of quality of life (SF-12) of groups of patients and the general Spanish
population.

Note. G1: absence T2DM; G2: presence T2DM; G3: absence obesity; G4: presence obesity; GSP:
general Spanish population; PCS: physical component summary; MCS: mental component summary;
N: null effect size; S: small effect size; M: medium effect size.

Table 5. Coping strategies (COPE-28) of patients with NAFLD by T2DM (absence and presence) and obesity (absence
and presence) variables.
T2DM Obesity Interaction
Main Effects
Ma (SD) Ma (SD) Effects
COPE-28 Absence Presence Absence Presence T2DM Obesity
F(1, 303)
(G1) (G2) (G3) (G4) F(1, 303) F(1, 303)
(p)
n = 250 n = 57 n = 165 n = 142 p (d) p (d)
0.47 4.15
2.0 2.1 2.2 1.9 1.72
Active coping 0.495 0.042
(0.8) (0.7) (1.0) (0.8) (0.191)
(−0.09 N) (0.25 S)
0.02 1.62
1.4 1.4 1.5 1.3 0.47
Planning 0.898 0.205
(1.1) (1.1) (1.5) (1.2) (0.494)
(0.02 N) (0.15 N)
2.52 1.67
Instrumental 1.2 1.4 1.4 1.2 0.01
0.114 0.197
support (0.9) (1.1) (1.5) (1.2) (0.902)
(−0.24 S) (0.14 N)
0.96 1.35
1.1 1.2 1.3 1.1 0.00
Emotional support 0.327 0.247
(1.1) (1.1) (1.5) (1.2) (1.000)
(−0.14 N) (0.13 N)
Self-distraction 0.8 0.8 0.8 0.8 0.22 0.14 1.30

147
 (0.9) (1.0) (1.4) (1.1) 0.641 0.707 (0.255)
(−0.07 N) (0.04 N)
0.29 1.56
1.0 1.1 0.9 1.1 0.53
Venting 0.592 0.213
(0.9) (1.1) (1.5) (1.2) (0.468)
(−0.09 N) (−0.14 N)
1.20 5.65 2.47
0.2 0.2 0.1 0.3
Disengagement 0.273 0.018 (0.117)
(0.5) (0.4) (0.6) (0.5)
(0.15 N) (−0.30 S)
0.50 3.34
1.4 1.5 1.6 1.3 2.77
Positive reframing 0.481 0.069
(0.9) (1.1) (1.5) (1.2) (0.097)
(−0.10 N) (0.20 S)
0.00 2.07
0.2 0.2 0.1 0.2 0.73
Denial 0.996 0.151
(0.3) (0.4) (0.5) (0.4) (0.392)
(0.00 N) (−0.18 N)
0.56 4.55
2.2 2.1 2.2 2.0 0.75
Acceptance 0.455 0.034
(0.6) (0.7) (1.0) (0.8) (0.388)
(0.11 N) (0.25 S)
0.15 0.01
0.9 0.9 0.9 0.9 0.11
Religion 0.697 0.940
(1.3) (1.2) (1.8) (1.3) (0.741)
(−0.06 N) (−0.01 N)
2.08 0.12
1.1 1.4 1.3 1.2 0.65
Humor 0.150 0.724
(1.1) (1.1) (1.5) (1.2) (0.421)
(−0.21 S) (0.04 N)
0.33 0.81 2.95
0.5 0.4 0.4 0.5
Self-blame 0.564 0.368 (0.087)
(0.6) (0.7) (1.0) (0.8)
(0.09 N) (−0.11 N)
0.16 0.16
0.16
Use Abuse 0 0 0 0 0.689 0.689
(0.689)
(0.00 N) (0.00 N)
N: null effect size; S: small effect size
2 x 2 factorial ANOVA was applied.
a
Higher scores show more use of the coping strategy.

Coping Strategies Predicting QoL

The results of the multiple linear regression analysis of diabetic (G2) and obese (G4) patients
are presented in Tables 6–8. In both groups, the final model (T2DM, F(1, 55) = 12.50, p = 0.001;
obesity, F(1, 140) = 16.10, p < 0.001) consisted of one significant PCS (SF-12) predictor: in
diabetics, denial (p = 0.001), and in obese patients active coping (p < 0.001). This model
explained 18.5% and 10.3% of the variance observed in PCS (SF-12) in diabetic and obese
patients, respectively (Table 6).

148
 Table 6. Coping strategies as predictors of physical component summary (SF-12).
Predictor
B SE β t (p) R2 ∆R2
Variables
T2DM
Step 1 0.18 0.17
−3.53
Denial −12.26 3.47 −0.43
(0.001)
Obesity
Step 1 0.10 0.10
4.01
Active coping 4.18 1.04 0.32
(<0.001)
A stepwise multiple linear regression analysis was applied.

Table 7. Coping strategies as predictors of mental component summary (SF-12).

Predictor
B SE β t (p) R2 ∆R2
Variables
T2DM
Step 4 0.40 0.35
Acceptance 4.11 1.51 0.33 2.73 (0.009)
Self-distraction −2.15 0.99 −0.24 −2.17 (0.034)
Disengagement −6.47 2.89 −0.27 −2.24 (0.029)
Religion −1.80 0.80 −0.24 −2.24 (0.030)
Obesity
Step 3 0.41 0.40
Positive reframing 3.55 0.66 0.36 5.34 (<0.001)
Self-blame −4.36 0.97 −0.32 −4.51(<0.001)
Denial −4.83 1.73 −0.20 −2.79 (0.006)
A stepwise multiple linear regression analysis was applied.

Table 8. Coping strategies as predictors of quality of life (total CLDQ-NAFLD).

Predictor
B SE β t (p) R2 ∆R2
Variables
T2DM
Step 2 0.41 0.38
−4.44
Denial −1.07 0.24 −0.48
(<0.001)
Positive reframing 0.27 0.09 0.31 2.86 (0.006)
Obesity
Step 3 0.32 0.31
−3.59
Denial −0.58 0.16 −0.28
(<0.001)
Active coping 0.30 0.08 0.28 3.78 (<0.001)
Self-blame −0.27 0.09 −0.23 −3.05 (0.003)
A stepwise multiple linear regression analysis was applied.

Concerning MCS (SF-12), the final model (T2DM, F(4, 52) = 8.53, p < 0.001; obesity, F(3,
138) = 32.53, p < 0.001) consisted of four predictors for diabetics (G2) and three for obese (G4)
patients. In diabetics these were acceptance (p = 0.009), self-distraction (p = 0.034),

149
disengagement (p = 0.029) and religion (p = 0.030), and in obese patients, positive reframing
(p < 0.001), self-blame (p < 0.001) and denial (p = 0.006). This model explained 39.6% and
41.4% of the variance observed in MCS (SF-12) in diabetic and obese patients, respectively
(Table 7).
The final CLDQ-NAFLD model (T2DM, F(2, 54) = 18.53, p < 0.001; obesity, F(3, 138) =
22.11, p < 0.001) consisted of two predictors for diabetic (G2) and three for obese (G4)
patients. In both groups, denial (T2DM, p < 0.001; obesity, p < 0.001). Furthermore, positive
reframing (p = 0.006) in diabetics, and active coping (p < 0.001) and self-blame (p = 0.003)
in obese patients. This model explained 40.7% and 32.5% of the variance observed in total
quality of life (CLDQ-NAFLD) in diabetic and obese patients, respectively (Table 8).

Discussion

This study analyzed the differences in QoL and coping strategies of NAFLD patients with
and without T2DM and obesity. It also determined what coping strategies predicted QoL in
diabetic and obese patients with NAFLD. There were no important sociodemographic
differences between the groups compared, except age, where diabetic participants were older
than those without metabolic pathology, as already observed in other studies (Kasteleyn et al.,
2016; Li et al., 2020).
Significant interaction effects of T2DM and obesity on QoL, but not on coping strategies,
were found in physical functioning, role-physical and activity. An additional analysis revealed
that of the diabetic patients, those who were obese scored worse on these three QoL
dimensions, as the obese patients with T2DM did. Thus, the combination of both metabolic
pathologies predicted worse patient QoL (Oldridge et al., 2001), particularly physical. This
deterioration in physical functioning and activity had already been recently mentioned in other
studies on diabetic and obese populations with NAFLD (Barcones-Molero et al., 2018;
Younossi et al., 2017).
When patients with and without T2DM were compared, whether obese or not, the diabetics
referred to worse QoL, again focusing on physical differences (physical functioning, role-
physical, bodily pain, social functioning, PCS, activity, fatigue, systemic symptoms, and total
CLDQ-NAFLD). Along the same line, obese patients also reported worse QoL, mainly
physical (physical functioning, role-physical, general health, vitality, social functioning, PCS,
activity, fatigue, and total CLDQ-NAFLD), than those who were not, regardless of absence
or presence of T2DM. Our results therefore contradicted the conclusions of Sayiner et al.
(2016), and Tapper and Lai (2016) and agreed with Younossi and Henry (2015) and Younossi

150
et al. (2017), as we confirmed the significant effect of T2DM and obesity on the QoL of
patients with NAFLD. Comparison with the general Spanish population ratified this
conclusion, with diabetics and obese people showing greater decline in their QoL, mainly
their physical health (physical functioning, role-physical, general health, vitality, role-
emotional and PCS). In line with previous studies in other countries (Hassan et al., 2003;
Kalka, 2014), diabetics and obese people generally perceived less functional capacity and
energy than healthy people, which is closely associated with characteristic problems in these
patients such as resistance to insulin or oxidative stress.
Despite previous evidence noting an impact of T2DM on patient coping (Coelho et al.,
2003; Féki et al., 2019), in our study, absence or presence of T2DM made no difference in the
coping strategies employed by participants. Nevertheless, obese patients did have
significantly lower scores on active coping and acceptance, and higher on disengagement,
than those who were not. Thus, as found by Fettich and Chen (2012), obesity was associated
with more passive/avoidance coping. Body dissatisfaction could partly explain these results,
as it has been linked with less active coping by the obese based on behavioral disengagement
as their main coping strategy (Brytek-Matera, 2011).
We were also able to confirm that coping strategies predict QoL of patients with NAFLD:
in diabetics, denial, and in the obese, active coping predicted PCS; acceptance, self-
distraction, disengagement and religion predicted MCS in diabetics, while positive reframing,
self-blame, and denial did so in the obese. Finally, denial and positive reframing predicted the
total CLDQ-NAFLD in diabetics, while denial, active coping and self-blame did in obese.
Our results therefore revealed that an active coping style, focused on action (active coping,
positive reframing or acceptance), was associated with better QoL in diabetics and obese
people, in line with other studies (Karimi et al., 2016; Terrazas-Romero et al., 2018). On the
contrary, a passive/avoidance coping style (denial, self-blame, self-distraction or
disengagement) was related to greater decline, mainly in the mental QoL, of these patients.
This type of coping, more focused on emotion, predicts worse mental health and a higher
presence of distress and maladaptive health behavior in people with T2DM or obesity, which
implies negative consequences to their QoL (Terrazas-Romero et al., 2018). Lastly, religion,
which may be active or passive/avoidance, predicted worse QoL in the diabetic participants
in this study. Religion as a coping strategy has previously been associated with more
depressive symptomatology and self-blame in these patients, who interpret the disease as
punishment for what they have done in their lives (Caballero, 2018).

151
 Summarizing, this study found differences in the QoL of patients with NAFLD by absence
or presence of T2DM and obesity, in which diabetics and obese patients had a worse QoL.
There were also differences in coping strategies used by patients by absence or presence of
obesity, where obese participants used more passive/avoidance coping. Finally, for the first
time, we can confirm the importance of coping strategies in NAFLD: active coping, positive
reframing and acceptance predicted better QoL, while denial, self-blame, self-distraction,
disengagement and religion predicted worse QoL in these patients. The results of this study
are clinically relevant, because they suggest the need for multidisciplinary treatments for
patients with NAFLD who have not yet developed significant fibrosis, in which intervention
in coping strategies should be a major element. The main goal would be to reduce the use of
passive/avoidance strategies associated with more helplessness and demotivation in
complying with therapeutic recommendations (Jurado et al., 2011), and therefore, with worse
therapeutic adherence. Considering that this is certainly low in patients with NAFLD (Serfaty,
2018), perception of controllability and confidence in managing the disease and its treatment
should be promoted, especially in diabetics and obese people. This would lead them to have
more faith in active coping strategies. An active coping style, based on acceptance of the
disease and on positive reinterpretation of its implications and treatment, would probably
involve stronger commitment and active participation of the patient in the NAFLD
intervention plan, based mainly on following the physical activity and diet plans. This would
lead to greater weight loss, better clinical evolution, and therefore, better patient quality of
life (Shayeghian et al., 2015).
The implementation of cognitive-behavioral intervention strategies has shown positive
effects on coping style and QoL of patients with chronic metabolic disorders (Riveros et al.,
2005). Thus, decision-making and problem-solving could be emphasized, first so patients
learn to identify the barriers that keep them from losing weight, and later, to plan, analyze and
carry out a series of alternatives for solving these problems; cognitive restructuration, which
modifies those cognitive biases and unrealistic expectations for losing weight, promoting a
more adaptive way of thinking and improving their functional status; and time management,
where times during the day that could be used for cooking healthy food or doing physical
exercise are planned with the patient (Bellentani et al., 2008). These techniques could promote
active coping in diabetics and obese patients diagnosed with NAFLD, which would contribute
to keeping the disease from evolving to its most advanced stages. This becomes especially
relevant, since in the coming years, cirrhosis secondary to NAFLD is expected to rank as the
first cause of liver transplant in the world (Mantovani et al., 2020). Furthermore, the absence
152
of effective pharmacological therapies in the treatment of NAFLD (Pennisi et al., 2019)
justifies the need to promote a multidisciplinary approach to NAFLD intervention, in which
psychological biomarkers would be an important target.
Our study had some limitations. For example, possible collinearity with age in T2DM.
Variables such as self-efficacy, responsibility for health or therapeutic adherence could also
have affected the relationship of QoL and coping described in this study, and its analysis
would be important to future multidisciplinary treatment of NAFLD. Finally, normative QoL
data for the general Spanish population were obtained from a cohort from a single Spanish
region (Schmidt et al., 2012). However, the large size of the sample, made up of patients from
real clinical practice in several different Spanish hospitals, constitutes a major strength of this
study, and all the participants were biopsy-proven NAFLD patients, which provides added
value to the validity of the study results.

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4.6. Sexto trabajo titulado “Influence of psychological biomarkers on therapeutic
adherence by patients with non-alcoholic fatty liver disease: A moderated mediation
model”

Este trabajo corresponde al artículo publicado que se referencia a continuación:

Funuyet-Salas, J., Martín-Rodríguez, A., Pérez-San-Gregorio, M. Á., & Romero-Gómez, M.

(2021). Influence of psychological biomarkers on therapeutic adherence by patients with non-
alcoholic fatty liver disease: A moderated mediation model. Journal of Clinical Medicine,
10(10), 2208. https://doi.org/10.3390/jcm10102208

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Abstract

Our aim was to analyze whether depressive symptoms mediated the association between
physical quality of life (QoL) and adherence to physical activity in patients with non-alcoholic
fatty liver disease (NAFLD), as well as the association between social support and adherence
to diet. We also examined whether self-efficacy exerted a moderating role in these
associations. QoL (SF-12), social support (MSPSS), depressive symptoms (HADS), self-
efficacy (GSE), physical activity (IPAQ) and diet (MEDAS) were evaluated in 413 biopsy-
proven NAFLD patients. Mediation and moderated mediation models were conducted using
the SPSS PROCESS v3.5 macro. Results showed that depressive symptoms mediated the
relationship between physical QoL and adherence to physical activity (indirect effect = 6.248,
CI = 1.917–10.727), as well as the relationship between social support and adherence to diet
(indirect effect = 0.148, CI = 0.035–0.275). Self-efficacy also moderated the indirect effects
of QoL and social support on therapeutic adherence through depressive symptoms.
Specifically, the higher self-efficacy was, the lower the negative impact on the NAFLD
patient’s mental health. In conclusion, self-efficacy is defined as a protective factor for
therapeutic adherence by NAFLD patients with a psychosocial risk profile. Self-efficacy
should, therefore, be a main psychological target in future multidisciplinary NAFLD
approaches. Keywords: NAFLD; therapeutic adherence; self-efficacy; quality of life; social
support; depressive symptoms; physical activity; Mediterranean diet.

Introduction

Today’s predominant lifestyle, based on sedentarism and a diet high in saturated fats and
sugars, has brought on severe metabolic consequences. Non-alcoholic fatty liver disease
(NAFLD), closely related to metabolic diseases, such as type 2 diabetes mellitus (T2DM) and
obesity, in recent years, has become the main cause of chronic liver disease (Marjot et al.,
2020; Younossi et al., 2016). It is even expected to emerge in the short-term future as the main
cause of liver transplantation in the world, which makes NAFLD an alarming public health
problem (Younossi et al., 2019).
NAFLD patients must comply with a therapeutic plan based on changing their lifestyle.
The combined plans of the European Association for the Study of the Liver, European
Association for the Study of Diabetes and the European Association for the Study of Obesity
(EASL-EASD-EASO) recommend 150–200 min of moderately intense aerobic physical
activity for a total of three to five weekly sessions. Resistance training is also effective. In
addition, they also recommend a Mediterranean diet, which restricts foods with a high

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saturated fat or sugar content and promotes foods rich in monounsaturated fatty acids and
omega-3 (EASL-EASD-EASO, 2016; Romero-Gómez et al., 2017). Compliance with these
plans is necessary to lose 10% of their body weight, which is fundamental to achieve a
reduction in steatosis, improvement in inflammation or regression of liver fibrosis (Reginato
et al., 2019; Vilar-Gómez et al., 2015). However, therapeutic adherence is inadequate in more
than half of NAFLD patients (Serfaty, 2018). This could be partly explained by the lack of
willpower these patients commonly have for changing (Centis et al., 2013) and the effects that
certain psychological biomarkers could have on following long-term therapeutic
recommendations.
In this sense, NAFLD is closely associated with a negative impact on the patient’s quality
of life (QoL) and mental health, mainly worse physical functioning (Assimakopoulos et al.,
2018; Golabi et al., 2016) and more depressive symptoms than other chronic liver diseases or
the general population (Huang et al., 2017; Weinstein et al., 2011). The state of physical and
mental health predicts regular practice of physical activity in diabetic and obese patients
(Daniele et al., 2013; Mazzeschi et al., 2012); however, there is no evidence in this respect in
NAFLD patients.
In addition, satisfactory social support favors successful continued behavior changes
related to weight loss (Karfopoulou et al., 2016) and has been linked to a decrease in the
intensity and frequency of concomitant depressive symptoms in chronic liver patients
(Blasiole et al., 2006). This is important, because both social support and mental health
determine how a person manages stressful everyday situations, such as those derived from
staying on a long-term diet (Sepúlveda et al., 2012; Steese et al., 2006). In fact, worse dieting
behavior has been found in diabetic and obese patients who report depression and insufficient
social support (Chang et al., 2008; Naicker et al., 2017; Simon et al., 2008; Tang et al., 2008).
The relationship between social support and mental health in NAFLD has recently been
demonstrated (Funuyet-Salas et al., 2020a); however, its impact on therapeutic adherence in
these patients is still unknown.
Finally, self-efficacy has demonstrated its importance in managing chronic illnesses, as it
can confirm the patient’s perception of his/her ability to change health-related behavior
(O'Sullivan & Strauser, 2009). To feel motivated to undertake a task, one must have
confidence in the chances of success (Bandura, 1977; Bandura, 1986). As less self-efficacy
has been found in NAFLD patients than in other chronic liver diseases (Frith et al., 2010), this
could be a critical factor in understanding the lack of motivation these patients have for their
treatment. Many studies have found better performance of physical activity and diet by
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 diabetic and obese patients who have high perceived self-efficacy (Adam & Folds, 2014;
Dutton et al., 2009; Leung et al., 2019; Leung et al., 2020). Similar results were found by
Zelber-Sagi et al. in a study with 146 ultrasound-diagnosed NAFLD patients (Zelber-Sagi et
al., 2017); however, more evidence is necessary to confirm the importance of self-efficacy in
these patients.
In this context, we proposed testing how physical QoL, perceived social support,
depressive symptoms, self-efficacy, adherence to diet and physical activity are interrelated in
NAFLD patients. We also analyzed whether depressive symptoms mediate the relationship
between physical QoL and adherence to physical activity, on one hand, and on the other, the
relationship between perceived social support and adherence to diet. Finally, in both cases,
we examined whether self-efficacy moderates these relationships.

Methods

Participants

We selected a group of 413 patients with biopsy-proven NAFLD (252 men and 161 women)
with a mean age of 55.5 ± 11.6 years. The study was approved by the Ethics Committee of
the Virgen del Rocío University Hospital of Seville. Table 1 shows the sociodemographic
characteristics of the patients who gave their informed consent for their participation. This
study followed the 1975 Helsinki Declaration guidelines for good clinical practice.

Table 1. Univariate analyses of the differences in adherence to physical activity and diet by sociodemographic and
clinic variables.
Adherence to Adherence to
M (SD) physical activity r (p) diet r (p)
M (SD) M (SD)
Age 55.1 (11.6) 925.9 (1130.2) −0.08 (0.112) 8.1 (2.3) 0.18 (<0.001)
BMI 30.8 (5.2) 925.9 (1130.2) −0.17 (<0.001) 8.1 (2.3) −0.11 (0.025)
Adherence to Adherence to
Total N (%) physical activity t/F (p) diet t/F (p)
M (SD) M (SD)
Gender t(1, 411) =
t(1, 398.052) = 2.43
Male 252 (61.0) 1027.1 (1228.5) 7.9 (2.3) −2.92
(0.016)
Female 161 (39.0) 767.5 (938.2) 8.5 (2.3) (0.004)
Marital status t(1, 133.560) =
t(1, 411) = 0.69
With partner 321 (77.7) 905.4 (1126.3) 8.2 (2.2) −1.09
(0.491)
Without partner 92 (22.3) 997.6 (1147.3) 7.9 (2.6) (0.279)
Education
F(2, 410) =
Low 182 (44.1) 883.7 (997.2) F(2, 410) = 0.25 8.4 (2.2)
2.50
Medium 118 (28.6) 941.8 (1241.7) (0.775) 7.9 (2.2)
(0.083)
High 113 (27.3) 977.3 (1214.7) 8.0 (2.6)
Employment t(1, 411) = 0.38 t(1, 411) =
Working 198 (47.9) 947.8 (1269.5) (0.706) 7.9 (2.3) −2.25

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 Not working 215 (52.1) 905.7 (987.4) 8.4 (2.3) (0.025)
NASH t(1, 411) =
t(1, 411) = 0.46
Absence 178 (43.1) 955.4 (1210.8) 8.3 (2.4) 1.37
(0.646)
Presence 235 (56.9) 903.6 (1067.3) 8.0 (2.2) (0.170)
Significant
t(1, 411) =
fibrosis t(1, 411) = 0.66
257 (62.2) 954.7 (1233.4) 8.1 (2.3) −0.09
Absence (0.508)
156 (37.8) 878.5 (937.7) 8.1 (2.3) (0.927)
Presence
Type 2 Diabetes t(1, 411) =
t(1, 411) = 0.31
Absence 279 (67.5) 914.0 (1135.2) 8.1 (2.3) −0.23
(0.757)
Presence 134 (32.4) 950.8 (1123.6) 8.2 (2.4) (0.815)
Obesity t(1, 411) =
t(1, 365.427) = 3.51
Absence 198 (47.9) 1128.7 (1265.3) 8.4 (2.3) 2.06
(0.001)
Presence 215 (52.1) 739.2 (955.3) 7.9 (2.3) (0.040)
The Pearson correlation (age, BMI), independent samples t-test (gender, marital status, employment, NASH,
significant fibrosis, type 2 diabetes, obesity) and analysis of variance (education) were applied.

Instruments

The 12-Item Short Form Health Survey (SF-12v.2) evaluates health-related QoL in 12 items
rated on three- or five-point Likert-type scales (Maruish, 2012; Ware et al., 2002). Using
Quality Metric Health Outcomes TM Scoring Software 5.0. (QualityMetric Incorporated
LLC, Johnston, RI, United States), two summary components can be calculated, the mental
and the physical component summary (PCS). In this study, we only analyzed the latter because
NAFLD mainly impacts on the patient’s physical quality of life (Assimakopoulos et al., 2018;
Golabi et al., 2016). Scores vary from 0 (worst health condition) to 100 (best heath condition),
with higher scores indicating better QoL. In our sample, the Cronbach’s alpha for the different
dimensions varied from 0.73 to 0.94, while for the PCS it was 0.92 (Maruish, 2012).
The Multidimensional Scale of Perceived Social Support (MSPSS) evaluates perceived
social support from family, friends and a partner or significant other in 12 items rated on a
seven-point Likert-type scale (Zimet et al., 1988). The instrument provides a total scale
corresponding to the average of the scores on each of its items. Scores vary from 1 to 7, with
higher scores indicating more social support. We used the Spanish version of the instrument
(Landeta & Calvete, 2002). The Cronbach’s alpha was 0.95 for the total scale, while it varied
from 0.96 to 0.99 for the various social support dimensions.
The Hospital Anxiety and Depression Scale (HADS) measures anxiety and depressive
symptoms in 14 items on a four-point Likert-type scale (Zigmond & Snaith, 1983). The
instrument provides a total score for anxiety and another for depression. In this study, we only
analyzed the latter because the NAFLD impact on the mental health of patients is mainly on
depressive symptoms (Huang et al., 2017; Weinstein et al., 2011). The scores vary from 0 to

162
21, with higher scores showing worse mental health. We used the Spanish version of the
instrument (Caro & Ibáñez, 1992). The Cronbach’s alpha was 0.89 for the total depression
score.
The General Self-Efficacy Scale (GSE) evaluates the perceived ability to manage stressful
situations in everyday life adequately in ten items on a ten-point Likert-type scale (Baessler
& Schwarzer, 1996). The instrument provides a total corresponding to the sum of scores on
each of the items. Scores vary from 10 to 100 for the total score, with higher scores indicating
more self-efficacy. We used the Spanish version of the instrument (Sanjuán-Suárez et al.,
2000). The Cronbach’s alpha was 0.95 for the total instrument.
The International Physical Activity Questionnaire—Short Form (IPAQ-SF) measures the
intensity, frequency and duration of an individual’s physical activity in seven items that ask
about the time spent during the past week doing vigorous- and moderate-intensity activities,
as well as walking and time spent sitting (Craig et al., 2003). The instrument provides a total
score corresponding to the individual’s weekly physical activity, which is calculated based on
the sum of the metabolic equivalent of task (METs) per minute and week found for vigorous,
moderate physical activity and for walking. High scores indicate more physical activity. Due
to the scale’s characteristics, the composite reliability index was used to check its internal
consistency (Fornell & Larcker, 1981), which varied from 0.91 to 0.95 for its different
dimensions.
The Mediterranean Diet Adherence Screener (MEDAS) measures dietary patterns in 14
items scored from 0 to 1 by their habits and frequency of eating certain foods (olive oil,
legumes, fruit and vegetables, etc.) in the traditional Mediterranean diet or not (Schröder et
al., 2011). Scores vary from 0 to 14 for the total scale, with higher scores indicating better
adherence to the Mediterranean diet. The Cronbach’s alpha was 0.52 for the total instrument
scale.

Procedure

The sample consisted of 413 NAFLD patients (Figure 1), from ten Spanish hospitals. The
inclusion criteria were: over 18 years of age, diagnosed with NAFLD by liver biopsy, give
their informed consent to participate, not have been diagnosed with any severe or disabling
psychopathological condition and able to understand the study assessment instruments. All of
the participants were assessed by the same psychologist, using the same assessment
instruments and always applied in the following order: psychosocial interview, SF-12, HADS,
EAG, MSPSS, IPAQ and MEDAS.

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 Figure 1. Participant selection for the study.

Statistical Analysis

The independent samples t-test and analysis of variance (ANOVA) were applied to examine
the differences in adherence to physical activity and diet in the sample by sociodemographic
(gender, age, marital status, education, employment) and clinic (NASH, significant fibrosis,
type 2 diabetes, body mass index (BMI) and obesity) characteristics.
Pearson correlations were used to analyze the associations between physical QoL,
perceived social support, self-efficacy, depressive symptoms, adherence to physical activity
and diet.
The mediation and moderated mediation models were computed using the SPSS
PROCESS macro (Version 3.5, Columbus, OH, United States) developed by Hayes (Hayes
& Rockwood, 2017). First, depressive symptoms were established as mediator in the
relationship between physical QoL and adherence to physical activity, using Model 4 (Hayes,
2018). The same model was applied to check whether the depressive symptoms mediated the
relationship between perceived social support and adherence to diet. In both cases, 5000
bootstrap samples were used to test the indirect effects estimated. The effect of mediation was
significant if the 95% confidence interval (CI) of the indirect effects did not contain 0. Then,
Model 7 (Hayes, 2018) was used, again with 5000 bootstrap samples, to analyze the
moderated mediation effect, that is, whether self-efficacy moderated the indirect effects of
physical QoL on adherence to physical activity through depressive symptoms. The same
model was applied to check whether self-efficacy also moderated the indirect effects of
perceived social support on adherence to diet through depressive symptoms.
The pick-a-point approach and Johnson–Neyman technique, using the PROCESS macro,
checked the significance of moderation. The pick-a-point approach found three groups for the
moderator, which could be classified as those participants with low, medium and high scores
on this variable. In continuation, this technique calculated the conditional effect of the
predictor variable on the criterion variable for each of those values, generating a confidence

164
 interval (Hayes & Matthes, 2009). The Johnson–Neyman technique determined the regions
of values in the range of the moderator variable where the effect of the predictor variable on
the continuous variable was significant (Hayes & Matthes, 2009). A two-sided p-value < 0.05
was considered statistically significant.

Results

Sociodemographic and Clinic Variables

Of the 413 participants with a mean age of 55.5 (SD = 11.6) and a BMI of 30.8 (SD = 5.2),
61% were men and 39% women, 77.7% had a partner, 44.1% had a low education, 47.9%
were actively employed, 56.9% had NASH, 37.8% had significant fibrosis, 32.4% were
diabetics, and 52.1% were obese. The mean score on physical activity was 925.9 (SD =
1130.2), while on adherence to diet, it was 8.1 (SD = 2.3). The results of the independent
samples t-test and ANOVA showed significant gender (p = 0.016) and obesity (p = 0.001)
differences in the scores on adherence to physical activity. The scores on adherence to diet
also showed significant gender (p = 0.004), obesity (p = 0.040) and employment (p = 0.025)
differences. Finally, there was a significant positive correlation between age and scores on
adherence to diet (p < 0.001) and a significant negative correlation between BMI and scores
on adherence to physical activity (p < 0.001) and diet (p = 0.025), as shown by the Pearson
correlation analysis (Table 1).

Correlation Analysis

The Pearson correlation analysis (Table 2) revealed that adherence to physical activity was
positively associated with physical QoL (r = 0.19, p < 0.001), while adherence to diet was
positively associated with perceived social support (r = 0.22, p < 0.001). Both were also
positively associated with self-efficacy (physical activity, r = 0.18, p < 0.001; diet, r = 0.18,
p < 0.001) and negatively associated with depressive symptoms (physical activity, r = −0.19,
p < 0.001; diet, r = −0.20, p < 0.001). Furthermore, both physical QoL and social support
were positively associated with self-efficacy (QoL, r = 0.46, p < 0.001; social support, r =
0.56, p < 0.001) and negatively associated with depressive symptoms (QoL, r = −0.52, p <
0.001; social support, r = −0.56, p < 0.001). Self-efficacy was negatively associated with
depressive symptoms (r = −0.70, p < 0.001).

Table 2. Intercorrelations of adherence to physical activity, adherence to diet, physical quality of life, social support,
self-efficacy and depressive symptoms.

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Variables M (SD) 1 2 3 4 5 6
1. Adherence to physical activity 925.9 (1130.2) 1 0.21 *** 0.19 *** 0.16 ** 0.18 *** −0.19 ***
2. Adherence to diet 8.1 (2.3) 0.21 *** 1 0.09 0.22 *** 0.18 *** −0.20 ***
3. Physical quality of life 46.9 (10.5) 0.19 *** 0.09 1 0.34 *** 0.46 *** −0.52 ***
4. Social support 5.9 (1.2) 0.16 ** 0.22 *** 0.34 *** 1 0.56 *** −0.56 ***
5. Self-efficacy 64.7 (18.8) 0.18 *** 0.18 *** 0.46 *** 0.56 *** 1 −0.70 ***
6. Depressive symptoms 2.8 (3.8) −0.19 *** −0.20 *** −0.52 *** −0.56 *** −0.70 *** 1
* p < 0.05; ** p < 0.01; *** p < 0.001; Pearson correlation was applied.

Mediation Analysis

Figure 2 shows the significant indirect effect of depressive symptoms mediating in the
association between physical QoL and adherence to physical activity (6.127, p = 0.047). The
bootstrapped 95% CI did not include 0 (1.633 to 10.566), confirming the significant indirect
effect of physical QoL on adherence to physical activity through depressive symptoms. The
direct effect of physical QoL on the adherence to physical activity was not significant after
mediation analysis (8.437, p = 0.190), showing full mediation of depressive symptoms.

Figure 2. Depressive symptoms mediate the

relationship between physical quality of life and
adherence to physical activity.

Note. The coefficients represent the indirect and

direct effects estimated. Gender, BMI and obesity
were entered in the analysis as covariates. * p <
0.05; ** p < 0.01; *** p < 0.001.

Figure 3 shows the significant indirect effect of depressive symptoms mediating in the
association between perceived social support and adherence to diet (0.136, p = 0.020). The
bootstrapped 95% CI did not include 0 (0.022 to 0.261), confirming the significant indirect
effect of social support on adherence to diet through depressive symptoms. The direct effect
of perceived social support on adherence to diet was significant after mediation analysis
(0.318, p = 0.004), showing partial mediation of depressive symptoms.

Figure 3. Depressive symptoms mediate the

relationship between perceived social support

166
 and adherence to diet.

Note. The coefficients represent the indirect and

direct effects estimated. Gender, age, employment,
BMI and obesity were entered in the analysis as
covariates. * p < 0.05; ** p < 0.01; *** p < 0.001.

Moderated Mediation Analysis

The moderated mediation analyses determined whether self-efficacy moderated the effects of
physical QoL and perceived social support on adherence to physical activity and diet,
respectively, through depressive symptoms.
Figure 4 shows the results of the moderated mediation model for adherence to physical
activity. The results revealed that self-efficacy moderated the relationship between physical
QoL and depressive symptoms (β = 0.004, p < 0.001). The Johnson–Neyman technique
showed that the effects of perceived social support on depressive symptoms were significant
at the different levels of self-efficacy from 10 to 71.474 (56.6% of the participants), where
the conditional effect of physical QoL was stronger, the lower self-efficacy was. Similarly,
the pick-a-point approach (Table 3 and Figure 5) showed that the negative effects of physical
QoL on depressive symptoms lessened with rising self-efficacy, measured at three levels: low
self-efficacy, equivalent to a standard deviation below the mean (effect = −0.147, p < 0.001);
medium self-efficacy, equivalent to the mean (effect = −0.061, p < 0.001); high self-efficacy,
equivalent to a standard deviation above the mean (effect = 0.025, p = 0.210), where the effect
of physical QoL on depressive symptoms was no longer significant.

Figure 4. The moderating effect of self-efficacy on the

relationship between physical quality of life and adherence to
physical activity through depressive symptoms.

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 Note. The coefficients represent the moderating, indirect and direct
effects estimated. Gender, BMI and obesity were entered in the
analysis as covariates. * p < 0.05; ** p < 0.01; *** p < 0.001.

Table 3. Effects of moderation by self-efficacy on the relationship between physical

quality of life and depressive symptoms.
Bootstrapped 95% CI
Self-Efficacy Effect (SE) t (p)
Lower Upper
Low: 45.6 (M − 1 SD) −0.147 (0.016) −9.06 (<0.001) −0.179 −0.115
Medium: 64.7 (M) −0.061 (0.014) −4.34 (<0.001) −0.089 −0.033
High: 83.8 (M + 1 SD) 0.025 (0.020) 1.25 (0.210) −0.014 0.064
M: mean; SD: standard deviation; SE: standard error; CI: confidence interval; the pick-a-
point approach was applied to check the significance of moderation effects.

Figure 5. Self-efficacy moderates the effect of physical quality of life on

depressive symptoms.

Note. M, mean; SD, standard deviation.

Table 4 shows the conditional indirect effects of physical QoL on adherence to physical
activity through depressive symptoms at the three self-efficacy levels. The results revealed a

168
significant fall in conditional indirect effect as self-efficacy increased (low self-efficacy,
effect = 5.043, 95% CI = 1.391 to 8.915; medium self-efficacy, effect = 2.091, 95% CI =
0.509 to 3.963; high self-efficacy, effect = −0.861, 95% CI = −3.030 to 0.534), and the
conditional indirect effect at this last level of self-efficacy was not even statistically significant
any longer. In the pairwise comparisons between conditional indirect effects, the bootstrapped
95% CI did not include 0 (medium level–low level of self-efficacy, effect = −2.952, 95% CI
= −5.513 to −0.760; high level–low level of self-efficacy, effect = −5.903, 95% CI = −11.026
to −1.520; high level–medium level of self-efficacy, effect = −2.952, 95% CI = −5.513 to
−0.760), confirming that the mediation effect was moderated by self-efficacy.
Table 4. Conditional indirect effect of physical quality of life on adherence to physical
activity through depressive symptoms.
Bootstrapped 95% CI
Self-Efficacy Effect (BootSE)
Lower Upper
Effect 1 Low: 45.6 (M − 1 SD) 5.043 (1.957) 1.391 8.915
Effect 2 Medium: 64.7 (M) 2.091 (0.904) 0.509 3.963
Effect 3 High: 83.8 (M + 1 SD) −0.861 (0.912) −3.030 0.534
Effect 2 − Effect 1 −2.952 (1.230) −5.513 −0.760
Effect 3 − Effect 1 −5.903 (2.460) −10.969 −1.520
Effect 3 − Effect 2 −2.952 (1.230) −5.513 −0.760
M: mean; SD: standard deviation; BootSE: bootstrap standard error; CI: confidence
interval; bootstrapping was employed to analyze the conditional indirect effect.

Figure 6 shows the results of the moderated mediation model for adherence to diet. The
results revealed that self-efficacy moderated the relationship between perceived social support
and depressive symptoms (β = 0.027, p < 0.001). The Johnson–Neyman technique showed
that the effects of perceived social support on depressive symptoms were significant at the
various levels of self-efficacy from 10 to 74.338 (62.1% of the participants), where the
conditional effect of perceived social support was stronger, the lower self-efficacy was.
Similarly, the pick-a-point approach (Table 5 and Figure 7) showed that the negative effects
of perceived social support on depressive symptoms decreased as self-efficacy increased,
measured at three levels: low self-efficacy, equivalent to a standard deviation below the mean
(effect = −1.060, p < 0.001); medium self-efficacy, equivalent to the mean (effect = −0.549,
p < 0.001); high self-efficacy, equivalent to a standard deviation above the mean (effect =
−0.037, p = 0.832), where the effect of perceived social support on depressive symptoms was
no longer significant.

Figure 6. The moderating effect of self-efficacy on the relationship between

perceived social support and adherence to diet through depressive symptoms.

169
 Note. The coefficients represent the moderating, indirect and direct effects
estimated. Gender, age, employment, BMI and obesity were entered in the
analysis as covariates. * p < 0.05; ** p < 0.01; *** p < 0.001

Table 5. Effects of moderation by self-efficacy on the relationship between perceived

social support and depressive symptoms.
Bootstrapped 95% CI
Self-Efficacy Effect (SE) t (p)
Lower Upper
Low: 45.6 (M − 1 SD) −1.060 (0.134) −7.92 (<0.001) −1.323 −0.797
Medium: 64.7 (M) −0.549 (0.128) −4.30 (<0.001) −0.799 −0.298
High: 83.8 (M + 1 SD) −0.037 (0.177) −0.21 (0.832) −0.385 0.310
M: mean; SD: standard deviation; SE: standard error; CI: confidence interval; the pick-a-
point approach was applied to check the significance of moderation effects.

Figure 7. Self-efficacy moderates the effect of social support on depressive symptoms.

Note. M, mean; SD, standard deviation.

Table 6 shows the conditional indirect effects of perceived social support on adherence to
diet at the different self-efficacy levels through depressive symptoms. The results revealed

170
significantly lower conditional indirect effects as self-efficacy increased (low self-efficacy,
effect = 0.090, 95% CI = 0.013 to 0.177; medium self-efficacy, effect = 0.047, 95% CI =
0.006 to 0.097; high self-efficacy, effect = 0.003, 95% CI = −0.027 to 0.036), and the
conditional indirect effect was not even statistically significant any longer on this level of self-
efficacy. In the pairwise comparisons between conditional indirect effects, the bootstrapped
95% CI did not include 0 (medium level–low level of self-efficacy, effect = −0.043, 95% CI
= −0.088 to −0.006; high level–low level of self-efficacy, effect = −0.087, 95% CI = −0.176
to −0.013; high level–medium level of self-efficacy, effect = −0.043, 95% CI = −0.088 to
−0.006), confirming that the mediation effect was moderated by self-efficacy.
Table 6. Conditional indirect effect of social support on adherence to diet through
depressive symptoms.
Bootstrapped 95% CI
Self-Efficacy Effect (BootSE)
Lower Upper
Effect 1 Low: 45.6 (M − 1 SD) 0.090 (0.042) 0.013 0.177
Effect 2 Medium: 64.7 (M) 0.047 (0.023) 0.006 0.097
Effect 3 High: 83.8 (M + 1 SD) 0.003 (0.015) −0.027 0.036
Effect 2 − Effect 1 −0.043 (0.021) −0.088 −0.006
Effect 3 − Effect 1 −0.087 (0.042) −0.176 −0.013
Effect 3 − Effect 2 −0.043 (0.021) −0.088 −0.006
M: mean; SD: standard deviation; BootSE: bootstrap standard error; CI: confidence
interval; bootstrapping was employed to analyze the conditional indirect effect.

Discussion

The impact of doing physical activity and following a Mediterranean diet on NAFLD
has been widely studied in recent years (Franco et al., 2021; Kim et al., 2021; Salehi-
Sahlabadi et al., 2021; Younossi et al., 2021). At the same time, the relevance of
psychological biomarkers has also been recently proven in NAFLD (Funuyet-Salas et
al., 2020a; Funuyet-Salas et al., 2021). However, to date, the influence of psychological
biomarkers on therapeutic adherence has not been studied in these patients. Our study,
therefore, examined whether physical QoL, social support, depressive symptoms and
self-efficacy were significantly associated with participants performing physical activity
and staying on their diet. It also examined whether depressive symptoms mediated, on
one hand, the relationship between physical QoL and the adherence to physical activity,
and on the other, the relationship between perceived social support and adherence to
diet. In both cases, it was further found whether self-efficacy moderated these
relationships.
This study found therapeutic adherence of participants to be similar to what was
171
found in other studies on NAFLD (Aller et al., 2019; Lotfi et al., 2019). The results of
the univariate analyses showed significant differences in therapeutic adherence of
participants by gender, employment, age, BMI and obesity. To begin with, women
reported better maintenance of the Mediterranean diet and less physical activity than
men, in agreement with previous studies on NAFLD (Khalatbari-Soltani et al., 2020;
Bullón-Vela et al., 2019). Concerning employment, those participants who were
actively employed followed the Mediterranean diet less, as also found previously
(Cuschieri & Libra, 2020). In line with Giraldi et al. (2020), age significantly correlated
with adherence to diet, such that older participants referred more to eating the
Mediterranean diet. Finally, a higher BMI and the presence of obesity were associated
with less physical activity and poorer adherence to the Mediterranean diet, confirming
the close link between metabolic pathology and an inadequate lifestyle (Giraldi et al.,
2020; Joo et al., 2020).
As expected, the results showed that physical QoL, perceived social support,
depressive symptoms and self-efficacy were significantly associated with therapeutic
adherence by NAFLD patients. Depressive symptoms fully mediated the relationship
between physical QoL and adherence to physical activity. First, poor QoL predicted
stronger depressive symptoms, confirming the relationship previously found between
QoL and depression in NAFLD (Funuyet-Salas et al., 2020a; Younossi et al., 2017).
Greater depression, in turn, predicted less physical activity by participants, as had
previously been found in healthy individuals (Ohmori et al., 2017), diabetics (Adam &
Folds, 2014) and obese (Mazzeschi et al., 2012). Metabolic alterations characteristic of
NAFLD would, thus, lead to deterioration in physical functioning, which through its
impact on mental health, would interfere negatively with the patient’s participation in
physical activities. This, in turn, would lead to an increase in body weight and worse
state of physical and mental health in a vicious circle with negative physical and
psychological consequences for the patient (Burgess et al., 2017; Gerber et al., 2014).
At the same time, depressive symptoms partially mediated the relationship between
perceived social support and adherence to diet. Low social support directly predicted
worse maintenance of the Mediterranean diet by participants, as had been proven
previously in patients with T2DM (Tang et al., 2008), obesity (Chang et al., 2008) and
cardiovascular disease (Aggarwal et al., 2010). Perception of social support could buffer
or strengthen the negative effects of certain factors, such as lack of time to cook or the
temptation to eat unhealthy foods, on long-term maintenance of a Mediterranean diet
172
(Aggarwal et al., 2010, Barberia et al., 2008). In fact, eating has been described as a
“social behavior”, determined by social norms and pressures and by the influence of the
closest setting (Ball et al., 2010). In our study, low social support further predicted
stronger depressive symptoms, which was also related to participants adhering less to
their diet. The relationship between social support and mental health of NAFLD patients
is, thus, confirmed (Funuyet-Salas et al., 2020a), as is that depressive symptoms predict
worse eating habits in adults who need to modify their lifestyle to lose weight (Somerset
et al., 2011).
In addition, the moderated mediation analyses revealed that self-efficacy moderated
the relationship between physical QoL and adherence to physical activity, on one hand,
and on the other, the relationship between perceived social support and adherence to
diet, both through depressive symptoms. The indirect effects of QoL and social support
on therapeutic adherence through depressive symptoms were reinforced in patients with
low self-efficacy and attenuated in those with high perceived self-efficacy. According
to Bandura, self-efficacy is a prerequisite for modifying behavior, since the person must
be confident that he/she can carry out the action and that the results will be favorable or
beneficial (Bandura, 1977; Bandura, 1986). Along this line, in the Health Belief Model
(Harvey & Lawson, 2009), self-efficacy is essential for patients to feel motivated to
modify their long-term physical activity and eating habits. This would explain the
protective role of self-efficacy in our study with regard to therapeutic adherence: the
higher self-efficacy was, the lower the negative effect that low physical QoL and low
social support had on doing physical activity and following the Mediterranean diet,
respectively, through depressive symptoms. Thus, high self-efficacy would protect from
physical discomfort and pressures or lack of support in one’s close social setting
(Burgess et al., 2017; Navidian et al., 2013), which in turn would be associated with
lower concomitant depressive symptoms (Adam & Folds, 2014; Gutteling et al., 2010;
Linde et al., 2004). Strengthening self-efficacy in NAFLD patients would then lead them
to tolerate and cope more adaptively with this type of obstacle or problem and, therefore,
show more optimism, commitment and engagement toward therapeutic
recommendations for physical activity and eating.
The results of this study demonstrate the need to progress from the traditional
lifestyle intervention model, in which the NAFLD patient is only encouraged to carry
out certain therapeutic recommendations, with poor adherence results, to a collaborative
intervention model (Franz et al., 2007; Serfaty, 2018). It is important to have
173
multidisciplinary teams comprising physicians, nurses, psychologists and nutritionists
who help the patient overcome the barriers that impede behavioral change, such as low
self-efficacy, poor physical or mental health or lack of social support, as corroborated
in our study (Funuyet-Salas et al., 2020b; Younossi et al., 2017). First, modification of
lifestyle must be undertaken with individualized therapeutic plans designed together
with the patient, in which quantifiable and specific, realistic and yet challenging goals
are set, for example, walk for 20 min a day, eat only when sitting at table or lose half a
kilo a week (Hunt et al., 2012). The achievement of these goals would normally be
associated with a gradual increase in the patient’s perceived self-efficacy (Bellentani et
al., 2008; Fabricatore, 2007), which would strengthen therapeutic adherence. For those
patients who refer to limited physical or mental health, recommended therapeutic
strategies include reducing the intensity of physical activity at first and increasing it
gradually as agreed with the patient; learning to manage those negative emotions linked
to doing physical activity; or providing the patient with resources, such as relaxation or
meditation that enable him/her to manage those stressful situations that lead him/her to
eating (Barberia et al., 2008; Hussien et al., 2020). Finally, intervention should include
support from a significant other, such as spouse or cohabiting family member who can
encourage the patient to make healthy changes in the home menu or go out for a walk,
which could reinforce behavioral change and, thereby, drive a healthier lifestyle and
better therapeutic adherence (Cohen, 2009).
Our study showed some limitations. First, the low Cronbach’s alpha of the MEDAS
questionnaire showed low internal consistency, as had been found in previous studies in
other countries that had also used this questionnaire (Mahdavi-Roshana et al., 2018;
Vieira et al., 2020). Second, the cross-sectional design of the study impeded determining
the long-term evolution of the results. Third, it would be necessary to validate
generalization of the results to NAFLD patients in other populations, since it would have
to be analyzed whether cultural diversity in lifestyle influences the relationship found
between psychological biomarkers and therapeutic adherence. Nevertheless, the large
size of the study sample, comprising biopsy-proven NAFLD patients from real clinical
practice in several Spanish hospitals may be considered the main strength of this study.
Our study confirmed for the first time the importance of psychological biomarkers
such as physical QoL, social support, depressive symptoms and self-efficacy in
therapeutic adherence by NAFLD patients. Depressive symptoms mediated, on one
hand, the relationship between physical QoL and adherence to physical activity, and on
174
the other, the relationship between social support and adherence to diet by participants.
Furthermore, self-efficacy exerted a moderating role in the indirect effects of physical
QoL and social support through depressive symptoms on adherence to physical activity
and dietary recommendations. The higher patient self-efficacy was, the more these
indirect effects were attenuated. Therefore, future multidisciplinary NAFLD treatments
should consider the impact of these psychological biomarkers on therapeutic adherence
and, especially, design therapeutic strategies to improve the self-efficacy of these
patients.

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5. OVERVIEW OF RESULTS

 Objective 1: Discuss the psychological biomarkers that could be significant for the
biopsychosocial profile associated with non-alcoholic fatty liver disease.
The first study in this Ph.D. thesis, “Psychological biomarker profile in NAFLD/NASH with
advanced fibrosis”, was intended to begin by examining the literature to find out the main
psychosocial repercussions of NAFLD. The evidence evaluating the impact of this disease on
patient quality of life and mental health found an inversely proportional relationship between
quality of life and the severity of liver pathology, in which mainly physical quality of life
deteriorates. The symptoms associated with the disease could contribute to this negative
impact on quality of life, mainly fatigue.
Liver damage severity, taking non-alcoholic steatohepatitis and liver fibrosis as references,
and considering presence of type 2 diabetes and obesity the main risk factors associated with
NAFLD, could contribute to the decline in quality of life generally experienced by these
patients. There is also evidence of the negative effect these factors have on the mental health
of NAFLD patients, which leads to greater prevalence of anxiety and depressive symptoms
than other chronic liver pathologies or in the general population.
This theoretical study also explored other psychological biomarkers that have not been
sufficiently studied in NAFLD, such as coping strategies, self-efficacy and social support.
However, considering their relevance to the subjective wellbeing and therapeutic adherence
of people with type 2 diabetes or obesity, they probably have an important role in the quality
of life, mental health and therapeutic adherence of NAFLD patients.
Lastly, questions related to the treatment of NAFLD were approached, finding a need for
multidisciplinary teams in which psychologists, nutritionists and other health professionals
cooperate with doctors and nurses in the design and application of treatments including
cognitive-behavioral intervention programs and disease awareness campaigns.

 Objective 2: Determine the biopsychosocial profiles of NAFLD patients associated with

the severity of the disease.
The second study for this Ph.D. thesis, “Psychological biomarkers and fibrosis: An innovative
approach to non-alcoholic fatty liver disease”, compared quality of life, mental health and
coping strategies of NAFLD patients by their level of social support and presence or absence
of steatohepatitis and significant fibrosis, compared to quality-of-life data from the general
Spanish population. Interactive effects were found in the vitality (p = 0.047), activity (p =

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0.005), anxiety (p = 0.044) and denial (p = 0.042) dimensions. Patients with steatohepatitis
who perceived less social support had a higher-risk biopsychosocial profile. Regardless of the
presence or absence of steatohepatitis, patients with little social support had lower quality of
life, worse mental health and more maladaptive coping than those with strong social support.
Patients with significant fibrosis had worse quality of life than those who did not have
significant fibrosis or the general Spanish population. They also had worse mental health and
a more maladaptive coping style than patients without significant fibrosis.
The same study also intended to determine what histological and psychosocial markers
predicted quality of life of NAFLD patients. First, it found a significant inverse association
between quality of life and female gender (OR = 0.500, CI 95% = 0.254-0.981, p = 0.04),
significant fibrosis (OR = 0.500, CI 95% = 0.253-0.987, p = 0.04) and anxiety (OR = 0.858,
CI 95% = 0.758-0.971, p = 0.01) and depressive (OR = 0.758, CI 95% = 0.661-0.869, p <
0.001) symptoms. It also found a significant direct association between quality of life related
to physical health (OR = 1.174, CI 95% = 1.123-1.227, p < 0.001) and mental health (OR =
1.073, IC 95% = 1.022-1.125, p = 0.004) and quality of life linked specifically to the impact
of the liver disease.
The third study for this Ph.D. Thesis, “Health-related quality of life in non-alcoholic fatty
liver disease: A cross-cultural study of Spain and the United Kingdom”, compared the quality
of life of NAFLD patients by place of origin (Spain or the United Kingdom), by absence or
presence of steatohepatitis and by liver fibrosis severity. It found interactive effects in the
fatigue (p = 0.003) and total quality of life (p = 0.039) dimensions. Specifically, Spanish
patients referred to more fatigue and lower total quality of life the more severe their fibrosis
was. In addition, focusing on patients with only mild or no fibrosis, those in the United
Kingdom felt more fatigue and had a lower total quality of life than the Spaniards. Patients in
the United Kingdom also had more systemic symptoms and worry than the Spaniards,
regardless of liver severity. And irrespective of place of origin, patients with severe fibrosis
showed more fatigue, systemic symptoms and worry, and lower total quality of life than those
with none or only mild fibrosis.
This study also found that in the Spanish cohort, lower quality of life was independently
associated with a higher stage of fibrosis (OR = 0.290, CI 95% = 0.165-0.507, p < 0.001), a
higher MELD score (OR = 0.855, CI 95% = 0.744-0.982, p = 0.027), higher body mass index
(OR = 0.921, CI 95% = 0.875-0.970, p = 0.002) and female gender (OR = 0.297, CI 95% =
0.176-0.501, p < 0.001). In the cohort in the United Kingdom, lower quality of life was
predicted by higher body mass index (OR = 0.942, CI 95% = 0.889-0.999, p = 0.047), female
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gender (OR = 0.448, CI 95% = 0.219-0.915, p = 0.028), not working (OR = 0.336, CI 95% =
0.152-0.745, p = 0.007) and lower age (OR = 1.065, CI 95% = 1.029-1.102, p < 0.001).
The same study was able to confirm that the emotional function, the body mass index and
fatigue mediated the relationship between gender and quality of life in NAFLD patients (-
0.006, p < 0.001). The place of origin had a moderating role in this relationship (0.103, p <
0.001). Thus, female gender was related to worse emotional function, a higher body mass
index and more fatigue, which in turn, predicted lower patient quality of life. This negative
impact on quality of life was higher in patients in the United Kingdom than in Spain.
Finally, the fourth study for this Ph.D. Thesis, “Quality of life mediates the influence of
coping on mental health and self-efficacy in patients with non-alcoholic fatty liver disease”,
found that mental quality of life (-6.435, CI = -8.399 to -4.542) and role physical (-1.137, CI
= -2.141 to -0.315) mediated in the relationship between passive/avoidance coping style and
self-efficacy, moderated by liver fibrosis (0.367, p < 0.001). Thus, a passive/avoidance coping
style was associated with worse mental and physical quality of life, which in turn, predicted
less patient self-efficacy. This negative impact on self-efficacy was especially strong in
patients with significant fibrosis.

 Objective 3: Determine the biopsychosocial profile associated with the main risk factors
for non-alcoholic fatty liver disease (type 2 diabetes and obesity).
The fourth study for this Ph.D. Thesis, “Quality of life mediates the influence of coping on
mental health and self-efficacy in patients with non-alcoholic fatty liver disease”, examined
the effect of metabolic pathology (type 2 diabetes and obesity) on the NAFLD patient
biopsychosocial profile. First, it was found that vitality mediated the relationship between
active coping and depressive symptoms of NALFD patients (-2.254, CI = -2.792 to -1.765).
Both diabetes (-0.043, p = 0.017) and body mass index (-0.005, p = 0.009) were found to
moderate this relationship. So, less use of active coping strategies was associated with less
vitality, which in turn, predicted stronger patient depressive symptoms. This negative impact
on mental health was especially strong in patients with diabetes and higher body mass index.
The fifth study in this Ph.D. Thesis, “Quality of life and coping in nonalcoholic fatty liver
disease: Influence of diabetes and obesity”, compared NAFLD patient quality of life and
coping strategies by absence or presence of type 2 diabetes and obesity, and then taking data
on quality of life in the general Spanish population into account. Interactive effects were found
in the physical functioning (p = 0.008), role physical (p = 0.016) and activity (p = 0.014)
dimensions. Diabetic patients reported worse quality of life when they were also obese, and

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vice versa, that is, obese patients had worse scores when they were also diabetics.
Furthermore, both diabetic and obese patients had worse quality of life than those with
NAFLD without comorbid metabolic pathology, or the general Spanish population. Obese
patients, in turn, had a more passive/avoidance coping style than those who were not.
This study also determined what coping strategies predicted quality of life of diabetic and
obese NAFLD patients. The results showed that strategies such as acceptance, positive
reframing or active coping predicted better quality of life, while denial, self-blame, self-
distraction, disengagement or religion predicted worse quality of life.

 Objective 4: Determine what psychological variables influence therapeutic adherence by

NAFLD patients.
The sixth study for this Ph.D. Thesis, “Influence of psychological biomarkers on therapeutic
adherence by patients with non-alcoholic fatty liver disease: A moderated mediation model”,
found with regard to the influence of psychological biomarkers on therapeutic adherence by
NAFLD patients that depressive symptoms mediated the association between physical quality
of life and physical activity (6.248, CI = 1.917-10.727), and also the relationship between
social support and following a Mediterranean diet (0.148, CI = 0.035-0.275). Self-efficacy
moderated both relationships (physical activity, 0.004, p < 0.001; diet, 0.027, p < 0.001).
Thus, lower physical quality of life was associated with stronger depressive symptoms, which
in turn predicted performing less physical activity. Furthermore, less social support was
related to more depressive symptoms, which also predicted following a Mediterranean diet
less. In both cases, the stronger self-efficacy, the less the negative impact on patient mental
health, and therefore, on therapeutic adherence.

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6. DISCUSIÓN

A continuación, se discutirán los resultados de cada uno de los trabajos que componen esta
Tesis Doctoral. Asimismo, se analizarán y se relacionarán los hallazgos obtenidos, así como
las implicaciones derivadas de estos trabajos.

6.1. Primer trabajo: biomarcadores psicológicos que conforman el perfil biopsicosocial

de los pacientes con EHGNA

El estudio teórico que constituye el primer trabajo de esta Tesis Doctoral ha explorado las
repercusiones psicosociales que puede implicar la EHGNA, habiendo encontrado evidencias
en la literatura sobre su impacto en la calidad de vida y en la salud mental del paciente. A este
respecto, se ha mostrado el efecto que la gravedad del daño hepático, representada mediante
la esteatohepatitis no alcohólica y el nivel de fibrosis hepática, puede ocasionar sobre la salud
física y mental del paciente.
Este primer trabajo también ha discutido el rol que podrían jugar otros biomarcadores
psicológicos como las estrategias de afrontamiento, la autoeficacia y el apoyo social. Estas
variables podrían ser de potencial interés dentro del perfil biopsicosocial asociado a la
EHGNA teniendo en cuenta su relevancia para la calidad de vida, la salud mental y la
adherencia terapéutica de personas con diabetes tipo 2 y obesidad, principales comorbilidades
y factores de riesgo asociados a la EHGNA.
Finalmente, se ha señalado la pertinencia de apostar por un enfoque multidisciplinar en el
abordaje terapéutico de la EHGNA, que considere la importancia de los biomarcadores
psicológicos para la adherencia terapéutica de estos pacientes.
En consecuencia, este primer trabajo ha sentado las bases de las investigaciones empíricas
que constituyen esta Tesis Doctoral, en las que se ha propuesto determinar el perfil
biopsicosocial (calidad de vida, salud mental, estrategias de afrontamiento, autoeficacia y
apoyo social) asociado, por una parte, a los distintos niveles de gravedad hepática y, por otra
parte, a las principales comorbilidades metabólicas y factores de riesgo de la EHGNA. Por
último, también se ha planteado identificar biomarcadores psicológicos relevantes para la
adherencia terapéutica de estos pacientes.

6.2. Segundo, tercer y cuarto trabajo: perfil biopsicosocial asociado a los distintos niveles
de gravedad de la EHGNA (esteatohepatitis y fibrosis hepática)

Los resultados de estos tres trabajos muestran la relación entre los niveles de gravedad de la
EHGNA y el perfil biopsicosocial de estos pacientes. Por una parte, la esteatohepatitis, que
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hace referencia a la inflamación y daño de las células hepáticas. Por otro lado, la fibrosis
hepática, que alude al depósito progresivo de matriz extracelular en el hígado. Ambos factores
han sido estudiados en esta Tesis Doctoral por ser determinantes respecto al perfil clínico del
paciente con EHGNA (Dulai et al., 2017; Younossi & Henry, 2021).
La presente Tesis Doctoral ha partido de la hipótesis general de que ambos marcadores
hepáticos son determinantes también desde un punto de vista biopsicosocial. Esto ha llevado
a explorar en el segundo y tercer trabajo de la Tesis la relación tanto de la esteatohepatitis
como de la fibrosis con distintos biomarcadores psicológicos en pacientes con EHGNA,
utilizando para ello modelos factoriales de análisis de varianza.
Primero, se han analizado las diferencias en la calidad de vida, salud mental y estrategias
de afrontamiento de pacientes con EHGNA, en función de la esteatohepatitis, la fibrosis y la
percepción de apoyo social. En base a esto, para empezar, se ha identificado un perfil
biopsicosocial de mayor riesgo (menor vitalidad y actividad, y mayor ansiedad y negación)
en pacientes con esteatohepatitis que perciben un escaso apoyo social. Asimismo,
independientemente del nivel de gravedad hepática, los pacientes con un bajo apoyo social,
en comparación con aquellos con una alta percepción de apoyo, presentan una peor calidad
de vida, más sintomatología ansiosa y depresiva y un menor empleo de estrategias de
afrontamiento adaptativas como el afrontamiento activo, la aceptación, la planificación o la
reinterpretación positiva. En consecuencia, nuestros resultados confirman la relevancia del
apoyo social respecto a la salud física y mental en personas diagnosticadas con una
enfermedad hepática crónica (Blasiole et al., 2006), y promueven la creación de redes de
apoyo, como grupos de autoayuda, que ya han demostrado su eficacia en la mejora de la salud
de pacientes con diversas enfermedades crónicas (Kasser y Kosma, 2018; Payne et al., 2019;
Swanson et al., 2018).
No obstante, considerando los resultados del segundo trabajo de esta Tesis Doctoral, que
son ratificados en el tercero, se puede llegar a la conclusión de que la esteatohepatitis no
alcohólica no marca las diferencias a nivel psicológico, dado que no se han encontrado
diferencias significativas en la calidad de vida, salud mental o estrategias de afrontamiento de
pacientes con EHGNA en función de la ausencia o presencia de esteatohepatitis. Por lo tanto,
el grado de inflamación en el hígado no sería determinante desde un punto de vista
biopsicosocial, apoyando los resultados de David et al. (2009) pero contradiciendo las
conclusiones de investigaciones previas que si habían hallado una peor calidad de vida
asociada a la presencia de esteatohepatitis no alcohólica (Doward et al., 2021; Younossi et al.,
2019c).
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 Centrándonos en la calidad de vida, éste ha sido el biomarcador psicológico protagonista
de la presente Tesis Doctoral, con el objetivo de estudiar en profundidad el bienestar y el
funcionamiento físico, mental y social del paciente con EHGNA. De manera opuesta a la
esteatohepatitis, la fibrosis hepática sí ha sido establecida como una variable determinante
para la calidad de vida de los pacientes con EHGNA. Esto ha sido hallado en los mencionados
modelos factoriales de análisis de varianza, y confirmado en posteriores análisis de regresión
logística tanto en el segundo como en el tercer trabajo de la Tesis.
Tal y como se esperaba (David et al., 2009), se observa una relación inversa entre la
gravedad de la fibrosis y la calidad de vida reportada por los pacientes. En línea con otros
estudios (Assimakopoulos et al., 2018; Golabi et al., 2016; Sayiner et al., 2016; Younossi et
al., 2016), este deterioro se da principalmente a nivel físico, hallando las diferencias más
significativas en dimensiones de la calidad de vida como el funcionamiento físico, rol físico,
fatiga, actividad o síntomas sistémicos.
Con respecto a los niveles de gravedad de la fibrosis, hay que tener en cuenta que en el
tercer trabajo de esta Tesis los pacientes fueron categorizados, en función de los resultados de
la biopsia hepática, en un nivel de fibrosis nulo/leve (estadíos de fibrosis 0 y 1), moderado
(estadíos 2 y 3) o severo (estadío 4 o cirrótico). Entre todos estos niveles, se ha encontrado
que son los pacientes cirróticos quienes informan de una peor calidad de vida. En consonancia
con lo hallado en la literatura (David et al., 2009; McSweeney et al., 2020; Sayiner et al.,
2016), se trata de un deterioro generalizado de la calidad de vida, centrándose en este caso el
declive en una mayor fatiga y preocupación sobre la enfermedad, y en una mayor presencia
de síntomas físicos. Cabría pensar que la capacidad predictiva de la fibrosis se debe
exclusivamente al fuerte deterioro de la calidad de vida que se observa en pacientes cirróticos.
Sin embargo, al haber también diferencias significativas entre los niveles de fibrosis nula/leve
y moderada, nuestros resultados demuestran que la capacidad predictiva de la fibrosis sobre
la calidad de vida se mantiene a través de todos los niveles de gravedad de la enfermedad.
El impacto de la EHGNA sobre la calidad de vida del paciente podría ser en parte explicado
por la sintomatología asociada a la EHGNA, entre la que destacan problemas que afectan a la
funcionalidad del paciente como la somnolencia diurna (Newton et al., 2008) o la fatiga
(Golabi et al., 2016). De hecho, la fatiga ha sido vinculada previamente con la
neuroinflamación y con mecanismos neurofisiológicos alterados (Austin et al., 2015; Swain,
2006), hallándose una correlación positiva entre el nivel de citoqueratina-18 y la fatiga
reportada por el paciente (Alt et al., 2016). Al mismo tiempo, se han encontrado niveles
séricos más altos de citoqueratina-18 en pacientes con EHGNA en comparación con otros
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enfermos hepáticos crónicos, con una asociación positiva entre los niveles de esta proteína y
el grado de fibrosis hepática en el paciente (Darweesh et al., 2019; Alt et al., 2016). En
consecuencia, la acción de este tipo de biomarcadores podría ayudar a entender la relación
establecida entre fibrosis y calidad de vida en la EHGNA.
La calidad de vida de los pacientes con fibrosis significativa, es decir, aquellos con un nivel
de fibrosis moderada o severa, ha sido también comparada en esta Tesis con la de la población
general española, hallándose una peor calidad de vida en los pacientes con fibrosis
significativa, lo cual concuerda con otros estudios que ya habían comparado la calidad de vida
de pacientes con EHGNA con la de poblaciones sanas de referencia (David et al., 2009;
Golabi et al., 2016; Sayiner et al., 2016).
Por otro lado, también hemos comparado la calidad de vida de la cohorte de pacientes
españoles con EHGNA que ha participado en esta Tesis Doctoral, con la de una cohorte de
pacientes con EHGNA procedentes del Reino Unido. Los resultados del tercer trabajo de esta
Tesis han encontrado que el mencionado efecto de la fibrosis sobre la calidad de vida se
observa únicamente en la cohorte española, no habiendo diferencias significativas en la
calidad de vida en función del nivel de fibrosis en la cohorte del Reino Unido.
En los pacientes del Reino Unido existe un deterioro en la calidad de vida ya desde un
nivel nulo/leve de fibrosis, y se mantiene estable, sin variaciones significativas, a pesar de la
evolución de la enfermedad. Según las conclusiones del estudio de Lazarus et al. (2021), el
Reino Unido es el país de Europa con un mejor desempeño en cuanto a campañas sociales o
gubernamentales para abordar la EHGNA. Por lo tanto, esto podría contribuir a que los
pacientes de este país muestren una mejor identificación, desde las primeras fases de la
enfermedad, de los síntomas característicos de la EHGNA, así como un mayor nivel de
preocupación sobre los efectos que pueda acarrear sobre su salud. Además, de acuerdo a las
conclusiones de este mismo estudio (Lazarus et al., 2021), el Reino Unido es el único país
europeo que cuenta con la participación de equipos multidisciplinares y la coordinación de
profesionales de la atención primaria y secundaria en la gestión de la EHGNA. Teniendo esto
en consideración, no sería de extrañar que estos pacientes, en comparación con sus homólogos
españoles, muestren un mejor ajuste físico y psicológico ante la evolución de la EHGNA, lo
que contribuiría a la ausencia de un deterioro significativo de la calidad de vida asociado a la
progresión de la enfermedad.
Además de la fibrosis, los análisis de regresión logística de este trabajo muestran que la
calidad de vida también es predicha por factores como el género o el índice de masa corporal,
tanto en pacientes de España como del Reino Unido. En la línea de investigaciones previas
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(Afendy et al., 2009; David et al., 2009; Huber et al., 2019; Ozawa et al., 2021; Younossi et
al., 2017), el género femenino y un elevado índice de masa corporal se asocian con un mayor
deterioro en la calidad de vida de los pacientes con EHGNA.
Otros factores que han sido demostrados en este estudio que afectan de manera distinta a
la calidad de vida de pacientes con EHGNA de España y del Reino Unido son la edad, el nivel
educativo y la situación laboral. Para empezar, la edad predice la calidad de vida,
exclusivamente en los pacientes del Reino Unido, donde una mayor edad se asocia a una
mejor calidad de vida, tal y como observan previamente Younossi et al. (2017). Teniendo en
cuenta que en este tercer trabajo la edad correlaciona positivamente con el nivel de fibrosis,
esto respaldaría la teoría sobre la mejor adaptación a la evolución de la enfermedad en
pacientes del Reino Unido. Por el contrario, la educación no predice la calidad de vida en
ninguna de las dos cohortes, contradiciendo los resultados de David et al. (2009) y Ozawa et
al. (2021). Finalmente, la situación laboral mantiene una relación significativa con la calidad
de vida en los pacientes del Reino Unido, donde aquellos que están activos laboralmente
muestran una mejor calidad de vida en comparación con los que no están en una situación de
empleo activo, lo cual ya había sido identificado previamente en un estudio sobre patología
hepática crónica (Stepanova et al., 2017).
Se han explorado también las diferencias en la calidad de vida de pacientes del Reino
Unido y de España, independientemente del nivel de gravedad hepática, encontrándose que
la cohorte del Reino Unido presenta una peor calidad de vida que la española, a nivel tanto
físico como mental. De hecho, los pacientes del Reino Unido reportan principalmente más
síntomas físicos y más preocupación sobre la evolución de la enfermedad. Este mayor nivel
de preocupación podría estar relacionado con el mayor nivel de concienciación sobre la
EHGNA que muestra Reino Unido desde una perspectiva de políticas de salud pública,
encontrándose España en un nivel inferior al respecto (Lazarus et al., 2021). Por lo tanto, sería
esperable que la conciencia de enfermedad, que de por sí es generalmente baja entre pacientes
con EHGNA (Wieland et al., 2015), sea inferior en pacientes de España en comparación con
los del Reino Unido, implicando en consecuencia un menor nivel de preocupación sobre la
enfermedad.
Asimismo, los modelos de mediación moderada del tercer trabajo de esta Tesis identifican
al índice de masa corporal, junto a la calidad de vida mental y la fatiga, como mediadores en
la relación entre género y calidad de vida en pacientes con EHGNA, con el lugar de origen
como factor moderador de dicha relación. Para empezar, el género femenino predice una peor
función emocional en los pacientes, tal y como apuntaron previamente Afendy et al. (2009).
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Al mismo tiempo, esta reducida función emocional se asocia con un mayor índice de masa
corporal y más fatiga, lo que conduce finalmente a una peor calidad de vida. Esto ratifica los
vínculos ya establecidos entre la obesidad y un deterioro en la calidad de vida, particularmente
a nivel emocional (Assari et al., 2016). El exceso de grasa tiende a acumularse principalmente
en regiones periféricas, como las caderas o los muslos, o en la cavidad abdominal, lo que
recibe el nombre de obesidad central (Aras et al., 2015). Las personas con obesidad central
son comúnmente resistentes a la insulina, condición metabólica estrechamente asociada a la
EHGNA, y que se vincula de manera significativa con una reducida capacidad funcional, un
menor nivel de energía y, en consecuencia, una mayor fatiga y una peor calidad de vida
(Angulo, 2006; Angulo, 2007). El lugar de origen modera esta relación, dado que el
mencionado impacto negativo sobre la calidad de vida resulta ser superior en pacientes del
Reino Unido, definiéndose estos como más vulnerables que los españoles desde un punto de
vista biopsicosocial.
En otro orden de cosas, esta Tesis también ha estudiado los efectos de la fibrosis hepática
sobre otros biomarcadores psicológicos en pacientes con EHGNA. En el segundo trabajo de
esta Tesis Doctoral la presencia de fibrosis significativa ha sido asociada a una mayor
sintomatología depresiva y a un estilo de afrontamiento desadaptativo basado en la
desconexión conductual y en un menor empleo de estrategias activas como el afrontamiento
activo o la aceptación. La relación entre fibrosis y salud mental ya había sido apuntada
previamente en otros estudios (Tomeno et al., 2015; Weinstein et al. 2011; Youssef et al.
2013), contradiciendo por lo tanto el trabajo de Kim et al. (2019) que no halló diferencias en
la sintomatología depresiva de una muestra de pacientes con EHGNA en función del grado
de fibrosis.
El cuarto trabajo de esta Tesis Doctoral también estudia la influencia de la fibrosis respecto
al afrontamiento, y explora además su efecto sobre la autoeficacia de los pacientes con
EHGNA, a través de modelos de mediación moderada. Primero, un estilo de afrontamiento
pasivo/evitativo, basado en el empleo predominante de estrategias como la autodistracción, la
desconexión conductual, la negación o la autoinculpación, se asocia con una peor calidad de
vida mental. Esto, a su vez, predice un peor funcionamiento físico en el paciente. Atendiendo
a la literatura, existen evidencias de que el empleo mayoritario de estrategias de afrontamiento
pasivas/evitativas suele venir acompañado de un peor ajuste psicológico y una mayor
presencia de conductas de salud desadaptativas, ansiedad y síntomas depresivos, que acaban
repercutiendo en una reducción de la calidad de vida y, por lo tanto, en una inferior percepción
de autonomía y una menor capacidad para realizar las actividades cotidianas (Terrazas-
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Romero et al., 2018). Este vínculo entre estado de salud físico y mental, que ya había sido
probado previamente en pacientes con síndrome metabólico (Danhauer et al., 2019), predice
la autoeficacia de los pacientes, dado que en nuestro estudio una peor calidad de vida mental
y física se asocia con una menor autoeficacia. Este modelo podría explicar en parte la falta de
autoeficacia para gestionar la enfermedad y realizar cambios comportamentales relacionados
con la salud que generalmente se observa entre pacientes con EHGNA (Frith et al., 2010).
Asimismo, la fibrosis hepática ejerce un rol moderador sobre dicha relación. De esta forma,
el impacto negativo que un perfil psicológico de riesgo, basado en un estilo de afrontamiento
pasivo/evitativo y una pobre calidad de vida mental y física, ejerce sobre la autoeficacia de
los pacientes con EHGNA, se incrementa en aquellos pacientes con un grado significativo de
fibrosis. Por lo tanto, se confirma por primera vez la presencia de fibrosis significativa como
un factor de riesgo para la autoeficacia de los pacientes con EHGNA. Esto es una evidencia
más del papel determinante de la fibrosis hepática en el perfil biopsicosocial de estos
pacientes.

6.3. Cuarto y quinto trabajo: perfil biopsicosocial asociado a los principales factores de
riesgo de la EHGNA (diabetes tipo 2 y obesidad)

En el cuarto y quinto trabajo de esta Tesis Doctoral se ha explorado el papel de la diabetes

tipo 2 y la obesidad, principales factores de riesgo de la EHGNA, en el perfil biopsicosocial
de los pacientes con esta enfermedad.
Esta Tesis Doctoral ha partido de la hipótesis general de que ambas patologías metabólicas
son determinantes desde un punto de vista biopsicosocial para los pacientes con EHGNA.
Esto ha llevado a analizar en el cuarto trabajo de la Tesis la influencia de la diabetes y la
obesidad respecto a las estrategias de afrontamiento, explorando además su efecto sobre la
salud mental de estos pacientes, a través de modelos de mediación moderada. Primero, se ha
hallado que un menor uso de estrategias de afrontamiento activo, como la reinterpretación
positiva o la aceptación, se asocia con una menor vitalidad. De hecho, la manera en que la
persona elige y desarrolla sus estrategias de afrontamiento depende en parte de cómo
construye su propia experiencia de enfermedad (Coelho et al., 2003). Así, un menor uso de
estrategias de afrontamiento activo estaría condicionado por la concepción que el paciente
tiene de la enfermedad como un proceso incontrolable que va más allá de sus propios recursos.
Este estilo de afrontamiento se asociaría a una menor autoestima y a una menor energía y
vitalidad (Vosvick et al., 2003), en consonancia con nuestros resultados. Esta fatiga o
deterioro en la vitalidad predice, a su vez, una mayor sintomatología depresiva. Esta relación

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podría estar vinculada con la activación de las vías inmunológicas-inflamatorias (Maes et al.,
2012), cuya relevancia ha sido demostrada en la fatiga experimentada tanto por la población
general como por pacientes con diversas enfermedades crónicas (Collado-Hidalgo et al.,
2006; Lasselin et al., 2012; Rohleder et al., 2012). Así, la presencia de niveles séricos elevados
de citoquinas proinflamatorias, como la interleucina-6, ha sido asociada con una peor calidad
de vida y con la falta de vitalidad debido a su efecto sobre el sistema nervioso central (Dantzer
et al., 2014; Younossi et al., 2018). Y, al mismo tiempo, se ha hallado una correlación positiva
entre la interleucina-6 y la sintomatología depresiva referida por el paciente (Bossola et al.,
2015). En consecuencia, la acción de este tipo de marcadores inflamatorios podría ayudar a
comprender la estrecha relación entre vitalidad y sintomatología depresiva hallada en este
estudio.
Asimismo, la diabetes y la obesidad ejercen un rol moderador sobre dicha relación. De esta
forma, el impacto negativo que la presencia de un perfil psicológico de riesgo, basado en un
menor afrontamiento activo y una menor vitalidad, implica sobre la salud mental de los
pacientes con EHGNA, se incrementa en pacientes con diabetes tipo 2 y un mayor índice de
masa corporal. Por lo tanto, se confirma que tanto la diabetes como la obesidad son factores
de riesgo para la salud mental del paciente con EHGNA. De hecho, existen evidencias de que
ambas patologías metabólicas, al igual que la EHGNA, se asocian con una menor vitalidad
en la persona (Feyisa et al., 2020; Svenningsson et al., 2011). Por lo tanto, es de esperar que
la comorbilidad metabólica agrave el problema con la vitalidad en nuestro modelo. Asimismo,
una menor energía o vitalidad implica una menor realización de actividad física por parte de
estos pacientes (Thiel et al., 2017; Tous-Espelosín et al., 2020), lo que a su vez se relaciona
con un mayor peso corporal (Aguirre-Urdaneta et al., 2012). La inactividad, una menor
autoeficacia respecto a la capacidad para realizar ejercicio físico, o el miedo y la
autoculpabilidad por el aumento de peso podrían contribuir al deterioro hallado en la salud
mental de estos pacientes, tal y como ha sido demostrado anteriormente (Beaulieu et al., 2012;
Levinson et al., 2020; McAuley et al., 2010).
El quinto trabajo de esta Tesis Doctoral también explora el papel de la patología metabólica
en el perfil biopsicosocial de los pacientes con EHGNA. En concreto, analiza las diferencias
en la calidad de vida y estrategias de afrontamiento de estos pacientes en función de la diabetes
tipo 2 y la obesidad, utilizando para ello modelos factoriales de análisis de varianza. En base
a esto, para empezar, se ha identificado un perfil biopsicosocial de mayor riesgo (menor
funcionamiento físico, rol físico y actividad) en pacientes con diabetes que tienen también
obesidad, y viceversa, es decir, pacientes con obesidad que tienen también diabetes. De esta
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forma, la combinación de ambas patologías metabólicas predice un deterioro en la calidad de
vida, especialmente en su esfera física, como ya había sido hallado previamente en otras
investigaciones sobre pacientes con EHGNA diabéticos y obesos (Barcones-Molero et al.,
2018; Younossi et al., 2017).
Asimismo, tanto los pacientes con diabetes como aquellos con obesidad perciben una peor
calidad de vida en comparación con los que no tienen patología metabólica comórbida a la
EHGNA, en ambos casos centrándose las diferencias a nivel físico. Estos resultados coinciden
con lo hallado en los estudios de Younossi y Henry (2015) y Younossi et al. (2017) al
confirmar el efecto significativo de la diabetes y la obesidad en la calidad de vida de los
pacientes con EHGNA, mientras que contradicen las conclusiones de Sayiner et al. (2016) y
Tapper y Lai (2016) sobre la ausencia de resultados significativos al respecto.
La calidad de vida de los pacientes con EHGNA ha sido también comparada en este trabajo
con la de la población general española. Así, se ha hallado una peor calidad de vida en
pacientes con diabetes u obesidad, principalmente a nivel físico. Tal y como ha sido sugerido
previamente (Hassan et al., 2003; Kalka, 2014), estos pacientes perciben por lo general una
menor capacidad funcional y energía que la población sana, lo cual está estrechamente
relacionado con problemas característicos asociados a estas patologías metabólicas, como la
resistencia a la insulina o el estrés oxidativo.
Con respecto al afrontamiento, no hay diferencias significativas en las estrategias de
afrontamiento que emplean los pacientes en función de la ausencia o presencia de diabetes, al
contrario de trabajos anteriores que sí encontraron un impacto de la diabetes tipo 2 en el estilo
de afrontamiento empleado (Coelho et al., 2003; Féki et al., 2019). La presencia de obesidad
sí se asocia con un menor uso de estrategias adaptativas como el afrontamiento activo o la
aceptación, y un mayor uso de estrategias desadaptativas como la desconexión conductual, lo
que lleva a concluir que la obesidad predice un estilo de afrontamiento predominantemente
pasivo/evitativo en pacientes con EHGNA, tal y como había sido concluido por Fettich y
Chen (2012). La insatisfacción corporal podría explicar en parte estos resultados, ya que ésta
ha sido vinculada a un afrontamiento más pasivo/evitativo, basado en la desconexión
conductual como principal estrategia de afrontamiento, por parte de personas con obesidad
(Brytek-Matera, 2011).
Este mismo trabajo también ha analizado qué estrategias de afrontamiento predicen la
calidad de vida de pacientes diabéticos u obesos con EHGNA, mediante un análisis de
regresión lineal múltiple. Por una parte, se ha observado que un estilo de afrontamiento
adaptativo, activo, basado en estrategias como la reinterpretación positiva, la aceptación o el
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afrontamiento activo, se asocia con una mejor calidad de vida en pacientes diabéticos u
obesos, en línea con estudios previos (Karimi et al., 2016; Terrazas-Romero et al., 2018). Por
el contrario, un estilo de afrontamiento pasivo/evitativo, basado en estrategias como la
negación, la autoinculpación, la autodistracción o la desconexión conductual, se asocia con
una peor calidad de vida en estos pacientes, principalmente a nivel de su esfera mental. Este
tipo de afrontamiento, más centrado en la emoción, ha sido relacionado con una peor salud
mental y una mayor presencia de angustia y conductas de salud desadaptativas en personas
con diabetes u obesidad, lo cual implica consecuencias negativas para su calidad de vida
(Terrazas-Romero et al., 2018). Finalmente, la religión, que dependiendo de la persona puede
funcionar como estrategia activa o pasiva/evitativa, predice una peor calidad de vida en los
pacientes diabéticos de nuestro estudio. Esto puede estar relacionado con la interpretación de
la enfermedad como un castigo, lo cual conduce a una mayor presencia de sintomatología
depresiva y autoculpabilidad en estos pacientes (Caballero, 2018). Esta Tesis, por lo tanto,
aporta numerosas evidencias sobre el papel determinante de la diabetes tipo 2 y la obesidad
en el perfil biopsicosocial de los pacientes con EHGNA.

6.4. Sexto trabajo: biomarcadores psicológicos relevantes para la adherencia

terapéutica de los pacientes con EHGNA

Una vez ha sido demostrada en los trabajos anteriores la influencia de los biomarcadores
psicológicos en la EHGNA, en el sexto trabajo de esta Tesis Doctoral se ha explorado su
relevancia en la adherencia terapéutica de estos pacientes, es decir, su impacto en la
realización de actividad física y en el seguimiento de un patrón de dieta mediterránea, sobre
lo cual no hay evidencias en la literatura hasta el momento.
Esta Tesis Doctoral ha partido de la hipótesis general de que variables como la calidad de
vida, la salud mental, el apoyo social o la autoeficacia ejercen una influencia significativa en
la adherencia terapéutica de estos pacientes. En efecto, los modelos de mediación moderada
del sexto trabajo de esta Tesis han identificado a la sintomatología depresiva como factor
mediador en la relación entre calidad de vida física y realización de actividad física, por un
lado, y entre apoyo social y seguimiento de una dieta mediterránea, por otro lado. Además, se
ha encontrado que la autoeficacia ejerce un rol moderador sobre ambas relaciones.
Para empezar, una pobre calidad de vida física se asocia con una mayor sintomatología
depresiva, confirmando el vínculo entre salud física y mental en la EHGNA ya sugerido por
Younossi et al. (2017). Esta mayor presencia de sintomatología depresiva predice, a su vez,
una menor realización de actividad física en los pacientes, tal y como ha sido observado

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anteriormente en población sana (Ohmori et al., 2017), diabética (Adam & Folds, 2014) y
obesa (Mazzeschi et al., 2012). De esta forma, las alteraciones metabólicas características de
la EHGNA conducen a un deterioro del funcionamiento físico que, a través de su impacto
sobre la salud mental del individuo, interfiere negativamente en su participación en
actividades físicas. Esto llevaría a un aumento del peso corporal y a un peor estado de salud
física y mental, estableciéndose un círculo vicioso con negativas consecuencias físicas y
psicológicas para el paciente (Burgess et al., 2017; Gerber et al., 2014).
Por otro lado, la sintomatología depresiva media de manera parcial la relación entre apoyo
social percibido y adherencia a la dieta mediterránea. Esto hace que un bajo apoyo social
prediga directamente un peor seguimiento de la dieta por parte de los pacientes, como se había
demostrado anteriormente en pacientes con diabetes (Tang et al., 2008), obesidad (Chang et
al., 2008) y patología cardiovascular (Aggarwal et al., 2010). El rol del apoyo social podría
ser determinante en este caso, pues es capaz de amortiguar o impulsar los efectos negativos
que ciertos factores, como la falta de tiempo para cocinar o la tentación por comer alimentos
poco saludables, ejercen sobre el mantenimiento a largo plazo de una dieta (Aggarwal et al.,
2010; Barberia et al., 2008). De hecho, el acto de comer ha sido descrito como un
comportamiento social, determinado por las normas y presiones sociales y por la influencia
del entorno más cercano (Ball et al., 2010).
Un bajo apoyo social predice también en este trabajo una mayor sintomatología depresiva,
lo que a su vez se asocia con una menor adherencia a la dieta. Se confirma así la relación entre
apoyo social y salud mental hallada previamente en esta Tesis, así como la relación entre la
depresión y peores hábitos alimentarios en personas que necesitan modificar su estilo de vida
para perder peso (Somerset et al., 2011).
Finalmente, la autoeficacia ejerce un rol moderador sobre las dos relaciones anteriores. De
esta forma, los efectos negativos que una pobre calidad de vida física y un bajo apoyo social
ejercen sobre la adherencia terapéutica, a través de su impacto sobre la sintomatología
depresiva, se ven reforzados en pacientes con una baja autoeficacia y, por el contrario,
atenuados en pacientes con una alta autoeficacia percibida. Según Bandura, la autoeficacia es
un prerrequisito para modificar la conducta, ya que la persona debe confiar en que puede
llevar a cabo la acción y que los resultados serán favorables o beneficiosos para ella (Bandura,
1977; Bandura, 1986). Por lo tanto, resultaría imprescindible contar con una autoeficacia
suficiente para sentirse motivado para modificar los hábitos de actividad física y alimentación
a largo plazo (Harvey & Lawson, 2009). Esto explicaría el rol protector que una elevada

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autoeficacia juega en este trabajo respecto a la adherencia terapéutica: cuanto mayor es la
autoeficacia, menor es el impacto negativo que una baja calidad de vida física y un bajo apoyo
social ejercen sobre la salud mental y, en consecuencia, sobre la adherencia terapéutica del
paciente. Así, una alta autoeficacia protegería del malestar físico y de las presiones o la falta
de apoyo en el entorno social cercano (Navidian et al., 2013; Younossi et al., 2017), lo que a
su vez se asociaría con una menor sintomatología depresiva concomitante (Adam & Folds,
2014; Gutteling et al., 2010; Linde et al., 2004). La mejora de la autoeficacia en los pacientes
con EHGNA les ayudaría a tolerar y afrontar de manera más adaptativa este tipo de obstáculos
o problemas y, por lo tanto, a mostrar más optimismo, compromiso y dedicación hacia las
pautas terapéuticas de actividad física y dieta. Esta Tesis, por lo tanto, aporta evidencias sobre
la influencia del perfil biopsicosocial del paciente con EHGNA respecto a su adherencia
terapéutica, jugando la autoeficacia percibida un rol determinante.

6.5. Limitaciones y procedimientos de minimización de las mismas en los seis trabajos

Con respecto a posibles limitaciones en los trabajos que conforman esta Tesis Doctoral, se
pueden enumerar las siguientes.
En primer lugar, las cinco investigaciones empíricas presentes en esta Tesis Doctoral han
adoptado un diseño transversal, dado que los participantes han sido evaluados en un único
momento temporal. Este tipo de diseño es conveniente para medir la prevalencia de un evento
determinado en una muestra, así como para estimar asociaciones entre dicho evento y otros
factores, proporcionando información con la que llevar a cabo intervenciones en el área de la
salud (Álvarez-Hernández & Delgado-de-la-Mora, 2015). Sin embargo, no permite
determinar inferencias causa-efecto (Aschengrau & Seage, 2003). Esto ha imposibilitado
establecer relaciones causales entre los factores implicados en los distintos trabajos, o evaluar
la evolución a largo plazo de los resultados obtenidos. Esta limitación queda patente
especialmente en el sexto trabajo de la Tesis, en el que se mide la influencia de una serie de
biomarcadores psicológicos en la adherencia terapéutica de los pacientes con EHGNA. Esta
adherencia es evaluada mediante el seguimiento del paciente, en un momento dado, de las
pautas terapéuticas de actividad física y dieta mediterránea. No obstante, de cara a futuras
líneas de investigación, el desarrollo de un estudio longitudinal que valorase cómo influye el
perfil biopsicosocial en el mantenimiento a medio y largo plazo de las pautas terapéuticas,
aportaría un gran valor a la investigación sobre la EHGNA. También sería de interés conocer
si la adherencia terapéutica continuada produce mejoras en la calidad de vida o la salud mental
del paciente. Un estudio longitudinal también permitiría analizar los cambios en los

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marcadores histológicos característicos de la enfermedad a lo largo del tiempo y su impacto
sobre la calidad de vida, salud mental o autoeficacia de estos pacientes.
Otra posible limitación es que no se ha estudiado la relación entre todas las variables
psicológicas abordadas. Por ejemplo, no se ha analizado cómo influye el apoyo social en la
percepción de autoeficacia del paciente. O qué estrategias de afrontamiento predicen su salud
mental o autoeficacia. No obstante, teniendo en cuenta que hasta ahora las evidencias en la
literatura sobre la relevancia de los biomarcadores psicológicos en EHGNA eran muy
limitadas, especialmente respecto a las estrategias de afrontamiento, autoeficacia y apoyo
social, esta Tesis Doctoral ha supuesto un punto de partida para continuar con el estudio en
profundidad de esta temática en el futuro.
Otra limitación es que la varianza explicada ha sido relativamente baja o moderada,
especialmente en el tercer trabajo de la Tesis. Sin embargo, esto no resulta incoherente
teniendo en cuenta la existencia de otras variables que muy probablemente han influido sobre
la calidad de vida de los pacientes, y que no han podido ser incluidas en el análisis, como la
ausencia o presencia de diabetes tipo 2, la salud mental o el estilo de vida. De hecho, de cara
a futuros estudios transculturales sería muy recomendable estudiar las diferencias en la
alimentación y la actividad física entre cohortes de pacientes con EHGNA de diferentes
poblaciones, incluyendo el estilo de vida en modelos de predicción de la calidad de vida de
estos pacientes.
Por otra parte, habría sido de interés haber incluido el análisis del impacto de patologías
asociadas a la EHGNA, como la hipertensión arterial, la hipercolesterolemia, la
hipertrigliceridemia, la patología cardiovascular, la enfermedad tiroidea o el síndrome de
apnea obstructiva del sueño, sobre el perfil biopsicosocial de los pacientes. Sin embargo, esta
Tesis se ha centrado en el estudio de la diabetes tipo 2 y la obesidad, pues hasta el momento
han demostrado tener un notable peso en el perfil clínico de los pacientes, siendo definidas
ambas como sus más importantes factores de riesgo y sus principales comorbilidades
metabólicas (Reeves et al., 2016).
En cuanto a los biomarcadores psicológicos, de cara a futuros estudios se podría incluir el
estudio de otras variables como el tipo de personalidad del paciente con EHGNA, la
percepción del paciente sobre la enfermedad y su tratamiento, o el estrés percibido. Estas
variables apenas han sido estudiadas hasta la fecha en la EHGNA, aunque las escasas
evidencias existentes (Kang et al., 2020; Stewart et al., 2015; Zelber-Sagi et al., 2017) parecen
indicar que su análisis en profundidad permitiría obtener un conocimiento más completo sobre
el perfil biopsicosocial del paciente con EHGNA.
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 A pesar de todas estas limitaciones, es importante resaltar que el gran tamaño de la muestra
con la que han contado nuestros estudios, compuesta por pacientes procedentes de la práctica
clínica real de diferentes hospitales españoles, constituye la principal fortaleza de la Tesis.
Otro punto fuerte es haber contado con la colaboración de una institución extranjera, la
Universidad de Newcastle (Reino Unido), que ha permitido incorporar un enfoque
transcultural a la Tesis. De hecho, la investigación transcultural ha sido ampliamente
recomendada en el campo de la atención sanitaria, ya que la experiencia de enfermedad puede
variar según el contexto sociocultural en el que se desarrolla la persona (Guitart, 2008).
Además, el hecho de que todos los pacientes hayan sido diagnosticados mediante biopsia
hepática, que es considerada el estándar de oro para el diagnóstico de la EHGNA (Nalbantoglu
& Brunt, 2014), otorga un valor añadido a la validez de los resultados de esta Tesis.

6.6. Aplicabilidad y utilidad práctica de los resultados en el área de la salud

Los resultados de esta Tesis Doctoral tienen importantes implicaciones tanto clínicas como
investigadoras.
Para empezar, a nivel general, la identificación de distintos perfiles biopsicosociales
asociados a una patología permite el diseño y desarrollo de programas de intervención
específicos para una determinada población clínica. El hecho de pasar de intervenciones
clínicas estandarizadas y genéricas, a programas terapéuticos diferenciales, que tienen en
cuenta las particularidades, fortalezas y debilidades de su población diana, supone por lo tanto
un impulso para la efectividad de la intervención. Además, obtener un conocimiento amplio
y en profundidad sobre el impacto que una determinada enfermedad genera en el bienestar y
funcionamiento físico, mental y social del paciente, facilita la labor de las instituciones
sanitarias y gubernamentales a la hora de estimar y asignar recursos económicos y
asistenciales (Varni et al., 2007). De hecho, esto es especialmente importante en el caso de la
EHGNA, la cual está asociada a importantes costes económicos y a un considerable uso de
recursos sanitarios en todo el mundo, que se prevé incluso que vayan en aumento en los
próximos años debido a la creciente incidencia del síndrome metabólico y de la EHGNA en
población infantil (Younossi & Henry, 2015).
Los resultados de esta Tesis, especialmente a raíz del estudio transcultural, también señalan
la necesidad de fomentar en España la concienciación sobre la EHGNA entre los profesionales
sanitarios y la población general, pues aún hoy resulta bastante limitada (Sanyal, 2018). De
hecho, a menudo el conocimiento de la enfermedad es inadecuado, subestimándose su
importancia clínica. Queda patente por lo tanto la necesidad urgente de implementar

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programas de información y educación pública sobre la EHGNA (Ghevariya et al., 2014; Goh
et al., 2016), e incrementar su presencia en los medios de comunicación. En cuanto a políticas
de prevención de la EHGNA, sería recomendable además reforzar la actividad física en las
escuelas, incentivar el uso de los parques y los carriles bici para hacer ejercicio, promover el
acceso a alimentos saludables por parte de las clases sociales más vulnerables, y advertir sobre
los perjuicios para la salud de la comida basura, los alimentos ultraprocesados y los azúcares
añadidos, regulando especialmente la publicidad dirigida a los niños (Joint WHO/FAO Expert
Consultation, 2003).
Esta Tesis Doctoral también subraya la importancia de incorporar aspectos emocionales y
cognitivos en la evaluación y el tratamiento de la EHGNA. Como se comentó en la
introducción, ante la ausencia de tratamientos farmacológicos definitivos (Pennisi et al.,
2019), la medida terapéutica más efectiva para los pacientes con EHGNA implica la pérdida
de peso a través de la modificación del estilo de vida, en concreto, mediante dieta y actividad
física (Geier & Rau, 2017; Romero-Gómez et al., 2017). Esto es necesario para promover la
resolución de la EHNA y la regresión de la fibrosis. Sin embargo, el principal problema es
que la adherencia terapéutica en estos pacientes es generalmente baja (Serfaty, 2018). Por lo
tanto, teniendo en cuenta los resultados obtenidos sobre la influencia que biomarcadores
psicológicos como la salud mental, las estrategias de afrontamiento, la autoeficacia o el apoyo
social ejercen sobre la calidad de vida o la adherencia terapéutica, una intervención
psicológica estructurada podría contribuir a la mejora de los factores de riesgo que conforman
el perfil biopsicosocial de los pacientes con EHGNA. Y, en consecuencia, a lograr un mejor
seguimiento de las pautas terapéuticas y una mejor evolución clínica (Moscatiello et al.,
2011).
Para ello, sería necesario pasar de la intervención tradicional de cambios en el estilo de
vida, donde únicamente se insta al paciente a llevar a cabo ciertas pautas terapéuticas, a un
modelo de intervención colaborativo (Franz et al., 2007; Serfaty, 2018), que ha sido asociado
a mejores resultados clínicos y a una mayor satisfacción por parte de los pacientes (Katon et
al., 2010). Sería fundamental contar, para ello, con equipos multidisciplinares formados por
profesionales procedentes del mundo de la medicina, enfermería, psicología, nutrición o
ciencias del deporte, que asistan al paciente durante la intervención y puedan reaccionar con
flexibilidad ante sus necesidades, ayudándolo a superar las barreras que impiden el cambio
comportamental y que reducen su calidad de vida. Entre estas barreras estarían los factores de
riesgo biopsicosocial identificados en esta Tesis, como una baja autoeficacia, un estilo de
afrontamiento pasivo/evitativo o la falta de apoyo social. En este sentido, sería especialmente
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recomendable, sobre todo en pacientes con riesgo de enfermedad hepática avanzada, la
aplicación de técnicas de intervención cognitivo-conductuales (Centis et al., 2010; Marchesini
et al., 2005), que han sido asociadas a cambios positivos en el estado de salud de pacientes
con EHGNA, como la normalización de las enzimas hepáticas, la mejora en la sensibilidad a
la insulina, o una mayor pérdida de peso a corto, medio y largo plazo (Moscatiello et al.,
2011).
Este tipo de intervención pretende modificar los patrones desadaptativos de pensamiento
y comportamiento con el objetivo de mejorar el funcionamiento psicosocial del individuo
(Stewart & Levenson, 2012). También ha mostrado una influencia positiva sobre la
autoeficacia, el estilo de afrontamiento o la calidad de vida de pacientes con trastornos
metabólicos crónicos (Riveros et al., 2005). Tal y como han demostrado los resultados de esta
Tesis, sería muy importante promover en el paciente una mayor percepción de controlabilidad
y confianza respecto al manejo de la enfermedad y su tratamiento, es decir, una mayor
autoeficacia percibida, especialmente en pacientes con diabetes tipo 2, obesidad o un grado
significativo de fibrosis. Esto conduciría a una mayor confianza en el uso de estrategias de
afrontamiento activo, como la aceptación de la enfermedad o la reinterpretación positiva de
sus implicaciones y su tratamiento. Este estilo de afrontamiento adaptativo implicaría muy
probablemente un mayor compromiso y una mayor participación activa del paciente en el plan
de intervención, lo que se asocia a una mayor pérdida de peso, una mejor evolución clínica y,
en consecuencia, una mejor calidad de vida (Shayeghian et al., 2015).
Algunas técnicas cognitivo-conductuales son recomendables para la intervención de la
EHGNA. Para empezar, sería importante la psicoeducación centrada en la EHGNA y en su
evolución, ya que muchos de los pacientes no son plenamente conscientes sobre su
enfermedad y las consecuencias a largo plazo para su salud (Cook et al., 2019). Además, la
reestructuración cognitiva tendría como objetivo promover un estilo de pensamiento más
adaptativo e intervenir sobre los sesgos cognitivos y las expectativas poco realistas
relacionadas con la pérdida de peso, las cuales están significativamente relacionadas con el
abandono terapéutico (Fabricatore, 2007). El entrenamiento en resolución de problemas
también podría ayudar a afrontar las situaciones que identifique el paciente que obstaculizan
el mantenimiento de la pérdida de peso a largo plazo, planificando una serie de pasos para
poder abordarlos con éxito (Bellentani et al., 2008). Al mismo tiempo, sería beneficioso
establecer compromisos y objetivos personales cuantificables y específicos, realistas y a la
vez desafiantes, respecto a la pérdida de peso o la realización de actividad física. Por ejemplo,

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comer únicamente cuando se esté sentado en la mesa o perder medio kilo a la semana
(Fabricatore, 2007). También puede ayudar el uso de autoinformes, en los que el paciente
anota todo lo que come, la actividad física que realiza y su peso (Cooper et al., 2003), o la
técnica de gestión del tiempo, donde se planifican con el paciente, por ejemplo, momentos del
día para cocinar alimentos saludables o realizar ejercicio físico (Bellentani et al., 2008). Otra
técnica cognitivo-conductual ampliamente recomendada es el reforzamiento de conductas
alternativas, donde los pacientes, por ejemplo, aprenden a identificar aquellas señales que les
llevan a comer aunque no tengan hambre, y sustituyen esta respuesta por otras conductas
como ducharse, hacer ejercicio, o técnicas de relajación o respiración (Bellentani et al., 2008).
Por último, el control de estímulos, que consiste en llevar a cabo cambios en el entorno,
eliminando las señales que conducen a la conducta problemática y fomentando las que
conducen a la respuesta deseada. Por ejemplo, colocando en un lugar accesible de la casa
alimentos aptos para la dieta, y manteniendo fuera del alcance aquellos ricos en grasa
(Fabricatore, 2007).
La modificación del estilo de vida mediante este tipo de técnicas debería llevarse a cabo a
través de planes terapéuticos individualizados, diseñados junto al paciente, con el objetivo de
que éste se sienta parte activa del proceso, y de que la intervención esté adaptada a su
necesidades y debilidades. Por ejemplo, en el caso de pacientes con un deterioro en su salud
física o mental, se debería reducir al principio la intensidad de la actividad física, pasando a
aumentarla gradualmente según lo acordado con el paciente. También sería positivo que el
paciente aprendiese a gestionar posibles emociones negativas vinculadas a la realización de
actividad física, o proporcionar al paciente recursos, como técnicas de relajación, respiración
o meditación, que le permitan gestionar posibles situaciones estresantes que le llevan a comer
(Barberia et al., 2008; Hussien et al., 2020). Por último, la intervención debería incluir el
apoyo de alguna persona cercana o con un vínculo significativo, como el cónyuge o un
familiar conviviente, que pueda animar y reforzar positivamente al paciente para seguir un
estilo de vida más saludable, por ejemplo, realizando cambios en la dieta o saliendo a caminar
diariamente (Cohen, 2009).
En definitiva, los resultados de la presente Tesis Doctoral confirman y extienden el
conocimiento sobre el impacto de la EHGNA en el paciente, identificando distintos perfiles
biopsicosociales asociados a sus niveles de gravedad y a sus principales factores de riesgo.
Esto permitirá a los profesionales de la salud comprender mejor los factores biopsicosociales
que predicen la salud física y mental, y la adherencia terapéutica de estos pacientes, con el
objetivo de mejorar la efectividad de futuros estudios multinacionales de intervención y
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eficacia del tratamiento de la EHGNA. Ésta debería comenzar a estar presente en campañas
de prevención y en las políticas de salud nacionales e internacionales, a ser incluida junto con
las directrices de gestión clínica de la diabetes, obesidad y enfermedad cardiovascular, y a ser
abordada desde un enfoque multidisciplinar centrado en el paciente (Lazarus et al., 2021). El
importante impacto de la enfermedad en la vida de los pacientes, así como sus enormes
implicaciones económicas y sociales, exigen todos los esfuerzos posibles para optimizar los
programas de prevención y tratamiento, y frenar así el crecimiento exponencial de una de las
llamadas epidemias del siglo XXI.

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7. CONCLUSIONS

The main objective of the first research paper done for this Ph.D. Thesis was a theoretical
study of the main psychosocial repercussions of NAFLD, and any potential psychological
biomarkers that make up the biopsychosocial profile of patients with this disease.
In general, this theoretical study recommended in-depth examination of psychological
biomarkers associated with NAFLD, as the evidence in the literature in this respect is
insufficient, and sometimes contradictory. The impact of NAFLD seems to be associated with
deterioration in the quality of life, mainly physical functioning, with a proportionally inverse
relationship between disease severity and quality of life referred to by the patient. NAFLD
also seems to be linked to a negative impact on mental health, leading to higher anxiety and
depressive symptoms than in other chronic liver pathologies. Considering the evidence on
type 2 diabetes and obesity, the main NAFLD comorbidities, certain psychological
biomarkers, such as coping strategies, self-efficacy or social support could be determinant due
to their possible effects on physical and mental health, and therapeutic adherence by NAFLD
patients. Lastly, cognitive behavioral intervention should be included in future
multidisciplinary treatment of NAFLD.
The main objective of the five empirical studies done for this Ph.D. Thesis was to
determine the biopsychosocial profiles associated with different levels of NAFLD severity,
and its main metabolic risk factors. It was also intended to find out what psychological
biomarkers predict therapeutic adherence by these patients.
The specific objective of the second study was to compare the quality of life, mental health
and coping strategies of NAFLD patients by level of social support and presence or absence
of steatohepatitis and significant fibrosis, and to determine what histological and psychosocial
markers predict quality of life of these patients.
The results concluded that there are differences in the quality of life, mental health and
coping strategies of NAFLD patients by their perceived social support and severity of liver
fibrosis. Patients with little social support and significant fibrosis had a worse quality of life
(mainly physical functioning), worse mental health (mainly depressive symptoms), and a
maladaptive coping style based on greater use of passive/avoidance strategies. Patients with
significant fibrosis also showed more decline in quality of life than the general Spanish
population. Finally, it was confirmed that the presence of significant fibrosis, female gender
and higher anxiety and depressive symptoms are significant predictors of decline in quality
of life of NAFLD patients.

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 The objective of the third study was to compare the quality of life of NAFLD patients
based on their place of origin, Spain or the United Kingdom, absence or presence of
steatohepatitis and liver fibrosis severity, as well as to determine the histological and
biopsychosocial markers that predict quality of life of patients in the two countries. It also
attempted to determine the biopsychosocial markers that mediate or moderate predictive
models of their quality of life.
The results showed that the cohort of patients in the United Kingdom had a lower quality
of life than the one in Spain, especially with regard to physical symptoms and worry about
the liver disease. Regardless of place of origin, cirrhotic patients showed generalized decline
in quality of life compared to those with mild or no fibrosis. Analysis of the quality-of-life
predictor variables in the two cohorts separately concluded that female gender and a higher
body mass index predicted worse quality of life of both Spanish and British patients. Finally,
this study was able to confirm that the emotional function, body mass index and fatigue
mediated the relationship between gender and quality of life of NAFLD patients, and this
relationship was moderated by place of origin. Female gender was specifically associated with
worse quality of mental quality of life, higher body mass index and more fatigue, which
predicted worse quality of life for them. This negative impact on quality of life was stronger
on British than Spanish patients.
The objective of the fourth study was to determine whether vitality mediates the
relationship between active coping style and depressive symptoms in NAFLD patients, and
whether type 2 diabetes and body mass index moderate this relationship. It also determined
whether mental and physical quality of life mediate the relationship between
passive/avoidance coping and patient self-efficacy, and whether liver fibrosis moderates this
relationship.
The results showed which psychological, liver and metabolic biomarkers can predict
depressive symptoms and self-efficacy of NAFLD patients. It was found that less active
coping was associated with less vitality, which predicted more depressive symptoms. This
negative impact on their mental health was stronger in patients with type 2 diabetes and higher
body mass index. In addition, more passive/avoidance coping was found to be related to worse
mental and physical quality of life, which in turn predicted less self-efficacy. This negative
impact on self-efficacy was stronger in patients with significant fibrosis. In conclusion, a
maladaptive coping style was associated with worse mental and physical quality of life in
NAFLD patients, which along with the presence of metabolic comorbidity and significant
fibrosis predicted wore mental health or self-efficacy.
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 The objective of the fifth study was to compare NAFLD patient quality of life and coping
strategies by presence or absence of type 2 diabetes and obesity, compared to the quality-of-
life data from the general Spanish population, and determine what coping strategies predict
quality of life in diabetic or obese NAFLD patients.
The results concluded that there were differences in quality of life of NAFLD patients by
diabetes and obesity. Thus, diabetic and obese patients had worse quality of life than those
without comorbid metabolic pathology or the general Spanish population. There were
differences in patient coping strategies used by presence or absence of obesity, in which obese
patients reported more passive/avoidance coping. It also confirmed the importance of coping
strategies in NAFLD for the first time. Active or adaptive coping strategies, such as
acceptance, positive reframing or active coping predicted better quality of life of diabetic or
obese NAFLD patients. On the contrary, passive/avoidance or maladaptive coping strategies
such as denial, self-blame, self-distraction or disengagement predicted worse quality of life.
The objective of the sixth and last study was to determine whether depressive symptoms
mediate the relationship between physical quality of life and physical activity of NAFLD
patients, as well as the relationship between social support and following a Mediterranean
diet. It also analyzed moderation of self-efficacy in both relationships.
The results confirmed for the first time the importance of psychological biomarkers in
therapeutic adherence by NAFLD patients. Poor physical quality of life was found to be
associated with stronger depressive symptoms, which predicted less physical activity. Low
social support was also related to more depressive symptoms, which in turn predicted
following a Mediterranean diet less. In both cases, the more self-efficacy, the less negative
impact on patient mental health, and therefore, on therapeutic adherence. In conclusion,
positive self-efficacy exerted a protective role on therapeutic adherence of NAFLD patients
with an at-risk psychosocial profile.
Summarizing, based on the studies done for this Ph.D. Thesis, several NAFLD patient
biopsychosocial profiles were drawn, in which the importance of variables such as quality of
life, mental health, coping strategies, self-efficacy and social support was demonstrated. This
will further healthcare professionals’ understanding of the biopsychosocial factors, especially
liver fibrosis, type 2 diabetes and obesity, predicting and contributing to the impact on
physical, mental and social functioning of the NAFLD patient. At the same time, the
importance of emotional and cognitive aspects of therapeutic adherence by NAFLD patients
was also demonstrated, suggesting the inclusion of a multidisciplinary patient-centered

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approach that considers the effect of psychological biomarkers, and that therefore integrates
psychological evaluation and intervention in follow-up protocols for these patients.

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8. RESUMEN / SUMMARY

En la presente Tesis Doctoral se han llevado a cabo un estudio teórico y cinco trabajos
empíricos y pioneros que abordan principalmente distintos perfiles biopsicosociales de
pacientes con EHGNA asociados, por un lado, a los distintos niveles de gravedad de la
enfermedad hepática y, por otro lado, a sus principales factores de riesgo, es decir, la diabetes
tipo 2 y la obesidad. También se explora la relevancia de los biomarcadores psicológicos en
la adherencia terapéutica de los pacientes con EHGNA.
En concreto, en el primer trabajo el objetivo era realizar un estudio teórico sobre las
principales repercusiones psicosociales de la EHGNA, así como discutir aquellos
biomarcadores psicológicos que pueden ser relevantes para el perfil biopsicosocial asociado
a la EHGNA. En cuanto al impacto de la EHGNA, ésta parece asociarse a un deterioro de la
calidad de vida, principalmente a nivel físico, y de la salud mental, reportando estos pacientes
una mayor sintomatología ansiosa y depresiva que en otras patologías hepáticas crónicas.
Además, las estrategias de afrontamiento, la autoeficacia o el apoyo social son definidas como
variables potencialmente relevantes para la EHGNA por sus posibles efectos sobre la salud
física y mental, y la adherencia terapéutica de estos pacientes. Finalmente, se sugiere la
inclusión de técnicas cognitivo-conductuales dentro de una intervención multidisciplinar de
la EHGNA.
En el segundo trabajo el objetivo era comparar la calidad de vida, salud mental y estrategias
de afrontamiento de pacientes con EHGNA en función del apoyo social y de la esteatohepatitis
y fibrosis hepática, así como determinar qué marcadores histológicos y psicosociales predicen
la calidad de vida de estos pacientes. Para ello, se aplicaron una serie de cuestionarios a una
muestra de 492 pacientes con EHGNA diagnosticada mediante biopsia hepática: Cuestionario
de Salud SF-12, Cuestionario para pacientes con Enfermedad Hepática Crónica CLDQ-
NAFLD, Escala Hospitalaria de Ansiedad y Depresión, Inventario de Depresión de Beck,
Cuestionario de Afrontamiento COPE-28, Escala de Autoeficacia General, y Escala
Multidimensional de Apoyo Social Percibido. Luego se llevaron a cabo diferentes pruebas
estadísticas de análisis de la varianza, comparación de medias y regresión logística binaria,
que permitieron llegar a la conclusión de que un bajo apoyo social y un nivel significativo de
fibrosis se asocian con una peor calidad de vida y salud mental, y con un estilo de
afrontamiento más desadaptativo, en comparación con aquellos pacientes con un alto apoyo
social y sin fibrosis significativa. Los pacientes con fibrosis significativa también mostraron
un mayor deterioro en su calidad de vida en comparación con la población general española.

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Asimismo, la fibrosis significativa, junto con el género femenino y una mayor sintomatología
ansiosa y depresiva, fueron establecidos como predictores significativos del deterioro en la
calidad de vida de los pacientes con EHGNA.
El objetivo en el tercer trabajo de esta Tesis era comparar la calidad de vida de pacientes
con EHGNA en función de su lugar de procedencia, la esteatohepatitis y la fibrosis, así como
establecer qué marcadores histológicos y biopsicosociales predicen la calidad de vida en los
pacientes de España y de Reino Unido. También se pretendió determinar qué marcadores
biopsicosociales ejercen un rol mediador o moderador en modelos predictores de la calidad
de vida en los pacientes con EHGNA. Para ello, el Cuestionario para pacientes con
Enfermedad Hepática Crónica CLDQ fue aplicado a una muestra de 737 pacientes con
EHGNA diagnosticada mediante biopsia hepática (447 pacientes de España y 290 del Reino
Unido). Luego fueron llevadas a cabo diferentes pruebas estadísticas de análisis de la
varianza, regresión logística binaria y modelos de mediación y mediación moderada, que
permitieron llegar a la conclusión de que los pacientes del Reino Unido tienen una peor
calidad de vida física y mental que los de España. Además, un mayor nivel de fibrosis predijo
una peor calidad de vida, fundamentalmente en la cohorte española. Tanto el género femenino
como un mayor índice de masa corporal contribuyeron al impacto negativo sobre la calidad
de vida tanto en España como en el Reino Unido. Finalmente, el género femenino predice una
peor calidad de vida al asociarse con una peor función emocional, un mayor índice corporal
y una mayor fatiga, siendo este impacto negativo sobre la calidad de vida superior en pacientes
del Reino Unido.
El cuarto trabajo de esta Tesis tuvo como objetivo determinar los biomarcadores
psicológicos, hepáticos y metabólicos que ejercen un rol mediador o moderador en modelos
predictores de la salud mental y autoeficacia de pacientes con EHGNA. Para ello, se aplicaron
los siguientes cuestionarios a una muestra de 509 pacientes con EHGNA diagnosticada
mediante biopsia hepática: Cuestionario de Salud SF-12, Inventario de Depresión de Beck,
Cuestionario de Afrontamiento COPE-28 y Escala de Autoeficacia General. Luego se
llevaron a cabo análisis estadísticos basados en modelos de mediación moderada, que
permitieron llegar a la conclusión de que un estilo de afrontamiento desadaptativo se vincula
con una peor calidad de vida física y mental en pacientes con EHGNA lo que, sumado a la
presencia de diabetes, un mayor índice de masa corporal y un nivel significativo de fibrosis,
predicen una peor salud mental o autoeficacia en estos pacientes.
El objetivo principal en el quinto trabajo de la presente Tesis Doctoral fue comparar la
calidad de vida y estrategias de afrontamiento de pacientes con EHGNA en función de la
212
diabetes tipo 2 y la obesidad, así como determinar qué estrategias de afrontamiento predicen
la calidad de vida de estos pacientes. Para ello, en una muestra de 307 pacientes con EHGNA
diagnosticada mediante biopsia hepática, fueron aplicados los cuestionarios Cuestionario de
Salud SF-12, Cuestionario para pacientes con Enfermedad Hepática Crónica CLDQ-NAFLD
y Cuestionario de Afrontamiento COPE-28. A continuación se realizaron pruebas estadísticas
consistentes en análisis de la varianza y regresión lineal múltiple, para llegar a la conclusión
de que los pacientes con diabetes u obesidad reportan una peor calidad de vida en comparación
con aquellos sin patología metabólica comórbida y con la población general española. Los
pacientes con obesidad también refieren un mayor empleo de estrategias de afrontamiento
desadaptativas que aquellos sin obesidad. Finalmente, el estilo de afrontamiento activo se
asocia con una mejor calidad de vida, mientras que el estilo pasivo/evitativo predice una peor
calidad de vida en estos pacientes.
Por último, en el sexto trabajo de esta Tesis Doctoral el objetivo fue determinar los
biomarcadores psicológicos que ejercen un rol mediador o moderador en modelos predictores
de la realización de actividad física y del seguimiento de una dieta mediterránea en pacientes
con EHGNA. Para ello, se aplicaron los siguientes cuestionarios a una muestra de 413
pacientes con EHGNA diagnosticada mediante biopsia hepática: Cuestionario de Salud SF-
12, Escala Hospitalaria de Ansiedad y Depresión, Escala de Autoeficacia General, Escala
Multidimensional de Apoyo Social Percibido, Cuestionario Abreviado para Evaluación de
Dieta Mediterránea MEDAS y Cuestionario Internacional de Actividad Física IPAQ. Luego
fueron llevados a cabo análisis estadísticos basados en modelos de mediación moderada, que
permitieron llegar a la conclusión de que tanto una pobre calidad de vida física como un bajo
apoyo social se vinculan con una mayor sintomatología depresiva, lo que predice a su vez una
menor adherencia terapéutica en los pacientes. En ambos casos, cuanto mayor es la
autoeficacia, menor es el impacto negativo sobre la adherencia terapéutica, por lo que una
elevada autoeficacia funciona como un factor protector para la realización de actividad física
y la alimentación en pacientes con EHGNA con un perfil psicosocial de riesgo.
Los biomarcadores psicológicos abordados en la presente Tesis Doctoral, es decir, calidad
de vida, salud mental, estrategias de afrontamiento, autoeficacia y apoyo social, se han
mostrado relevantes para predecir y contribuir al impacto en el funcionamiento físico, mental
y social del paciente con EHGNA. Marcadores hepáticos y metabólicos como la fibrosis, la
diabetes tipo 2 y la obesidad también han demostrado su influencia en el perfil biopsicosocial
de estos pacientes. Por lo tanto, todos estos factores psicológicos, hepáticos y metabólicos
deberían ser considerados en futuros tratamientos multidisciplinares de la EHGNA, lo que
213
sugiere la integración de la evaluación e intervención psicológica en los protocolos de
seguimiento de estos pacientes.

-----------------------------------------------------------

A theoretical study and five pioneering empirical studies were done for this Ph.D. Thesis
which mainly approached the various biopsychosocial profiles of NAFLD patients associated
with severity of the liver disease, and its main risk factors, that is, type 2 diabetes and obesity.
It also explored the importance of psychological biomarkers in therapeutic adherence by
NAFLD patients.
The objective of the first study was theoretical analysis of the main psychosocial
repercussions of NAFLD and discussion of those psychological biomarkers that could be
important to the biopsychosocial profile associated with NAFLD. The impact of NAFLD
seems to be associated with deterioration in quality of life, mainly physical, and mental health,
as these patients report more anxiety and depressive symptoms than other chronic liver
pathologies. Furthermore, coping strategies, self-efficacy and social support were defined as
potentially important NAFLD variables because of their possible effects on physical and
mental health and therapeutic adherence by these patients. Finally, cognitive-behavioral
techniques should be included in multidisciplinary intervention for NAFLD.
The second study compared the quality of life, mental health and coping strategies of
NAFLD patients by social support and steatohepatitis and liver fibrosis, and also determined
what histological and psychosocial markers predicted the quality of life of these patients. A
series of questionnaires were administered to a sample of 492 biopsy-proven NAFLD patients,
including the 12-Item Short-Form Health Survey (SF-12), Chronic Liver Disease
Questionnaire - Non-alcoholic Fatty Liver Disease (CLDQ-NAFLD), Hospital Anxiety and
Depression Scale (HADS), Beck Depression Inventory-II (BDI-II), Brief-COPE (COPE-28),
General Self-Efficacy Scale (GSE), and Multidimensional Scale of Perceived Social Support
(MSPSS). Then analysis of variance, comparison of means and binary logistic regression were
calculated, arriving at the conclusion that low social support and significant fibrosis are
associated with worse quality of life and mental health, and with a more maladaptive coping
style than patients with strong social support and no significant fibrosis. Patients with
significant fibrosis also showed more decline in quality of life than the general Spanish
population. Significant fibrosis, along with female gender and higher anxiety and depressive

214
symptoms were found to be significant predictors of decline in quality of life of NAFLD
patients.
The objective in the third study was to compare quality of life of NAFLD patients by place
of origin, steatohepatitis and fibrosis, and determine the histological and biopsychosocial
markers that predict quality of life in patients in Spain and the United Kingdom. It was also
intended to determine what biopsychosocial markers mediate or moderate NAFLD patient
quality of life predictor models. The Chronic Liver Disease Questionnaire (CLDQ) was
applied to a sample of 737 biopsy-proven NAFLD patients (513 in Spain and 224 in the United
Kingdom) for that purpose. Then analysis of variance, binary logistic regression and
mediation and moderation models were calculated, arriving at the conclusion that patients in
the United Kingdom had a worse physical and mental quality of life than those in Spain.
Moreover, a higher stage of fibrosis predicted worse quality of life, mainly in the Spanish
cohort. Both female gender and a higher body mass index contributed to the negative impact
on quality of life in both Spain and the United Kingdom. Finally, female gender predicted
worse quality of life as it was associated with worse emotional function, higher body mass
index and greater fatigue, and this negative impact on quality of life was greater in patients in
the United Kingdom.
The objective of the fourth study for this Thesis determined the psychological, liver and
metabolic biomarkers that mediate or moderate NAFLD patient mental health and self-
efficacy predictor models. The following questionnaires were applied to a sample of 509
biopsy-proven NAFLD patients: the 12-Item Short-Form Health Survey (SF-12), Beck
Depression Inventory-II (BDI-II), Brief-COPE (COPE-28), and General Self-Efficacy Scale
(GSE). Then statistical analyses based on moderated mediation models were calculated, which
led to the conclusion that maladaptive coping was linked to worse physical and mental quality
of life of NAFLD patients, which added to presence of diabetes, a higher body mass index
and significant fibrosis, predicted worse mental health or self-efficacy of these patients.
In the fifth study, the objective was to compare NAFLD patient quality of life and coping
strategies by type 2 diabetes and obesity, and determine what coping strategies can predict
their quality of life. For this a sample of 307 biopsy-proven NALFD patients were
administered the 12-Item Short-Form Health Survey (SF-12), Chronic Liver Disease
Questionnaire - Non-alcoholic Fatty Liver Disease (CLDQ-NAFLD), and Brief-COPE
(COPE-28). Then statistical tests consisting of analysis of variance and multiple linear
regression were performed, leading to the conclusion that patients with diabetes or obesity
reported worse quality of life than those without comorbid metabolic pathology or the general
215
Spanish population. Obese patients also referred to more use of maladaptive coping strategies
than those who were not. Finally, the style of active coping was associated with a better quality
of life, while passive/avoidance style predicted worse quality of life.
The sixth and last study in this thesis determined the psychological biomarkers that mediate
or moderate NAFLD patient physical activity predictor models and following a Mediterranean
diet. The following questions were administered to 413 biopsy-diagnosed NAFLD patients
for this: the 12-Item Short-Form Health Survey (SF-12), Hospital Anxiety and Depression
Scale (HADS), General Self-Efficacy Scale (GSE), Multidimensional Scale of Perceived
Social Support (MSPSS), International Physical Activity Questionnaire - Short Form (IPAQ-
SF) and Mediterranean Diet Adherence Screener (MEDAS). Statistical analyses based on
moderated mediation models led to the conclusion that both poor physical quality of life and
low social support were related to more depressive symptoms, which predicted less
therapeutic adherence by patients. In both cases, the greater self-efficacy, the less the negative
impact on therapeutic adherence was, so that high self-efficacy was a protective factor for
doing physical activity and eating properly in psychosocially at-risk NAFLD patients.
The psychological biomarkers undertaken in this Ph.D. Thesis, that is, quality of life,
mental health, coping strategies, self-efficacy and social support, have been shown to be
important in predicting and contributing to the impact on physical, mental and social
functioning of NAFLD patients. The influence of liver and metabolic markers, such as
fibrosis, type 2 diabetes and obesity on the biopsychosocial profile of these patients was also
demonstrated. Therefore, all these psychological, liver and metabolic factors should be taken
into account in future multidisciplinary NAFLD treatments, which suggests the integration of
psychological evaluation and intervention in their follow-up protocols

216
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10. ANEXOS

10.1. Separata del trabajo titulado: “Psychological biomarker profile in

NAFLD/NASH with advanced fibrosis”

i
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10.2. Separata del trabajo titulado: “Psychological biomarkers and fibrosis: An
innovative approach to non-alcoholic fatty liver disease”

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10.3. Separata del trabajo titulado: “Health-related quality of life in non-alcoholic
fatty liver disease: A cross-cultural study between Spain and the United Kingdom”

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10.4. Separata del trabajo titulado: “Quality of life mediates the influence of coping
on mental health and self-efficacy in patients with non-alcoholic fatty liver disease”

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10.5. Separata del trabajo titulado: “Quality of life and coping in nonalcoholic fatty
liver disease: Influence of diabetes and obesity”

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10.6. Separata del trabajo titulado: “Influence of psychological biomarkers on
therapeutic adherence by patients with non-alcoholic fatty liver disease: A
moderated mediation model”

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10.7. Hoja de información y consentimiento informado

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