Annals of Medicine

ISSN: (Print) (Online) Journal homepage: www.tandfonline.com/journals/iann20

Inflammatory biomarkers and psychological

variables to assess quality of life in patients with
inflammatory bowel disease: a cross-sectional
study

Rafael González-Moret, Ausias Cebolla-Martí, Isabel Almodóvar-Fernández,

Jaime Navarrete, Ángeles García-Esparza, José M. Soria & Juan F. Lisón

To cite this article: Rafael González-Moret, Ausias Cebolla-Martí, Isabel Almodóvar-

Fernández, Jaime Navarrete, Ángeles García-Esparza, José M. Soria & Juan F. Lisón (2024)
Inflammatory biomarkers and psychological variables to assess quality of life in patients with
inflammatory bowel disease: a cross-sectional study, Annals of Medicine, 56:1, 2357738, DOI:
10.1080/07853890.2024.2357738

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Annals of Medicine
2024, VOL. 56, NO. 1, 2357738
https://doi.org/10.1080/07853890.2024.2357738

Research Article

Inflammatory biomarkers and psychological variables to assess quality of

life in patients with inflammatory bowel disease: a cross-sectional study
Rafael González-Moreta , Ausias Cebolla-Martíb,c , Isabel Almodóvar-Fernándezd ,
Jaime Navarretee,f , Ángeles García-Esparzag , José M. Soriah,i and Juan F. Lisónc,h,i
a
Department of Nursing and Physiotherapy, Faculty of Health Sciences, University CEU-Cardenal Herrera, CEU Universities, Valencia, Spain;
b
Department of Psychology, Universidad de Valencia, Valencia, Spain; cCentre of Physiopathology of Obesity and Nutrition (CIBERobn),
Instituto de Salud Carlos III, Madrid, Spain; dNursing Pre-departmental Unit, Universitat Jaume I, Castellón, Spain; eTeaching, Research &
Innovation Unit, Parc Sanitari Sant Joan de Déu, Barcelona, Spain; fCIBER of Epidemiology and Public Health (CIBERESP), Madrid, Spain;
g
Department of Pharmacy, Faculty of Health Sciences, University CEU-Cardenal Herrera, CEU Universities, Valencia, Spain; hDepartament of
Biomedical Science, Faculty of Health Sciences, University CEU-Cardenal Herrera, CEU Universities, Valencia, Spain; iInstitute of Biomedical
Sciences, University CEU-Cardenal Herrera, CEU Universities, Valencia, Spain

ABSTRACT ARTICLE HISTORY

Background: Inflammatory bowel disease (IBD) is a chronic gastrointestinal condition. While Received 23 February
inflammatory biomarkers are valuable for diagnosing and monitoring the disease, their correlation 2024
with patients’ quality of life (QoL) is not well-established. Revised 29 April 2024
Purpose: This study aims to investigate the correlations between inflammatory biomarkers and Accepted 30 April 2024
the quality of life (QoL) variables of individuals diagnosed with IBD in clinical remission. KEYWORDS
Methods: The sample of this cross-sectional study included 74 patients (80% women; 45 ± 11 years Inflammatory bowel
old) diagnosed with IBD. Outcome variables included faecal calprotectin (FC), C-reactive protein disease; quality of life;
(CRP), cortisol levels from hair samples, and anxiety and depression assessed using the Hospital biomarkers; anxiety;
Anxiety and Depression Scale (HADS-A and HADS-D, respectively), alongside QoL evaluated with depression
the Inflammatory Bowel Disease Questionnaire 32 (IBDQ-32). Bivariate correlations were calculated
using the Pearson correlation coefficient, and stepwise linear regression analyses were conducted
to identify independent factors contributing to IBDQ-32 scores.
Results: The IBDQ-32 did not significantly correlate with any biomarkers. However, it exhibited a
large and statistically significant negative correlation with HADS-A (r = −0.651) and HADS-D
(r = −0.611) scores (p < 0.001). Stepwise linear regression analyses indicated that HADS-A was a
significant and independent predictor for IBDQ-32 scores (Adjusted R2 = 0.41, β = −0.65, p < 0.001).
Conclusions: Inflammatory markers such as CRP, FC, or cortisol in hair do not play a decisive role
in assessing the QoL of IBD patients. These findings emphasize the significance of considering
psychological factors in evaluating and managing QoL in IBD patients in order to identify severity,
suggesting that instruments like HADS should be integral to comprehensive patient assessments.

Introduction Biomarkers such as C-reactive protein (CRP), faecal cal-

protectin (FC), or cortisol have been used to monitor
Inflammatory bowel disease (IBD) is a chronic disease
inflammatory processes [3] and have proven very use-
of unknown aetiology comprising ulcerative colitis
(UC) and Crohn’s disease (CD). People affected by IBD ful for diagnosing and monitoring IBD [4,5].
usually have disease flare ups in which digestive ulcers However, while these biomarkers offer insight into
and damage to the intestinal mucosa occur. Thus, it inflammatory activity, their direct correlation with
has been widely described those patients with IBD patient-reported outcomes, particularly quality of life
present periods of activation of symptoms and periods (QoL), remains nuanced [6,7]. Remarkably, no study to
of remission. This may be because of the sum of pre- date has comprehensively explored the relationship
disposing genetic and environmental factors such as between these biomarkers and QoL in the con-
diet, tobacco use, or stress at any given time [1,2]. text of IBD.

CONTACT José Miguel Soria López [email protected] Department of Biomedical Sciences, Universidad CEU Cardenal Herrera – Campus Elche,
Plaza Reyes católicos, 19, 03204, Elche, Alicante, Spain.
© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which
permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been
published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.
2 R. GONZÁLEZ-MORET ET AL.

Beyond the physiological manifestations of diges- preceding 12 months and should not have undergone
tive ulcers, mounting evidence underscores the pro- alterations in their medication regimen or modifica-
found impact of IBD on mental health, with a tions to their standard treatment within the previous
substantial proportion of patients experiencing comor- 3 months. Exclusions from the study comprised individ-
bid conditions such as anxiety and depression [8–11]. uals who lacked proficiency in the Spanish language,
Notably, poor mental health has been consistently those with diagnosed psychiatric disorders, individuals
linked to disease severity among IBD patients [12–16]. who had recently experienced significant emotional
For instance, recent research highlights the mediat- distress, or individuals who were pregnant at the time
ing role of psychological distress in exacerbating of recruitment. It’s important to note that all study
Crohn’s disease activity in response to stressful life participants gave written informed consent, signifying
events [11]. In this context, one plausible psychological their willingness to participate in the research before
construct influencing symptom severity is somatiza- its start.
tion, defined as distress stemming from somatic symp-
toms [17].
Data collection (outcome measures)
Given this context, our study aims to uncover con-
nections between the QoL of individuals with IBD and The concentration of faecal calprotectin (FC) was
biomarker profiles, including CRP, FC, and cortisol, as determined through fluorescent enzyme immunoassay
well as psychological variables like anxiety and depres- analysis, with a measurement range spanning from 0
sion. In addition, the innovative use of hair cortisol to 100 mg/g of dry weight. This analysis was con-
analysis here seeks to offer valuable insights into the ducted using a UniCap 100 analyser. Simultaneously,
feasibility of this measure and the intricate interplay of levels of plasma C-reactive protein (CRP) and cortisol
biological and psychosocial factors in IBD. were assessed using hair samples collected during the
patients’ most recent hospital consultations. For CRP
quantification, an immunoturbidimetric assay was per-
Methods formed utilizing a Cobas 8000 analyser (module c701).
Design This method relies on the formation of insoluble
immune complexes proportional to the CRP concentra-
This cross-sectional study obtained approval (Identification tion, with changes in turbidity quantified spectropho-
code: MINDFULNESS-EII2016) from the Human Ethics tometrically in milligrams per millilitre. Cortisol levels
Committee of Sagunto Hospital, in compliance with the were determined following the manufacturer’s instruc-
ethical principles delineated in the Declaration of Helsinki. tions (DRG Instruments GmbH, Germany) using a
The data were collected as part of a previous random- high-sensitivity cortisol enzyme-linked immunosorbent
ized controlled trial [2] and were used for secondary assay kit designed for saliva and hair samples (ELISA,
analysis. Salivary Cortisol ELISA DRG, DRG Instruments GmbH;
Ref.: SLV 2930. Lot.: 63K047). This assay exhibited a
sensitivity of 0.024 ng/ml and a detection range span-
Participants
ning from 0 to 30 ng/ml.
Eligible participants in this study were individuals aged To mitigate potential biases arising from different
between 18 and 55 years, diagnosed with either kit lots, all sample analyses were conducted simultane-
Crohn’s disease (CD) or ulcerative colitis (UC) in accor- ously at the study’s conclusion [19]. Hair samples were
dance with the diagnostic criteria established by the obtained from the posterior vertex area of each
European Crohn’s and Colitis Organization (ECCO). patient, meticulously cleaned with 2.5 ml of isopropa-
Additionally, these participants were required to be in nol through agitation (1,800 rpm for 2.5 min) to elimi-
clinical remission for a period of three months prior to nate contaminants and external steroids without
enrolment, as previously documented [1,2,18]. affecting internal steroid levels. After drying for 36 h at
Furthermore, the following inclusion criteria were room temperature, the samples were cut into frag-
applied: participants were expected to be free from ments measuring less than 2 mm with scissors.
cognitive impairment, UC patients were required to Subsequently, 120–150 mg of each sample was placed
have a partial Mayo Score of 2 points or less with no into microtubes, and 1.5 ml of methanol was added,
individual item scores exceeding 1 point, while CD followed by an 18-h incubation at 30 °C with stirring
patients were expected to exhibit a Harvey-Bradshaw (100 rpm, Mixer block®). After centrifugation of the
score of less than 5 points. Moreover, participants vials at 7,000 g for 2 min, 750 μl of the liquid phase was
must have remained free from disease flare-ups for the recovered and incubated in fresh microtubes at 38 °C
 Annals of Medicine 3

until complete desiccation. The obtained residue was computed bivariate correlations for all study partici-
then reconstituted in 0.2 ml of 0.05 M phosphate- pants using the Pearson correlation coefficient. To
buffered saline. avoid increasing type I error by repeating the statisti-
To measure the patient QoL we used the cal tests for each of the dependent variables, a
Inflammatory Bowel Disease Questionnaire 32 Bonferroni adjustment was applied to the significance
(IBDQ-32); which contains 32 items distributed into 4 level. Thus, the alpha level for the 5 comparisons was
dimensions (bowel and systemic symptoms, emotional 0.05/5, that is, p = 0.01. The strength of the Pearson
condition and social function). The responses to each correlation was interpreted in accordance with recom-
item are expressed on a 7-point scale, where 7 corre- mendations by Hopkins et al. where correlations in the
sponds to the best perception of health-related QoL range of 0.0–0.1 were considered trivial, 0.1–0.3
and 1 to the worst. In this study, the global score was denoted small, 0.3–0.5 signified moderate, 0.5–0.7 rep-
used for all 32 items. The IBDQ-32 has also been vali- resented large, 0.7–0.9 indicated very large, and 0.9–1
dated in Spanish and showed adequate psychometric approximated an almost perfect correlation [22].
properties [20]. In addition, the levels of anxiety and Furthermore, stepwise linear regression analyses were
depression in the patients were evaluated using the executed to develop a model aimed at identifying
Hospital Anxiety and Depression Scale (HADS), a tool independent factors contributing to IBDQ-32 scores.
encompassing a total of 14 questions. Within this Prior to variable selection, we scrutinized the correla-
questionnaire, 7 questions pertain to the assessment tion coefficients between the independent variables
of anxiety symptoms (referred to as HADS-A), while and QoL, selecting only those with statistically signifi-
the remaining 7 questions gauge symptoms of depres- cant correlations for further analysis. All statistical anal-
sion (referred to as HADS-D). Each individual item in yses were carried out using SPSS software (version
the scale is assigned a score within the range of 0 to 27.0 for Windows, SPSS Inc., Chicago, IL).
3, resulting in a possible score range of 0 to 21 points
for each subscale.
Moreover, this scale has also been validated in Results
Spanish for which it showed adequate psychometric
A comprehensive screening process involved a total of
properties [21]. In addition, it had an internal consis-
93 patients for this study. Of these, 19 individuals were
tency (Cronbach alpha) of 0.90 for the full scale, with
excluded; four patients declined participation, and 15
the depression subscale and anxiety subscale reaching
did not meet the specified inclusion criteria. An over-
0.84 and 0.85, respectively. Completion of theIBDQ-32
view of the demographic and clinical characteristics of
and HADS assessments was managed by a nurse who
the study population is presented in Table 1. The mean
delivered the questionnaires to the patients to be
age of the included participants was 45 years (SD =
immediately filled in.
11), with a predominance of female participants (80%).
All data are available in Zenodo.
Regarding the distribution of IBD subtypes among the
participants, it was evenly distributed, with each sub-
Data analysis type comprising 50% of the cohort. The mean dura-
tion of disease was 10.8 years (SD = 8.4), indicating a
No studies have investigated the correlation between
substantial period of illness management among the
hair cortisol levels and quality of life in patients with
participants. Notably, all participants were in clinical
Inflammatory Bowel Disease (IBD). The following
assumption was made to test the hypothesis that hair
cortisol levels are related to quality of life: higher lev-
Table 1. Characteristics of the study population with ulcer-
els of cortisol in hair are associated with worse quality
ative colitis or Crohn’s disease.
of life. We conducted an exploratory power analysis
Age (y) 45.0 (11.0)
using the G*Power (v3.1.9.2, Heinrich-Heine-Universität Sex (men/women) 15/59
Düsseldorf, Germany) software and determined that 67 CD/UC (%) 50/50
Disease duration (y) 10.8 (8.4)
participants would yield 80% statistical power at a 5% Faecal calprotectin (μg/g) 212 (342)
significance level for a small to moderate effect size Cortisol in hair (μg/mL) 1.9 (3.0)
C-reactive protein (mg/dL) 2.0 (2.7)
(r = 0.3). Compliance with the assumption of normality IBDQ-32 10.5 (4.6)
was checked for each dependent variable using HADS Anxiety 10.6 (4.6)
HADS Depression 6.2 (4.3)
Shapiro–Wilks tests. To establish the independent asso-
Abbreviations: CD = Crohn’s disease; UC = ulcerative colitis; IBDQ = Inflammatory
ciation between IBDQ-32 and the other outcome mea- Bowel Disease Questionnaire; HADS = Hospital Anxiety and Depression Scale.
sures (FC, CRP, hair cortisol, HADS-A, and HADS-D), we Data are presented as means with SD.
4 R. GONZÁLEZ-MORET ET AL.

remission at the time of enrollment, ensuring a homo- progression. Indeed, several investigations have demon-
geneous baseline for the study. strated strong correlations between gastrointestinal dis-
Interestingly, the IBDQ-32 did not significantly cor- ease remission and reduced levels of specific biomarkers
relate with any of the biomarkers (fecal calprotectin [23,24]. Furthermore, associations between certain gas-
[FC], C-reactive protein [CRP], or hair cortisol), as trointestinal assessments and QoL parameters linked to
shown in Table 2. However, the IBDQ-32 demonstrated disease severity have been documented. Notably, faecal
a large and statistically significant negative correlation calprotectin, a biomarker previously associated with
with the Hospital Anxiety and Depression Scale-Anxiety intestinal inflammation and dysbiosis, has shown cor-
(HADS-A) and Hospital Anxiety and Depression Scale- relations with increased digestive symptoms and dimin-
Depression (HADS-D) scores. The associations between ished QoL scores [25]. Nevertheless, consistent with our
IBDQ-32 and the independent variables are systemati- findings, the relationship between fluctuations in bio-
cally summarized in Table 2. Furthermore, stepwise lin- marker concentrations during the course of gastrointes-
ear regression analyses were conducted to explore the tinal disease and the QoL index may sometimes be
predictors of IBDQ-32 scores, as detailed in Table 3. insignificant [26,27]. This could be attributed, in part, to
Notably, our analysis revealed that HADS-A was a sig- the comprehensive nature of the QoL index, which is
nificant and independent predictor for the IBDQ-32 influenced by various parameters, with certain factors
outcome (Adjusted R2 = 0.41, β = −0.65, p < 0.001). such as the perception of anxiety disorders or depres-
Model 1, which included HADS-A as the sole predictor, sion carrying significant weight [28]. In this regard,
explained 41.3% of the variation in the IBDQ-32 scores. alongside physical symptoms, IBD presents substantial
Subsequently, Model 2 was constructed by adding psychosocial challenges, with rates of depression as
HADS-D alongside HADS-A, resulting in an increased high as 25.3% and anxiety as high as 32.1%, escalating
explanatory power, with 45.6% of the variation in to 38.9% and 57.6%, respectively, during active disease
IBDQ-32 scores being accounted for. states [29]. Moreover, recent meta-analyses have indi-
cated that depression and anxiety predict poorer clini-
cal outcomes in IBD, including disease flares,
Discussion hospitalization, therapy escalation, and surgery [30].
This study endeavors to elucidate the intricate inter- Therefore, addressing mental health concerns should be
play between C-reactive protein (CRP), fecal calprotec- prioritized in IBD treatment and taken into account in
tin (FC), hair cortisol levels, and psychological variables order to stablish the severity of the disorder [31].
such as anxiety and depression in relation to the qual- Consistent with these findings, our study revealed
ity of life (QoL) among patients diagnosed with inflam- that scores on the Hospital Anxiety and Depression
matory bowel disease (IBD). To our knowledge, this Scale (HADS-D and HADS-A) accounted for 45.6% of the
investigation represents the inaugural effort to estab- variance in IBDQ-32 scores. Thus, parameters such as
lish correlations between concentrations of inflamma- HADS-A or HADS-D are pivotal in assessing QoL and,
tion biomarkers and QoL in this context. consequently, integral to QoL index scores [32–35].
Contrary to our initial hypotheses, the correlations Indeed, therapies aimed at ameliorating anxiety or
between concentrations of inflammation biomarkers depression processes in these patients, evaluated using
and QoL were found to be weak and non-significant. HADS-A and HADS-D, improved QoL perceptions and
However, as anticipated, levels of anxiety and depres- mean QoL index scores [36]. Moreover, a meta-analysis
sion exhibited a robust and significant negative correla-
tion with QoL. Previous studies have underscored the
utility of biological markers in tracking disease Table 3. Multiple stepwise linear regression analyses with the
Inflammatory Bowel Disease Questionnaire-32 as the depen-
dent variable.
Table 2. Correlation coefficients for the Inflammatory Bowel IBDQ-32
Disease Questionnaire-32 and independent variables. Standardised
Cortisol in Independent Adjusted R2 Beta Beta
Variables FC CRP hair HADS-A HADS-D variables R2 R2 change coefficient significance
IBDQ-32 0.219 −0.103 0.102 −0.651* −0.611* Model 1 0.42 0.41 0.42
FC 0.073 0.032 −0.278 −0.108 HADS-A −0.65 < 0.001
CRP −0.010 0.014 0.120 Model 2 0.47 0.45 0.05
Cortisol in hair −0.229 −0.194 HADS-A −0.43 0.002
HADS-A 0.684* HADS-D −0.31 0.025
Abbreviations: CRP = C-reactive protein; FC = faecal calprotectin ; HADS = Abbreviations: HADS-A = Hospital Anxiety and Depression Scale-Anxiety;
Hospital Anxiety and Depression Scale and IBDQ = Inflammatory Bowel HADS-D = Hospital Anxiety and Depression Scale-Depression and IBDQ-32 =
Disease Questionnaire, *p < 0.01. Inflammatory Bowel Disease Questionnaire-32.
 Annals of Medicine 5

across various medical conditions demonstrated that Strengths and limitations

psychosocial interventions reduced inflammation and
One strength of this study is the use of objective mea-
proinflammatory cytokine levels by 18–48% compared
sures of inflammation, minimizing potential bias asso-
to controls [37]. The precise mechanisms underlying this
ciated with self-reported data. Another strength is the
phenomenon remain incompletely understood, but
novel use of hair cortisol levels in IBD patients, provid-
interventions targeting negative psychological factors
ing insight into cortisol levels over an extended period.
appear to influence immune system function and
However, the cross-sectional design of this study pre-
inflammation, partly through activation of the parasym-
cludes solid conclusions regarding causality.
pathetic nervous system [38,39]. This could be particu-
Additionally, the HADS questionnaire does not differ-
larly relevant for IBD, as psychological and behavioral
entiate between trait anxiety and state anxiety, despite
factors are believed to influence intestinal inflammation
being a useful tool for determining levels of anxiety
and disease activity via the gut-brain axis [40].
and depression. Furthermore, the small sample size
Another possible explanation for the absence of
prevented independent analysis of patients with ulcer-
correlation between inflammation biomarkers and QoL
ative colitis and Crohn’s disease. Finally, as our partici-
in IBD may be that all patients included in this study
pants were in clinical remission, our results may not be
were in clinical remission, thus excluding those with
generalizable to other disease statuses, such as active
active disease, wherein inflammatory marker levels sig-
disease. Further investigation into the timing of inflam-
nificantly elevate [4,5]. Finally, as proposed by Knisely
mation and disease activity in a larger sample, allow-
and colleagues, the lack of correlation between bio-
ing for independent analysis of patients with ulcerative
markers and patients could also be associated with
colitis and Crohn’s disease, is warranted.
cytokine gene polymorphisms. Therefore, genetic stud-
ies of these polymorphisms could serve as valuable
predictive and monitoring tools for IBD [6]. Conclusion
The results of our study demonstrated a small neg-
ative correlation between anxiety levels and fecal cal- In summary, the findings of this study suggest that
protectin levels (r = −0.278, p = 0.038). This finding inflammation biomarkers such as CRP, FC, and corti-
aligns with results obtained by Narula et al. who con- sol are valuable for the follow-up and monitoring of
ducted a prospective longitudinal follow-up study with IBD but do not determine patient QoL. Conversely,
414 IBD patients and found that IBD patients with variables such as anxiety and depression, measured
abnormal anxiety sub-scores had poorer IBD-related using instruments like the HADS, appear to correlate
outcomes compared to those without elevated anxiety more strongly with QoL in these patients. Therefore,
sub-scores [41]. Additionally, a recent meta-analysis these instruments should be considered in the com-
involving 28 RCTs and 1789 participants with IBD con- prehensive assessment of patients to enhance
cluded that treatments addressing mood outcomes, their QoL.
such as anxiety, have beneficial effects on both generic
inflammation and disease-specific biomarkers, such as
Acknowledgments
fecal calprotectin [42]. Moreover, psychological inter-
ventions demonstrated larger treatment effects on We are grateful to the CIBER of Epidemiology and Public Health
mood compared to exercise or antidepressants. (CIBERESP CB22/02/00052) and to the CIBER of Physiopathology
of Obesity and Nutrition (CIBERobn, CB06/03/0052) for its sup-
Regarding depression, our results did not exhibit
port. CIBER is an initiative of the Instituto de Salud Carlos III
significant correlations with any of the studied bio- (ISCIII). The CIBER and ISCIII did not play any role in the analysis
markers. Cross-sectional studies have shown significant and interpretation of data, in the writing of the manuscript, or
variability in this regard, with some indicating modest in the decision to submit the paper for publication.
to moderate correlations between CRP and fecal cal-
protectin levels and depressive symptoms [43,44],
while others report no significant findings [45,46]. Authors contributions
Consistent with our findings, no differences in IBD- All authors contributed to the conception and design of
related outcomes were observed in individuals with the study, analysis and interpretation of data, critical review,
abnormal depression sub-scores compared to those and final approval of the manuscript for publication. Data
acquisition was conducted by RGM, JMS, IAF, JFL, JN, ACM,
without elevated depression scores [41]. Longitudinal
and AGE. Drafting of the manuscript was primarily led by
data on IBD are more limited and, also in line with our RGM, JMS, and JFL. Each author affirms their dedication to
results, indicate non-significant associations between maintaining the accuracy and integrity of all aspects of
inflammation and depression [47]. the study.
6 R. GONZÁLEZ-MORET ET AL.

Authorship statement [6] Knisely MR, Conley YP, Szigethy E. Cytokine genetic
variants and health-related quality of life in crohn’s dis-
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are in agreement with the content of the manuscript. 551. doi: 10.1177/1099800419860906.
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Disclosure statement tients with irritable bowel syndrome. Biol Res Nurs.
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No potential conflict of interest was reported by the author(s).
[8] Addolorato G, Capristo E, Stefanini GF, et al.
Inflammatory bowel disease: a study of the association
between anxiety and depression, physical morbidity,
Ethics statement and nutritional status. Scand J Gastroenterol. 1997;
This study was approved by the Human Ethics Committee at 32(10):1013–1021. doi: 10.3109/00365529709011218.
the Hospital Universitario de Sagunto (Spain). [9] Knowles SR, Graff LA, Wilding H, et al. Quality of life in
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