Content uploaded by Alba Panarese
Author content
All content in this area was uploaded by Alba Panarese on Jun 09, 2022
Content may be subject to copyright.
World Journal of
Gastroenterology
World J Gastroenterol 2019 April 14; 25(14): 1640-1782
ISSN 1007-9327 (print)
ISSN 2219-2840 (online)
Published by Baishideng Publishing Group Inc
W J G World Journal of
Gastroenterology
Contents Weekly Volume 25 Number 14 April 14, 2019
REVIEW
1640 Precision surgical approach with lymph-node dissection in early gastric cancer
Kinami S, Nakamura N, Tomita Y, Miyata T, Fujita H, Ueda N, Kosaka T
MINIREVIEWS
1653 Update on hepatocellular carcinoma: Pathologists’ review
El Jabbour T, Lagana SM, Lee H
1666 Application of artificial intelligence in gastroenterology
Yang YJ, Bang CS
ORIGINAL ARTICLE
Basic Study
1684 Clinical significance of programmed death 1/programmed death ligand 1 pathway in gastric
neuroendocrine carcinomas
Yang MW, Fu XL, Jiang YS, Chen XJ, Tao LY, Yang JY, Huo YM, Liu W, Zhang JF, Liu PF, Liu Q, Hua R, Zhang ZG,
Sun YW, Liu DJ
1697 Functional role of long non-coding RNA CASC19/miR-140-5p/CEMIP axis in colorectal cancer progression
in vitro
Wang XD, Lu J, Lin YS, Gao C, Qi F
1715 Seven-senescence-associated gene signature predicts overall survival for Asian patients with hepatocellular
carcinoma
Xiang XH, Yang L, Zhang X, Ma XH, Miao RC, Gu JX, Fu YN, Yao Q, Zhang JY, Liu C, Lin T, Qu K
Case Control Study
1729 Chronic functional constipation is strongly linked to vitamin D deficiency
Panarese A, Pesce F, Porcelli P, Riezzo G, Iacovazzi PA, Leone CM, De Carne M, Rinaldi CM, Shahini E
Retrospective Study
1741 Clinical characteristics of non-alcoholic fatty liver disease in Chinese adult hypopituitary patients
Yuan XX, Zhu HJ, Pan H, Chen S, Liu ZY, Li Y, Wang LJ, Lu L, Yang HB, Gong FY
Observational Study
1753 Measurement of prostaglandin metabolites is useful in diagnosis of small bowel ulcerations
Matsuno Y, Umeno J, Esaki M, Hirakawa Y, Fuyuno Y, Okamoto Y, Hirano A, Yasukawa S, Hirai F, Matsui T, Hosomi S,
Watanabe K, Hosoe N, Ogata H, Hisamatsu T, Yanai S, Kochi S, Kurahara K, Yao T, Torisu T, Kitazono T, Matsumoto T
WJG https://www.wjgnet.com
April 14, 2019 Volume 25 Issue 14
I
Contents World Journal of Gastroenterology
Volume 25 Number 14 April 14, 2019
Prospective Study
1764 Endoscopic response to tumor necrosis factor inhibitors predicts long term benefits in Crohn’s disease
Alfaro I, Masamunt MC, Planell N, López-García A, Castro J, Gallego M, Barastegui R, Giner A, Vara A, Salas A, Ricart E,
Panés J, Ordás I
CASE REPORT
1775 Application of a 3D-printed ”fistula stent” in plugging enteroatmospheric fistula with open abdomen: A
case report
Xu ZY, Ren HJ, Huang JJ, Li ZA, Ren JA
WJG https://www.wjgnet.com
April 14, 2019 Volume 25 Issue 14
II
Contents World Journal of Gastroenterology
Volume 25 Number 14 April 14, 2019
ABOUT COVER Editorial board member of World Journal of Gastroenterology, Jun-Te Hsu,
MD, Professor, Surgeon, Surgical Oncologist, Department of Surgery,
Chang Gung Memorial Hospital, Taoyuan County and Chang Gung
Medicine Colledge, Tao Yuan 333, Taiwan
AIMS AND SCOPE World Journal of Gastroenterology (World J Gastroenterol, WJG, print ISSN 1007-
9327, online ISSN 2219-2840, DOI: 10.3748) is a peer-reviewed open access
journal. The WJG Editorial Board consists of 642 experts in gastroenterology
and hepatology from 59 countries.
The primary task of WJG is to rapidly publish high-quality original
articles, reviews, and commentaries in the fields of gastroenterology,
hepatology, gastrointestinal endoscopy, gastrointestinal surgery,
hepatobiliary surgery, gastrointestinal oncology, gastrointestinal radiation
oncology, etc. The WJG is dedicated to become an influential and
prestigious journal in gastroenterology and hepatology, to promote the
development of above disciplines, and to improve the diagnostic and
therapeutic skill and expertise of clinicians.
INDEXING/ABSTRACTING The WJG is now indexed in Current Contents®/Clinical Medicine, Science Citation
Index Expanded (also known as SciSearch®), Journal Citation Reports®, Index
Medicus, MEDLINE, PubMed, PubMed Central, Scopus and Directory of Open
Access Journals. The 2018 edition of Journal Citation Report® cites the 2017 impact
factor for WJG as 3.300 (5-year impact factor: 3.387), ranking WJG as 35th among 80
journals in gastroenterology and hepatology (quartile in category Q2).
RESPONSIBLE EDITORS
FOR THIS ISSUE Responsible Electronic Editor: Han Song Proofing Editorial Office Director: Ze-Mao Gong
NAME OF JOURNAL
World Journal of Gastroenterology
ISSN
ISSN 1007-9327 (print) ISSN 2219-2840 (online)
LAUNCH DATE
October 1, 1995
FREQUENCY
Weekly
EDITORS-IN-CHIEF
Subrata Ghosh, Andrzej S Tarnawski
EDITORIAL BOARD MEMBERS
http://www.wjgnet.com/1007-9327/editorialboard.htm
EDITORIAL OFFICE
Ze-Mao Gong, Director
PUBLICATION DATE
April 14, 2019
COPYRIGHT
© 2019 Baishideng Publishing Group Inc
INSTRUCTIONS TO AUTHORS
https://www.wjgnet.com/bpg/gerinfo/204
GUIDELINES FOR ETHICS DOCUMENTS
https://www.wjgnet.com/bpg/GerInfo/287
GUIDELINES FOR NON-NATIVE SPEAKERS OF ENGLISH
https://www.wjgnet.com/bpg/gerinfo/240
PUBLICATION MISCONDUCT
https://www.wjgnet.com/bpg/gerinfo/208
ARTICLE PROCESSING CHARGE
https://www.wjgnet.com/bpg/gerinfo/242
STEPS FOR SUBMITTING MANUSCRIPTS
https://www.wjgnet.com/bpg/GerInfo/239
ONLINE SUBMISSION
https://www.f6publishing.com
© 2019 Baishideng Publishing Group Inc. All rights reserved. 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA
E-mail: bpgoffice@wjgnet.com https://www.wjgnet.com
WJG https://www.wjgnet.com
April 14, 2019 Volume 25 Issue 14
III
W J G World Journal of
Gastroenterology
Submit a Manuscript: https://www.f6publishing.com World J Gastroenterol 2019 April 14; 25(14): 1729-1740
DOI: 10.3748/wjg.v25.i14.1729 ISSN 1007-9327 (print) ISSN 2219-2840 (online)
ORIGINAL ARTICLE
Case Control Study
Chronic functional constipation is strongly linked to vitamin D
deficiency
Alba Panarese, Francesco Pesce, Piero Porcelli, Giuseppe Riezzo, Palma Aurelia Iacovazzi, Carla Maria Leone,
Massimo De Carne, Caterina Mammone Rinaldi, Endrit Shahini
ORCID number: Alba Panarese
(0000-0002-4909-043); Francesco
Pesce (0000-0002-2882-4226); Piero
Porcelli (0000-0002-2263-8051);
Giuseppe Riezzo
(0000-0002-1800-4830); Palma
Aurelia Iacovazzi
(0000-0003-3590-4125); Carla Maria
Leone (0000-0003-0465-3781);
Massimo De Carne
(0000-0001-8753-5486); Caterina
Mammone Rinaldi
(0000-0003-0223-6976); Endrit
Shahini (0000-0002-4909-0436).
Author contributions: Panarese A
has conceived the protocol; Shahini
E and Panarese A drafted the
initial and final manuscript;
Panarese A enrolled patients;
Panarese A, and Leone CM
collected in a database the baseline
and on-treatment information;
Shahini E, Pesce F and Porcelli P
systematically reviewed the data
entries for completeness and
consistency, checked for
completeness of information and
performed the statistical analysis;
all the authors reviewed and
approved the final draft.
Institutional review board
statement: National Institute of
Gastroenterology “S. De Bellis”
Research Hospital (0807/16) and
by the Research Ethics Committee
of the National Oncological
Institute of Bari (CAAE:147/16)
(Trial registration number:
NCT03096704).
Informed consent statement: All
study participants or their legal
guardian provided informed
written consent about personal and
Alba Panarese, Massimo De Carne, Endrit Shahini, Department of Gastroenterology and
Digestive Endoscopy, Scientific Institute for Digestive Disease "Saverio de Bellis" Hospital,
Castellana Grotte (Bari) 70013, Italy
Francesco Pesce, Nephrology section, Department of Emergency and Organ Transplantation,
University of Bari, Bari 70013, Italy
Piero Porcelli, Department of Psychological, Health, and Territorial Sciences, D'Annunzio
University of Chieti-Pescara, Chieti 70013, Italy
Giuseppe Riezzo, Palma Aurelia Iacovazzi, Carla Maria Leone, Department of Clinical Pathology,
Scientific Institute for Digestive Disease "Saverio de Bellis" Hospital, Castellana Grotte (Bari)
70013, Italy
Caterina Mammone Rinaldi, Department of Radiology, Scientific Institute for Digestive Disease
"Saverio de Bellis" Hospital, Castellana Grotte (Bari) 70013, Italy
Endrit Shahini, Department of Emergency and Organ Transplantation, University of Bari, Bari
70124, Italy
Corresponding author: Alba Panarese, MD, Doctor, Department of Gastroenterology and
Digestive Endoscopy, Scientific Institute for Digestive Disease "Saverio de Bellis" Hospital,
Turi Street n. 27, Castellana Grotte (Bari) 70013, Italy. alba.panarese@irccsdebellis.it
Telephone: +39-3471401487; +39-0804994251
Fax: +39-0804994250
Abstract
BACKGROUND
Few studies have examined intestinal motility disorders, which are disabling
conditions associated with chronic functional constipation, whose pathogenesis is
actually not well-defined.
AIM
To investigate the relationship between serum 25-hydroxyvitamin D levels and
functional chronic constipation associated to intestinal motility disorders.
METHODS
We performed a prospective case-control study, from May-June to November
2017. Glucose/lactulose breath tests, radiopaque markers (multiple capsule
techniques) and wireless motility capsule analysis were used to assess colonic
WJG https://www.wjgnet.com
April 14, 2019 Volume 25 Issue 14
1729
medical data collection prior to
study enrolment.
Conflict-of-interest statement: All
authors declare no conflict of
interest related to this publication.
STROBE statement: The guidelines
of the STROBE Statement have
been adopted.
Open-Access: This article is an
open-access article which was
selected by an in-house editor and
fully peer-reviewed by external
reviewers. It is distributed in
accordance with the Creative
Commons Attribution Non
Commercial (CC BY-NC 4.0)
license, which permits others to
distribute, remix, adapt, build
upon this work non-commercially,
and license their derivative works
on different terms, provided the
original work is properly cited and
the use is non-commercial. See:
http://creativecommons.org/licen
ses/by-nc/4.0/
Manuscript source: Invited
manuscript
Received: February 16, 2019
Peer-review started: February 18,
2019
First decision: February 26, 2019
Revised: March 11, 2019
Accepted: March 24, 2019
Article in press: March 25, 2019
Published online: April 14, 2019
P-Reviewer: Feretis M, Luthin DR,
Negreanu L
S-Editor: Yan JP
L-Editor: A
E-Editor: Song H
and oro-cecal transit time, after excluding small-intestinal bacterial overgrowth
condition. Then, we measured 25-hydroxyvitamin D levels in patients with
intestinal motility disorders and we further evaluated the influence of intestinal
motility disorders on psychological symptoms/quality of life using validated
questionnaires, the Irritable Bowel Syndrome Quality of life (IBS-QOL), the Short
Form Health Survey 12, and the Hospital Anxiety and Depression Scale 14
(HADS-14 A and HADS-14 D).
RESULTS
We enrolled 86 patients with chronic functional constipation associated to
intestinal motility disorders and 86 matched healthy subjects. Patients with
intestinal motility disorders had lower 25-hydroxyvitamin D levels (P < 0.001),
and they showed a significant impairment of all health-related quality of life and
psychological tests (IBS-QOL, Short Form Health Survey 12-Physical Component
Summary, Short Form Health Survey 12-Mental Component Summary, HADS-14
A and HADS-14 D), as compared to the control group (P < 0.001), which
significantly correlated with low vitamin D levels (r = - 0.57, P < 0.001; r = 0.21, P
= 0.01; r = - 0.48, P < 0.001; r = - 0.57, P < 0.001; r = - 0.29, P < 0.001, respectively).
At multivariate analysis vitamin D low levels remained a significant independent
risk factor for the occurrence of intestinal motility disorder (odds ratio = 1.19;
95% confidence interval: 1.14-1.26, P < 0.001).
CONCLUSION
Vitamin D deficiency, anxiety and depression symptoms are commonly
associated with chronic functional constipation induced by intestinal motility
disorders. Vitamin D serum levels should be routinely measured in these
patients.
Key words: Chronic constipation; Intestinal motility; Vitamin D; Quality of life; Anxiety;
Depression
©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
Core tip: Intestinal motility disorders, which are disabling conditions associated with
chronic constipation, have been examined in only A few studies. Patients with intestinal
motility disorders are frequently affected by vitamin D deficiency, which is strongly
associated to anxiety, depression symptoms and to severe impairment of quality of life.
These data suggest that vitamin D serum levels should be routinely measured, and its
supplementation should be evaluated in patients with intestinal motility disorders.
Citation: Panarese A, Pesce F, Porcelli P, Riezzo G, Iacovazzi PA, Leone CM, De Carne M,
Rinaldi CM, Shahini E. Chronic functional constipation is strongly linked to vitamin D
deficiency. World J Gastroenterol 2019; 25(14): 1729-1740
URL: https://www.wjgnet.com/1007-9327/full/v25/i14/1729.htm
DOI: https://dx.doi.org/10.3748/wjg.v25.i14.1729
INTRODUCTION
The term “Constipation” has a broad definition both for physicians and patients[1].
The most common form is functional chronic constipation, which is a gastrointestinal
disorder defined by symptom criteria, after the exclusion of secondary causes[2-4]. This
clinical condition usually affects women, older subjects, particularly those of lower
socioeconomic status[5], and has a prevalence ranging between 2% and 27% in western
countries with a high burden on global health-care system[2,6,7]. The main symptoms of
functional chronic constipation are difficulty with evacuation, bloating, abdominal
pain, discomfort or hard stools that significantly impair health-related quality of
life[2,8]. Since depression has been commonly observed in patients with the
constipation variant of irritable bowel syndrome (IBS), specific questionnaires have
been endorsed to evaluate some aspects of the quality of life of these patients,
especially the IBS Quality of life (IBS-QOL), the Short Form Health Survey 12 (SF-12),
WJG https://www.wjgnet.com
April 14, 2019 Volume 25 Issue 14
Panarese A et al. Vitamin D and intestinal motility disorder
1730
and the Hospital Anxiety and Depression Scale 14 (HADS-14-A/D)[9-12]. Moreover,
previous studies showed a possible role of vitamin D deficiency in the pathophysi-
ology of IBS and depression, and also beneficial effects of vitamin D supplementation
in alleviating depression and certain gastrointestinal symptoms in a population of
study prevalently affected by diarrhea or by alternating subtype, and the minority by
constipation symptoms[13-20]. Normal transit constipation is probably the most common
form, and it frequently overlaps with the constipation variant of IBS[9].
Among patients with functional chronic constipation, intestinal motility disorders
have been reported. Although the overall prevalence of intestinal motility disorders is
not currently well-defined[2], it involves more commonly patients affected by slow
transit constipation (STC)[2], and rarely subjects with delayed oro-cecal transit time[21],
In addition, defecation disorders significantly overlap with normal and STC[9,22]. While
STC is characterized by an altered colonic motor activity, and reduced reaction after a
meal and when waking up, decreased “high amplitude propagated contractions”,
which have been associated to altered regulation of enteric nervous system, reduction
of neurons and axons in the myenteric plexus[2,22-24], delayed oro-cecal transit time
could be partially associated with an underlying small-intestinal bacterial overgrowth
(SIBO)[25].
Moreover, the most severe form of intestinal motility disorder may be considered
chronic intestinal pseudo-obstruction, which is a symptomatic and disabling disease,
related to a visceral myopathy or/and neuropathy[26]. Hence, colonic transit time
could be objectively measured by radiopaque markers (single or multiple capsule
techniques), and this diagnostic tool is also used to rule out dyssynergia defeca-
tion[2,23]. Radiopaque markers studies are useful, inexpensive and widely available[2,23].
In addition, even if not definitively recommended by guidelines, lactulose breath test
(LBT) and glucose breath test (GBT), are commonly used in clinical practice to
evaluate the presence of SIBO as well as small-bowel motility by estimating oral-cecal
transit time[25,27]. Other expensive tests such as colonic scintigraphy and wireless
ingestible motility capsule, measure more accurately overall transit time[23,27], whereas
advanced physiologic tests identify anorectal dysfunctions in patients not responding
to initial therapy[2,27]. In this paper we hypothesized that serum vitamin D deficiency
could be associated with chronic functional constipation secondary to delayed
intestinal transit time and consequently we investigated this relationship and the
related psychological aspects.
MATERIALS AND METHODS
Study design
This case-control study was performed from May-June to November 2017, in the
Outpatients Clinic of our Institution, in Apulia, a Mediterranean region located in
southeast of Italy. As shown in Figure 1, we enrolled 86 subjects from a population of
152 consecutive constipated patients affected by intestinal motility disorders.
Inclusion criteria were the following: Caucasian subjects ≥ 18 years old, body mass
index (BMI) ≥ 18.5 kg/m2, affected by functional chronic constipation associated to
delayed intestinal transit time, supported by Roma IV criteria[8,26,28]. Exclusion criteria
were the following: Subjects > 75 years old, IBS, pregnancy, significant comorbidities
such as cardiac, respiratory, chronic renal insufficiency, anorectal and pelvic floor
dysfunctions, metabolic/endocrine (diabetes mellitus, hypothyroidism, hypercal-
caemia, panhypopituitarism), medications (opiates, antihypertensive agents, iron
preparations, anti-epileptic drugs, tryciclic antidepressants, anticholinergics or
dopaminergics), organic (extra-intestinal mass, colorectal cancer, ischaemic or surgical
stenosis, anal fissure, anal strictures, inflammatory bowel disease, intestinal
malabsorption and diverticular diseases), neurological (Parkinson disease, multiple
sclerosis, paraplegia, autonomic neuropathy, chronic intestinal pseudo-obstruction,
gastroparesis, Hirschsprung disease and stroke), past psychiatric disease, and
myogenic (scleroderma, amyloidosis and myotonic dystrophy dermatomyositis)[2,21,26].
In addition, we also assessed a control group of 86 healthy subjects (sex, age and BMI
matched), recruited from a population-based cohort study of 150 healthy subjects,
which underwent routine clinical exams in our Institute to check their healthy status,
after excluding the presence of a functional chronic constipation during the clinical
interview.
Our research was carried out in compliance with the Helsinki Declaration and
procedures received approval by the Institutional review board of the National
Institute of Gastroenterology “S. De Bellis” Research Hospital (0807/16) and by the
Research Ethics Committee of the National Oncological Institute of Bari
(CAAE:147/16) (Trial registration number: NCT03096704). Informed consent was
WJG https://www.wjgnet.com
April 14, 2019 Volume 25 Issue 14
Panarese A et al. Vitamin D and intestinal motility disorder
1731
Figure 1
Figure 1 Flow diagram describing the process of patients’ selection. CT: Computerized tomography; ROM: Radiopaque markers.
obtained from all participants of the study. The statistical review of the study was
performed by a biomedical statistician.
Definition of functional chronic constipation
All selected patients were inquired, before, for any possible secondary causes of
functional chronic constipation, including alarm features, lifestyle factors and medical
treatments and we also identified the response (or lack of) to previous treatment
about constipation symptoms, by interviewing patients. Then, they were considered
affected by functional chronic constipation only when they showed a frequency of
evacuation less than twice a week with increased stool consistency[8,26,28]. All the
selected patients underwent blood tests, colonoscopy, nutritional assessment (with
daily food frequency questionnaires), stool frequency diary, LBT, GBT, wireless
motility testing, radiopaque markers studies, and when required, tests for pelvic floor
dysfunction, and psychological tests exploring patient’s quality of life.
Accordingly, when not eligible, patients were excluded (Figure 1): 152 consecutive
subjects affected by functional chronic constipation with intestinal motility disorders
met the eligibility criteria, along with 150 healthy subjects. Patients and controls in
each group were first randomly sampled from the pool of available individuals (152
with intestinal motility disorders and 150 controls) and, then matched for age, sex and
BMI, using MatchIt[29]. This analysis resulted in 86 patients and 86 matched controls
that were enrolled for the study. Our patients did not receive any pharmacological
treatment before all evaluations.
Colonic transit time, breath tests and wireless motility analysis
The colon transit time was measured with radiopaque markers, using multiple
capsule techniques (P and A Mauch CH-4142 Munchenstein). The patient ingested 1
capsule a day (at 9.00 am, during breakfast) for 3 consecutive days and each capsule
with 24 different shaped radio-opaque polyurethane markers, and then performed
abdominal x-rays (100KV) on day 7, at 9.00 am, to reconstruct the colon activity
during the last week[30,31]. Normal transit time was considered about 30-40 h, whereas
the upper limit, above 70 h. Markers scattered about the colon was due most likely to
STC, whereas markers gathered in the recto-sigmoid tract was considered a
defecatory disorder[5,27] (Supplementary material).
Moreover, LBT and GBT were used for measuring oro-cecal transit time. A rise in
hydrogen of ≥ 20 ppm by 90 min was considered the cut-off value used to exclude
SIBO for both tests[25]. Time to the second peak and rise of 5-10 ppm of hydrogen, or a
level of positivity for methane ≥ 10 ppm on a breath test, were considered useful in
estimating oro-cecal transit time[25,27,32] (Supplementary material). Wireless motility
WJG https://www.wjgnet.com
April 14, 2019 Volume 25 Issue 14
Panarese A et al. Vitamin D and intestinal motility disorder
1732
analysis was also used to quantify oro-cecal transit time (Smartpill, Medtronic,
Sunnyvale, California, United States), in order to define the presence of a delayed
small intestinal transit time. Normal small-bowel transit should be 6 hours or less[25]
(Supplementary material). Finally, STC and/or delayed oro-cecal transit time were
definitively endorsed when radiopaque markers and/or breath tests with wireless
motility analysis identified a specific intestinal motility disorder[27].
Questionnaires for the evaluation of quality of life in patients with intestinal motility
disorders
The IBS-QOL questionnaire is a 34-item tool validated to quantify quality of life in
non-subtyped IBS patients, but also used to assess the severity of IBS-like symptoms,
and psychological factors[10]. The SF-12 includes a subset of 12 items, used to assess the
physical and mental health domain in many diseases. All these scores are converted
into a standardized 0-100 score. Higher scores indicate a better self-reported health
status[11]. Furthermore, the HADS-14 represents a global measure of psychological
distress and includes 14 items, 7 of them evaluate anxiety symptoms, and 7 depressive
ones. Each item is coded from 0 to 3. The total scores for anxiety and depression can
range between 0-21, based on symptoms characteristics[12].
Vitamin D and parathyroid hormone levels measurement
Serum 25-hydroxyvitamin D [25-(OH)-D] (Supplementary material) and parathyroid
hormone (PTH) levels were measured in patients and healthy controls within 1 hour
from blood draw. Overall subjects were enrolled in the interval time of the year with
major sunlight exposition, when 25-(OH)-D values are usually higher[13]. The 25-(OH)-
D levels status was categorized as usually proposed by experts in literature: using a
standardized cut-off (deficiency less than 20 ng/mL, insufficiency from 20 to 29
ng/mL and sufficient when equal or higher than 30 ng/mL)[13].
Statistical analysis
Screened patients and controls in each group were matched for age, sex and BMI
using the nearest neighbor matching algorithm implemented in MatchIt[29]. Normal
distribution of continuous variables was assessed with the Shapiro-Wilk test and data
were expressed as mean and standard deviation and compared using Student’s t-test.
Categorical variables were reported as percentages and compared using the Chi-
squared test or Fisher’s exact test, when needed.
Spearman’s test was performed to evaluate possible correlations of vitamin D
values with quality of life scores and psychological functions (IBS-QOL, SF12-PCS,
SF12-MCS, HADS-14 A and HADS-14 D). The impact of the vitamin D levels on
patient’s risk to have intestinal motility disorders was analysed using univariate and
multivariate logistic regression analyses. The association between each explanatory
variable and the outcome (intestinal motility disorders occurrence) was tested using
the likelihood ratio test. We included in the multivariate model all explanatory
variables showing a P < 0.05 at univariate analysis. For each variable included in the
multivariate model, we calculated both unadjusted and adjusted odds ratios (OR),
with their 95% confidence intervals (CI), and the level of significance (using the
likelihood ratio test). Statistical significance was set at P < 0.05. All statistical analyses
were performed using SPSS 23.0 software (SPSS, Chicago, IL, United States) and R
version 3.4.3 (http://www.R-project.org/).
RESULTS
Characteristics of patients with intestinal motility disorders
As shown in Figure 1, 86 patients along with 86 healthy matched subjects, were finally
enrolled. The characteristics of patients are shown in Table 1. About 85% of patients
suffering from intestinal motility disorders were female, and mean age was 49.9 ± 17.4
years. Patients with intestinal motility disorders had significantly lower intermediate
and bachelor schooling degree, as compared to the control group (P = 0.001 and P <
0.001, respectively).
The proportion of patients with intestinal motility disorders was more affected by
constipation, abdominal pain, swelling, anxiety and depression symptoms as well as
by quality of life alterations, as compared to healthy subjects (P < 0.001). The results of
the various questionnaires compiled by patients (IBS-QOL, HADS-14 A, HADS-14 D,
SF12-PCS and SF12-MCS) showed a significant impairment in all health-related
domains (P < 0.001) (Table 1). Patients with intestinal motility disorders had lower
vitamin D serum levels, as compared to the control group (P < 0.001). Moreover, the
poor results of psychological tests (IBS-QOL, SF12-PCS, SF12-MCS, HADS-14 A and
WJG https://www.wjgnet.com
April 14, 2019 Volume 25 Issue 14
Panarese A et al. Vitamin D and intestinal motility disorder
1733
Table 1 Characteristics of patients with functional chronic constipation with intestinal motility
disorders and of controls
Variables Intestinal motility disorders (n = 86) Controls (n = 86)
Age, mean ± SD , yr 49.9 (17.4) 50 (17.1)
Sex, n (%)
Male 13 (15.1) 13 (15.1)
Female 73 (84.9) 73 (84.9)
BMI, mean ± SD, kg/m223.7 (2.8) 24.6 (3.4)
Education, n (%)
Primary 5 (5.8) 5 (5.8)
Intermediate 33 (38.4)a14 (16.3)a
High school 38 (44.2) 37 (43)
Bachelor degree 10 (11.6)a28 (32.6)a
No data 0 2 (2.3)
Marital status
Single 30 (34.9) 22 (25.6)
Married 53 (61.6) 58 (67.4)
Widower 3 (3.5) 4 (4.7)
Divorced 0 1 (1.2)
No data 0 1 (1.2)
Symptoms
Constipation 78 (90.1)a3 (3.5)a
Abdominal pain 73 (84.9)a2 (2.3)a
Swelling 79 (91.9)a14 (16)a
IBS-QOL (total score) 108.4 (23.7)a39.8 (7.7)a
Dysphoria 24.1 (7.7)a8.7 (1.5)a
Interference 15.9 (5.5)a8 (1.6)a
Body image 15 (2.1)a4.8 (1.4)a
Anxiety health 13.5 (1.8)a3.7 (1.4)a
Food avoidance 13.6 (1.6)a3.7 (1.4)a
Social reaction 10.8 (3.2)a5 (1.1)a
Interpersonal relationships 6.3 (3.3)a3.3 (0.6)a
Sexuality 4.6 (2.2)a2 (0.1)a
HADS-14 A 14.6 (4.3)a2.4 (1.8)a
HADS-14 D 14.6 (3.1)a4.5 (2.6)a
SF12-PCS 37.3 (9.8)a47.2 (7.6)a
SF12-MCS 29.1 (7.4)a56 (7.1)a
PTH, mean ± SD, 10-70 pg/mL 51.1 (12.1) -
Vitamin D, mean ± SD, IU/mL 14.6 (7.7)a28.4 (8.8)a
aP < 0.01 vs controls by t, F or χ2. Values are absolute numbers and percentages (in parentheses) or average
numbers and standard deviation (in parentheses). BMI: Body mass index; IBS-QOL: Irritable Bowel
Syndrome Quality of life; HADS-14 A: Hospital Anxiety and Depression Scale-14 for Anxiety; HADS-14 D:
Hospital Anxiety and Depression Scale-14 for Depression; SF12-PCS: Short Form Health Survey12-Physical
Component Summary; SF12-MCS: Short Form Health Survey12-Mental Component Summary; PTH:
Parathyroid hormone.
HADS-14 D) significantly correlated with low vitamin D levels (r = - 0.57, P < 0.001; r
= 0.21, P = 0.01; r = - 0.48, P < 0.001; r = - 0.57, P < 0.001; r = - 0.29, P < 0.001,
respectively). Other parameters, such as the age, sex and marital status did not differ
between the two groups (Table 1).
In the groups with intestinal motility disorders, 32, 28 and 26 patients, after
completing all diagnostic tests, received a diagnosis of delayed oro-cecal transit time
(37.2%), STC (32.6%) or delayed oro-cecal transit time with STC (30.2%), respectively.
In the group with delayed oro-cecal transit time and with STC, the proportion of
patients who suffered constipation, swelling, abdominal pain and vitamin D
deficiency (< 20 ng/mL) was higher than groups with delayed oro-cecal transit time
or with STC (P = 0.03, P = 0.02, P = 0.03 and P = 0.04 respectively) (Figure 2). When we
WJG https://www.wjgnet.com
April 14, 2019 Volume 25 Issue 14
Panarese A et al. Vitamin D and intestinal motility disorder
1734
considered the three groups: subjects with delayed transit time in both intestinal tracts
(26), to patients with delayed transit time in only one tract (60) and to controls (86),
the quality of life showed worsening functions. Moreover, vitamin D and BMI were
significantly reduced with decreasing values as following for the variables: delayed
oro-cecal transit time with STC group less than delayed oro-cecal transit time or STC
group, less than controls (P < 0.001, respectively) (Supplementary material).
Patients with delayed transit time of both intestinal tracts, as compared to patients
with delayed transit time involving only one tract, showed significantly reduced
levels of vitamin D and higher PTH levels (for both P < 0.001), and showed worsening
quality of life (P < 0.001) (Supplementary material). Patients with delayed transit time
in both intestinal tracts showed significantly reduced serum levels of vitamin D and
higher PTH serum levels (for both P < 0.001), and showed worsening quality of life (P
< 0.001) than patients with delayed transit time in only one tract (Supplementary
material).
Risk factors associated to intestinal motility disorders
Results from linear regression analysis are shown in Table 2. At univariate and
multivariate analysis adjusted for BMI, vitamin D levels remained a significant
independent risk factor for intestinal motility disorders occurrence (OR = 1.19; 95%CI:
1.14-1.26, P < 0.001).
DISCUSSION
In this study, we demonstrated for the first time that serum vitamin D deficiency
could be associated to functional chronic constipation induced by intestinal motility
disorders. Furthermore, patients showing the latter clinical condition are frequently
affected by anxiety and depression symptoms which severely impair their quality of
life.
About 1 billion people have vitamin D insufficiency or deficiency[13]. Nowadays,
this phenomenon is associated with significant disability and healthcare costs[14,15].
Several studies showed that hypovitaminosis D may be a risk factor for many chronic
diseases and for mortality[16,33-36]. Notably, vitamin D deficiency has been involved in
the pathophysiology of inflammatory bowel disease, IBS and also depression[13-17,19]
Some multicentric studies, reported a higher prevalence of hypovitaminosis D in
the southern Europe[37,38]. Interestingly, Italian elderly subjects showed the lowest
levels of vitamin D in Europe in the winter season[37,38]. In our study, we found low
serum levels of vitamin D, mainly checked during the summer season, among
patients affected by intestinal motility disorders during an interval time when vitamin
D values are usually high, due to beta-ultraviolet rays exposition[13,36]. Moreover, our
patients were prevalently female (84.9%) and relatively younger, although, vitamin D
deficiency has not been limited to the elderly age[35-38]. While low levels of vitamin D
have been also observed in winter in 33% of pre-menopausal women, especially if
obese[39], in our study the majority of patients with intestinal motility disorders had
normal BMI.
How vitamin D deficiency and intestinal motility disorders are linked remains an
open question. One intriguing hypothesis may be that STC and/or delayed small
intestinal transit time could negatively modify the gut microbiota[36], or conversely
altered microbiome could primarily affect mucosal barrier and gut motility due to
microbial-derived metabolites[40]. In addition, some studies suggested that vitamin D
deficiency could predispose to gastrointestinal infections[16], which could be
responsible of the “leaky gut” alteration and of loss of immune homeostasis[40,41].
However, in our patients we also performed LBT and GBT, to exclude SIBO. When
the clinical suspicion of the latter condition remained, we treated them “ex
juvantibus”, and we further excluded SIBO as the main cause of bowel symptoms,
especially when they did not disappear after a gut-targeted antibiotic therapeutic
cycle.
Anyway, the presence of vitamin D receptor on gut epithelial cells, macrophages
and lymphocytes surface, has suggested a possible link between vitamin D deficiency,
the dysfunction of its receptor and gut microbiota composition, leading to the onset of
autoimmune diseases[40,42,43]. Finally, the influence of vitamin D deficiency on human
immune system is also supported by its involvement in the development of multiple
sclerosis[44]. As concerning this aspect, an interesting study supported a role of
autoantibodies against enteric nervous system targets in B cell-deficient mice with
experimental autoimmune encephalomyelitis model of multiple sclerosis, showing
that serum immunoreactivity (idiopathically or secondary to another autoimmune
disease), could be implicated in the induction of autoimmune gastrointestinal
WJG https://www.wjgnet.com
April 14, 2019 Volume 25 Issue 14
Panarese A et al. Vitamin D and intestinal motility disorder
1735
Figure 2
Figure 2 Proportion of patients who suffered constipation, swelling, abdominal pain and vitamin D serum
levels, in delayed small intestinal transit time, slow transit constipation, and delayed small intestinal transit
time (with) slow transit constipation groups. STC: Slow transit constipation. Significantly different by aP < 0.05.
dysmotility[45]. In fact, in humans with multiple sclerosis, whose pathogenesis has
been linked to vitamin D deficiency, a slow colonic motility in the proximal tract as
well as autonomic rectal dysfunction has been observed[44-48].
We may suppose that the intestinal motility disorder could be the “primum
movens” of an underlying autoimmune process in a specific genetic background and
unmasked by chronic vitamin D deficiency, which could exert metabolic/immu-
nologic damage on epithelial and neuromuscular structures of the gut. The latter
alterations could include gut hyper-permeability and bacterial translocation, whose
degree of injury and extension could be influenced by the severity of vitamin D
deficiency[22,45]. This hypothesis may be supported by our results, which showed that
levels of vitamin D were independently associated with intestinal motility disorders
and by the fact that the prevalence of symptoms associated to functional chronic
constipation grew up in concordance with the worsening of vitamin D levels,
especially in patients involving more extensively the bowel tract. Furthermore,
patients with intestinal motility disorders had high levels of psychological distress
with impaired quality of life, and hypovitaminosis D significantly correlated with the
worsening of the psychological functions. In our study, a potential bias could derive
from disease misclassification, which could be a negligible factor since intestinal
motility disorder was diagnosed following standardized criteria, and from the small
sample size of our population. Moreover, we did not check fecal microbiota
composition.
WJG https://www.wjgnet.com
April 14, 2019 Volume 25 Issue 14
Panarese A et al. Vitamin D and intestinal motility disorder
1736
Table 2 Probability of intestinal motility disorder occurrence at the univariate and multivariate
analysis
Variable
Univariate analysis Multivariate analysis
OR (95%CI) P value OR1(95%CI) P value
Age, yr 1.0 (0.98-1.01) 0.76 - -
BMI, kg/m20.91 (0.82-1.0) 0.04 0.98 (0.86-1.11) 0.72
Vitamin D, IU/mL 0.82 (0.78-0.87) < 0.001 0.83 (0.78-0.87) < 0.001
1Adjusted for all variables in the multivariate model. BMI: Body mass index. OR: Odds ratio; CI: Confidence
interval.
In conclusion, we demonstrated that vitamin D deficiency could be strongly related
to intestinal motility disorders. Moreover, patients with intestinal motility disorders
are very commonly affected by anxiety and depression symptoms which severely
influence their quality of life. If the latter two psychiatric symptoms are caused by
intestinal factors, it will be confirmed only through a cross-sectional study. Therefore,
we suggest that vitamin D serum levels should be routinely measured and vitamin D
supplementation should be considered, to better evaluate its effects on intestinal
motility and quality of life of patients with intestinal motility disorders.
ARTICLE HIGHLIGHTS
Research background
Functional chronic constipation is a gastrointestinal disorder that affects more commonly women
and older subjects, with a deep impact on global health-care system. Nowadays, only few studies
have examined intestinal motility disorders, which are severe clinical conditions associated with
chronic functional constipation, whose pathogenesis and prevalence are actually partially
known. In this subgroup are inclued patients with slow transit constipation, as well as with slow
oro-cecal transit time, whereas their extreme clinical form, could be considered chronic intestinal
pseudo-obstruction, which has been related to the structural damage of neural and smooth
muscle cells of gut.
Research motivation
Although some studies have shown a possible link between vitamin D deficiency and irritable
bowel syndrome (IBS), as well as with depression (and with several other diseases), the same
link has never been detected before in patients affected by intestinal motility disorders, and the
indications to look for vitamin D in these patients relied only of opinions of experts in the field.
Therefore we investigated this relationship and the psychological aspects in this subgroup of
patients.
Research objectives
To investigate the relationship between serum 25-hydroxyvitamin D levels and functional
chronic constipation linked to intestinal motility disorders.
Research methods
Herein, we applied rigorous statistical methods to elucidate this relationship. We performed a
prospective case-control study, from May-June to November 2017. We used Glucose/lactulose
breath tests, radiopaque markers (multiple capsule techniques) and wireless motility capsule
analysis to estimate both oro-cecal and colonic transit time. After receiving a diagnosis of
intestinal motility disorders, patients underwent to blood sampling, for checking 25-
hydroxyvitamin D levels. Furthermore, we evaluated for these patients the influence on
psychological features and on their quality of life, which were estimated by using validated
questionnaires, the IBS Quality of life (IBS-QOL), the Short Form Health Survey 12 (SF-12), and
the Hospital Anxiety and Depression Scale 14 (HADS-14 A and HADS-14 D).
Research results
Our cohort included 86 patients with chronic functional constipation associated to intestinal
motility disorders and 86 age, sex, body mass index (BMI)-matched healthy subjects. Patients
with intestinal motility disorders had lower 25-hydroxyvitamin D levels (P < 0.001), and they
showed a significant impairment of all health-related quality of life domains and psychological
tests (IBS-QOL, SF12-PCS, SF12-MCS, HADS-14 A and HADS-14 D), as compared to the control
group (P < 0.001). Moreover, the latter tests significantly correlated with reduced vitamin D
levels (r = - 0.57, P < 0.001; r = 0.21, P = 0.01; r = - 0.48, P < 0.001; r = - 0.57, P < 0.001; r = - 0.29, P
< 0.001, respectively). In multivariate analysis, vitamin D low levels remained significantly
associated with the occurrence of intestinal motility disorder, after adjusting for BMI (odds ratio
= 1.19; 95% confidence interval: 1.14-1.26, P < 0.001).
WJG https://www.wjgnet.com
April 14, 2019 Volume 25 Issue 14
Panarese A et al. Vitamin D and intestinal motility disorder
1737
Research conclusions
We demonstrated for the first time a strong association between vitamin D deficiency and
intestinal motility disorders. Moreover, these patients are very commonly affected by anxiety
and depression symptoms which deeply impact on their quality of life. These findings suggest
that vitamin D serum levels should be routinely measured in this category of patients and
consequently vitamin D supplementation could represent a further therapeutic aid for this
clinical condition.
Research perspectives
Our findings may confirm how vitamin D deficiency could exert a wide spectrum of action in
many gastrointestinal (or not) diseases, being highly associated with intestinal motility disorders
and with certain neuropsychiatric symptoms, but remains unclear if it could have a causative
role in this process, and for this reason, future cross-sectional studies are needed, also to
investigate if anxiety and depression symptoms are caused by intestinal factors.
ACKNOWLEDGEMENTS
We thank to Vanessa Terenzio and Domenico Flavio Terenzio, native English
speakers, for the language revision of this manuscript.
REFERENCES
1Pare P, Ferrazzi S, Thompson WG, Irvine EJ, Rance L. An epidemiological survey of constipation in
canada: Definitions, rates, demographics, and predictors of health care seeking. Am J Gastroenterol 2001;
96: 3130-3137 [PMID: 11721760 DOI: 10.1111/j.1572-0241.2001.05259.x]
2Tack J, Müller-Lissner S, Stanghellini V, Boeckxstaens G, Kamm MA, Simren M, Galmiche JP, Fried M.
Diagnosis and treatment of chronic constipation--a European perspective. Neurogastroenterol Motil 2011;
23: 697-710 [PMID: 21605282 DOI: 10.1111/j.1365-2982.2011.01709.x]
3Palsson OS, Baggish JS, Turner MJ, Whitehead WE. IBS patients show frequent fluctuations between
loose/watery and hard/lumpy stools: Implications for treatment. Am J Gastroenterol 2012; 107: 286-295
[PMID: 22068664 DOI: 10.1038/ajg.2011.358]
4Palsson OS, Baggish J, Whitehead WE. Episodic nature of symptoms in irritable bowel syndrome. Am J
Gastroenterol 2014; 109: 1450-1460 [PMID: 24980882 DOI: 10.1038/ajg.2014.181]
5Wald A, Scarpignato C, Kamm MA, Mueller-Lissner S, Helfrich I, Schuijt C, Bubeck J, Limoni C, Petrini
O. The burden of constipation on quality of life: Results of a multinational survey. Aliment Pharmacol
Ther 2007; 26: 227-236 [PMID: 17593068 DOI: 10.1111/j.1365-2036.2007.03376.x]
6Suares NC, Ford AC. Prevalence of, and risk factors for, chronic idiopathic constipation in the
community: Systematic review and meta-analysis. Am J Gastroenterol 2011; 106: 1582-1591; quiz 1581,
1592 [PMID: 21606976 DOI: 10.1038/ajg.2011.164]
7Cottone C, Tosetti C, Disclafani G, Ubaldi E, Cogliandro R, Stanghellini V. Clinical features of
constipation in general practice in Italy. United European Gastroenterol J 2014; 2: 232-238 [PMID:
25360307 DOI: 10.1177/2050640614527283]
8Belsey J, Greenfield S, Candy D, Geraint M. Systematic review: Impact of constipation on quality of life
in adults and children. Aliment Pharmacol Ther 2010; 31: 938-949 [PMID: 20180788 DOI:
10.1111/j.1365-2036.2010.04273.x]
9Shekhar C, Monaghan PJ, Morris J, Issa B, Whorwell PJ, Keevil B, Houghton LA. Rome III functional
constipation and irritable bowel syndrome with constipation are similar disorders within a spectrum of
sensitization, regulated by serotonin. Gastroenterology 2013; 145: 749-757; quiz e13-4 [PMID: 23872499
DOI: 10.1053/j.gastro.2013.07.014]
10 Drossman DA, Patrick DL, Whitehead WE, Toner BB, Diamant NE, Hu Y, Jia H, Bangdiwala SI. Further
validation of the IBS-QOL: A disease-specific quality-of-life questionnaire. Am J Gastroenterol 2000; 95:
999-1007 [PMID: 10763950 DOI: 10.1111/j.1572-0241.2000.01941.x]
11 Gandek B, Ware JE, Aaronson NK, Apolone G, Bjorner JB, Brazier JE, Bullinger M, Kaasa S, Leplege A,
Prieto L, Sullivan M. Cross-validation of item selection and scoring for the SF-12 Health Survey in nine
countries: Results from the IQOLA Project. International Quality of Life Assessment. J Clin Epidemiol
1998; 51: 1171-1178 [PMID: 9817135 DOI: 10.1155/2016/9282087]
12 Pallant JF, Tennant A. An introduction to the Rasch measurement model: an example using the Hospital
Anxiety and Depression Scale (HADS). Br J Clin Psychol 2007; 46: 1-18 [PMID: 17472198 DOI:
10.1348/014466506X96931]
13 Holick MF. Vitamin D deficiency. N Engl J Med 2007; 357: 266-281 [PMID: 17634462 DOI:
10.1056/NEJMra070553]
14 Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional burden of disease and
risk factors, 2001: Systematic analysis of population health data. Lancet 2006; 367: 1747-1757 [PMID:
16731270 DOI: 10.1016/S0140-6736(06)68770-9]
15 Plum LA, DeLuca HF. Vitamin D, disease and therapeutic opportunities. Nat Rev Drug Discov 2010; 9:
941-955 [PMID: 21119732 DOI: 10.1038/nrd3318]
16 Autier P, Mullie P, Macacu A, Dragomir M, Boniol M, Coppens K, Pizot C, Boniol M. Effect of vitamin
D supplementation on non-skeletal disorders: A systematic review of meta-analyses and randomised trials.
Lancet Diabetes Endocrinol 2017; 5: 986-1004 [PMID: 29102433 DOI: 10.1016/S2213-8587(17)30357-1]
17 Tazzyman S, Richards N, Trueman AR, Evans AL, Grant VA, Garaiova I, Plummer SF, Williams EA,
Corfe BM. Vitamin D associates with improved quality of life in participants with irritable bowel
syndrome: Outcomes from a pilot trial. BMJ Open Gastroenterol 2015; 2: e000052 [PMID: 26719813
DOI: 10.1136/bmjgast-2015-000052]
18 Abbasnezhad A, Amani R, Hajiani E, Alavinejad P, Cheraghian B, Ghadiri A. Effect of vitamin D on
gastrointestinal symptoms and health-related quality of life in irritable bowel syndrome patients: A
WJG https://www.wjgnet.com
April 14, 2019 Volume 25 Issue 14
Panarese A et al. Vitamin D and intestinal motility disorder
1738
randomized double-blind clinical trial. Neurogastroenterol Motil 2016; 28: 1533-1544 [PMID: 27154424
DOI: 10.1111/nmo.12851]
19 Anglin RE, Samaan Z, Walter SD, McDonald SD. Vitamin D deficiency and depression in adults:
Systematic review and meta-analysis. Br J Psychiatry 2013; 202: 100-107 [PMID: 23377209 DOI:
10.1192/bjp.bp.111.106666]
20 Li G, Mbuagbaw L, Samaan Z, Falavigna M, Zhang S, Adachi JD, Cheng J, Papaioannou A, Thabane L.
Efficacy of vitamin D supplementation in depression in adults: A systematic review. J Clin Endocrinol
Metab 2014; 99: 757-767 [PMID: 24423304 DOI: 10.1210/jc.2013-3450]
21 Rao SS, Rattanakovit K, Patcharatrakul T. Diagnosis and management of chronic constipation in adults.
Nat Rev Gastroenterol Hepatol 2016; 13: 295-305 [PMID: 27033126 DOI: 10.1038/nrgastro.2016.53]
22 De Giorgio R, Camilleri M. Human enteric neuropathies: Morphology and molecular pathology.
Neurogastroenterol Motil 2004; 16: 515-531 [PMID: 15500508 DOI: 10.1111/j.1365-2982.2004.00538.x]
23 Rao SS, Kuo B, McCallum RW, Chey WD, DiBaise JK, Hasler WL, Koch KL, Lackner JM, Miller C,
Saad R, Semler JR, Sitrin MD, Wilding GE, Parkman HP. Investigation of colonic and whole-gut transit
with wireless motility capsule and radiopaque markers in constipation. Clin Gastroenterol Hepatol 2009;
7: 537-544 [PMID: 19418602 DOI: 10.1016/j.cgh.2009.01.017]
24 Parthasarathy G, Chen J, Chen X, Chia N, O'Connor HM, Wolf PG, Gaskins HR, Bharucha AE.
Relationship Between Microbiota of the Colonic Mucosa vs Feces and Symptoms, Colonic Transit, and
Methane Production in Female Patients With Chronic Constipation. Gastroenterology 2016; 150: 367-
379.e1 [PMID: 26460205 DOI: 10.1053/j.gastro.2015.10.005]
25 Rezaie A, Buresi M, Lembo A, Lin H, McCallum R, Rao S, Schmulson M, Valdovinos M, Zakko S,
Pimentel M. Hydrogen and Methane-Based Breath Testing in Gastrointestinal Disorders: The North
American Consensus. Am J Gastroenterol 2017; 112: 775-784 [PMID: 28323273 DOI:
10.1038/ajg.2017.46]
26 Di Nardo G, Karunaratne TB, Frediani S, De Giorgio R. Chronic intestinal pseudo-obstruction: Progress
in management? Neurogastroenterol Motil 2017; 29 [PMID: 29143474 DOI: 10.1111/nmo.13231]
27 Rao SS, Camilleri M, Hasler WL, Maurer AH, Parkman HP, Saad R, Scott MS, Simren M, Soffer E,
Szarka L. Evaluation of gastrointestinal transit in clinical practice: Position paper of the American and
European Neurogastroenterology and Motility Societies. Neurogastroenterol Motil 2011; 23: 8-23 [PMID:
21138500 DOI: 10.1111/j.1365-2982.2010.01612.x]
28 Mearin F, Lacy BE, Chang L, Chey WD, Lembo AJ, Simren M, Spiller R. Bowel Disorders.
Gastroenterology 2016; pii: S0016-5085(16)00222-5 [PMID: 27144627 DOI:
10.1053/j.gastro.2016.02.031]
29 Ho DE, Imai K, King G, Stuart EA. MatchIt: Nonparametric reprocessing for parametric causal inference.
J Stat Softw 2011; 42: 1-28 [DOI: 10.18637/jss.v042.i08]
30 Metcalf AM, Phillips SF, Zinsmeister AR, MacCarty RL, Beart RW, Wolff BG. Simplified assessment of
segmental colonic transit. Gastroenterology 1987; 92: 40-47 [PMID: 3023168 DOI:
10.1016/0016-5085(87)90837-7]
31 Chaussade S, Roche H, Khyari A, Couturier D, Guerre J. Measurement of colonic transit time:
Description and validation of a new method. Gastroenterol Clin Biol 1986; 10: 385-389 [PMID: 3732742]
32 Ghoshal UC. How to interpret hydrogen breath tests. J Neurogastroenterol Motil 2011; 17: 312-317
[PMID: 21860825 DOI: 10.5056/jnm.2011.17.3.312]
33 Hess AF, Unger LJ. The cure of infantile rickets by sunlight. JAMA 1921; 77: 39-41 [DOI:
10.1001/jama.1921.02630270037013]
34 Stamp TC. Sources of vitamin D nutrition. Lancet 1980; 1: 316 [PMID: 6101773 DOI:
10.1016/S0140-6736(80)90814-4]
35 van der Wielen RP, Löwik MR, van den Berg H, de Groot LC, Haller J, Moreiras O, van Staveren WA.
Serum vitamin D concentrations among elderly people in Europe. Lancet 1995; 346: 207-210 [PMID:
7616799 DOI: 10.1016/s0140-6736(95)91266-5]
36 Vaes AMM, Brouwer-Brolsma EM, van der Zwaluw NL, van Wijngaarden JP, Berendsen AAM, van
Schoor N, van der Velde N, Uitterlinden A, Lips P, Dhonukshe-Rutten RAM, de Groot LCPGM. Food
sources of vitamin D and their association with 25-hydroxyvitamin D status in Dutch older adults. J
Steroid Biochem Mol Biol 2017; 173: 228-234 [PMID: 27777183 DOI: 10.1016/j.jsbmb.2016.10.004]
37 Cashman KD, Dowling KG, Škrabáková Z, Gonzalez-Gross M, Valtueña J, De Henauw S, Moreno L,
Damsgaard CT, Michaelsen KF, Mølgaard C, Jorde R, Grimnes G, Moschonis G, Mavrogianni C, Manios
Y, Thamm M, Mensink GB, Rabenberg M, Busch MA, Cox L, Meadows S, Goldberg G, Prentice A,
Dekker JM, Nijpels G, Pilz S, Swart KM, van Schoor NM, Lips P, Eiriksdottir G, Gudnason V, Cotch MF,
Koskinen S, Lamberg-Allardt C, Durazo-Arvizu RA, Sempos CT, Kiely M. Vitamin D deficiency in
Europe: Pandemic? Am J Clin Nutr 2016; 103: 1033-1044 [PMID: 26864360 DOI:
10.3945/ajcn.115.120873]
38 Carnevale V, Modoni S, Pileri M, Di Giorgio A, Chiodini I, Minisola S, Vieth R, Scillitani A.
Longitudinal evaluation of vitamin D status in healthy subjects from southern Italy: Seasonal and gender
differences. Osteoporos Int 2001; 12: 1026-1030 [PMID: 11846328 DOI: 10.1007/s001980170012]
39 Adami S, Bertoldo F, Braga V, Fracassi E, Gatti D, Gandolini G, Minisola S, Battista Rini G. 25-hydroxy
vitamin D levels in healthy premenopausal women: Association with bone turnover markers and bone
mineral density. Bone 2009; 45: 423-426 [PMID: 19465168 DOI: 10.1016/j.bone.2009.05.012]
40 Clark A, Mach N. Role of Vitamin D in the Hygiene Hypothesis: The Interplay between Vitamin D,
Vitamin D Receptors, Gut Microbiota, and Immune Response. Front Immunol 2016; 7: 627 [PMID:
28066436 DOI: 10.3389/fimmu.2016.00627]
41 Ge X, Zhao W, Ding C, Tian H, Xu L, Wang H, Ni L, Jiang J, Gong J, Zhu W, Zhu M, Li N. Potential role
of fecal microbiota from patients with slow transit constipation in the regulation of gastrointestinal
motility. Sci Rep 2017; 7: 441 [PMID: 28348415 DOI: 10.1038/s41598-017-00612-y]
42 He L, Liu T, Shi Y, Tian F, Hu H, Deb DK, Chen Y, Bissonnette M, Li YC. Gut Epithelial Vitamin D
Receptor Regulates Microbiota-Dependent Mucosal Inflammation by Suppressing Intestinal Epithelial Cell
Apoptosis. Endocrinology 2018; 159: 967-979 [PMID: 29228157 DOI: 10.1210/en.2017-00748]
43 Shahini E, Iannone A, Romagno D, Armandi A, Carparelli S, Principi M, Viggiani MT, Ierardi E, Di Leo
A, Barone M. Clinical relevance of serum non-organ-specific antibodies in patients with HCV infection
receiving direct-acting antiviral therapy. Aliment Pharmacol Ther 2018; 48: 1138-1145 [PMID: 30375693
DOI: 10.1111/apt.14999]
44 Thompson AJ, Baranzini SE, Geurts J, Hemmer B, Ciccarelli O. Multiple sclerosis. Lancet 2018; 391:
1622-1636 [PMID: 29576504 DOI: 10.1016/S0140-6736(18)30481-1]
WJG https://www.wjgnet.com
April 14, 2019 Volume 25 Issue 14
Panarese A et al. Vitamin D and intestinal motility disorder
1739
45 Spear ET, Holt EA, Joyce EJ, Haag MM, Mawe SM, Hennig GW, Lavoie B, Applebee AM, Teuscher C,
Mawe GM. Altered gastrointestinal motility involving autoantibodies in the experimental autoimmune
encephalomyelitis model of multiple sclerosis. Neurogastroenterol Motil 2018; 30: e13349 [PMID:
29644797 DOI: 10.1111/nmo.13349]
46 Chia YW, Gill KP, Jameson JS, Forti AD, Henry MM, Swash M, Shorvon PJ. Paradoxical puborectalis
contraction is a feature of constipation in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry
1996; 60: 31-35 [PMID: 8558147 DOI: 10.1136/jnnp.60.1.31]
47 Li Q, Michel K, Annahazi A, Demir IE, Ceyhan GO, Zeller F, Komorowski L, Stöcker W, Beyak MJ,
Grundy D, Farrugia G, De Giorgio R, Schemann M. Anti-Hu antibodies activate enteric and sensory
neurons. Sci Rep 2016; 6: 38216 [PMID: 27905561 DOI: 10.1038/srep38216]
48 De Giorgio R, Bovara M, Barbara G, Canossa M, Sarnelli G, De Ponti F, Stanghellini V, Tonini M,
Cappello S, Pagnotta E, Nobile-Orazio E, Corinaldesi R. Anti-HuD-induced neuronal apoptosis underlying
paraneoplastic gut dysmotility. Gastroenterology 2003; 125: 70-79 [PMID: 12851872 DOI:
10.1016/s0016-5085(03)00664-4]
WJG https://www.wjgnet.com
April 14, 2019 Volume 25 Issue 14
Panarese A et al. Vitamin D and intestinal motility disorder
1740
Published By Baishideng Publishing Group Inc
7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA
Telephone: +1-925-2238242
Fax: +1-925-2238243
E-mail: bpgoffice@wjgnet.com
Help Desk:http://www.f6publishing.com/helpdesk
http://www.wjgnet.com
© 2019 Baishideng Publishing Group Inc. All rights reserved.
