NEUROGASTRO 2017 – MEETING OF THE

ROMANIAN SOCIETY OF
NEUROGASTROENTEROLOGY

with Rome IV Regional Central East European Meeting

(Iasi, Romania, 16-18 March 2017)

Editors
Vasile Drug, Dan L. Dumitraşcu

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INDEX

Foreword 7

Functional digestive disorders – general aspects 8

Functional Gastrointestinal Disorders in Poland 9

MULAK Agata

The Prevalence of Irritable Bowel Syndrome among Gastrointestinal Diseases

in Belarus 13
RUSTAMOV Mirzabey

Ethics of Genetic Testing in Functional Gastro Intestinal Disease 18

GAVRILOVICI Cristina, STARCEA Magdalena, MIRON Ingrith

How Important are Genetics in Functional Gastrointestinal Diseases? 23

CABA Lavinia, GORDUZA Eusebiu Vlad

Functional Gastrointestinal Disorders and IBS in Serbia 29

SNEZANA Lukic, DRĂGAN Popovic, SOKIC MILUTINOVIC Aleksandra,
MILOSAVLJEVIC Tomica

Esophageal motility disorders 31

High-resolution Esophageal Manometry is Superior to Conventional Manometry

in the Diagnosis of Patients with Non-Obstructive Dysphagia
and Especially Achalasia 32
BANCILA Ion, DIMITRIU Anca, COTRUTA Bogdan,
GHEORGHE Cristian

Correlations between Symptoms and High-Resolution Manometry Metrics

in Different Types of Achalasia 36
BANCILA Ion, DIMITRIU Anca, GHEORGHE Cristian

High-resolution Esophageal Manometry: Gold Standard for Achalasia? 41

HERZIG Marcus, CAPRARU Sandra Maria, TUTUIAN Radu

Gastroesophageal reflux disease 46

Non-Cardiac Chest Pain and Gastroesophageal Reflux Disease 47

BARBOI Oana-Bogdana, CIJEVSCHI-PRELIPCEAN Cristina,
COBZEANU Dan, FLORIA Mariana, BALAN Gheorghe, DRUG Vasile

Gastroesophageal Reflux Disease (GERD) and Helicobacter Pylori (H. pylori) –

A Continuing Dilemma 52
DIMACHE Mihaela, ANTON Carmen, BISTRICEANU Sandina

3
Heart Rate Variability in Patients with Gastroesophageal Reflux Disease –
A Prospective Study 56
FLORIA Mariana, BĂRBOI Oana, BOCÎNCĂ Cristina, DÎRZU Iulia,
ŞAVLOVSCHI Dumitriţa, CIJEVSCHI-PRELIPCEAN Cristina,
BĂLAN Gheorghe, DRUG Vasile Liviu

Gastroesophageal Reflux Disease and Coronary Heart Disease –

From Pathophysiology to Treatment Controversies 60
FLORIA Mariana, BĂRBOI Oana, BOCÎNCĂ Cristina,
CIJEVSCHI-PRELIPCEAN Cristina, BĂLAN Gheorghe,
DRUG Vasile Liviu

Gas Reflux in Children 65

GALOȘ Felicia, BOBOC Cătălin, STOICESCU Mihai, MUNTEANU Mihai,
BĂLGRĂDEAN Mihaela

IBS 71

Markers of Inflammation in IBS: Road Still Open? 72

CHIRA Alexandra, CHIRA Romeo Ioan, DUMITRASCU Dan Lucian

Diet in IBS: Old Problems. New Solutions? 77

IOAN Chirila

Fecal Calprotectin – Can Differentiate IBD from IBS? 82

DRANGA Mihaela, MIHAI Cătălina, MIHAI Bogdan, GAVRILESCU Otilia,
CIJEVSCHI PRELIPCEAN Cristina

Irritable Bowel Syndrome Versus Crohn Disease – Impact on Quality of Life 87

GAVRILESCU Otilia, DRANGA Mihaela, CARDONEANU Anca,
MIHAI Cătălina, CIJEVSCHI-PRELIPCEAN Cristina

Useful Tools to Differentiate Irritable Bowel Syndrome from

Inflammatory Bowel Disease 92
GOLDIS Adrian, GOLDIS Ramona, LAZAR Daniela

Connections Between Systemic Inflammation and Pathophysiologic Mechanisms

of Irritable Bowel Syndrome 99
HALIGA Raluca Ecaterina, MORARASU Bianca Codrina, SORODOC Laurentiu

Trust in Doctor Patient Relationship in the Context of IBS 105

ROTARU Tudor-Ștefan

Do TLRs Play a Role in IBS? 110

RUSU Flaviu, DUMITRASCU Dan Lucian

Predictive Factors of Depression in Irritable Bowel Syndrome Patients 115

FADGYAS STANCULETE Mihaela, POJOGA Cristina,
DUMITRASCU Dan Lucian

4
Irritable Bowel Syndrome and the Off – Label Therapy: Ethical Perspectives 121
TOADER Elena, HORDILA Alexandra

Neurogastroenterology topics in children 127

Celiac Disease in the Pediatric Patient: Serological and

Histopathological Correlations 128
BACIU Ginel, FOTEA Silvia

Clinico-Therapeutic Particularities of Anorexia Nervosa in Children and

Adolescents 132
BOLOS Alexandra, UNTU Ilinca, SAVLOVSCHI Dumitrita,
SZALONTAY Andreea Silvana

Clinical and Histopathological Aspects of Idiopathic Eosinophilic

Duodenitis in Children 137
FOTEA Silvia, DOINA Mihaila, TRANDAFIR Laura,
ANTON Dana Teodora, BACIU Ginel

Gastrointestinal Disorders in Childhood Obesity 142

TRANDAFIR Laura Mihaela, FRĂSINARIU Otilia Elena,
SUBOTNICU Mirabela, MIRON Ingrith Crenguța

Gastrointestinal Manifestations in Children with Cystic Fibrosis 147

TRANDADFIR Laura Mihaela, TESLARIU Oana,
ANTON-PADURARU Dana Teodora

Varia 151

The Management of Gastrointestinal Motility Disorders in Pregnancy 152

ANTON Carmen, DIMACHE Mihaela, HARTIE Codrina,
BISTRICEANU Sandina, ANTON Emil

The Role of Stress Hormones and Gastrin in Gastroduodenal Dysfunction

in Patients with Chronic Viral Hepatitis 158
LUPASCO Iulianna, DUMBRAVA Vlada-Tatiana,
DUMITRAȘCU Dan-Lucian, VENGHER Inna, BEREZOVSCAIA Elena

First Line Helicobacter Pylori Eradication in Dyspeptic Patients 166

MIHAI Catalina, MIHAI Bogdan, CARDONEANU Anca, GRANGA Mihaela,
GAVRILESCU Otilia, DRUG Vasile, CIJEVSCHI PRELIPCEAN Cristina

Gluten: the Link between Dyspepsia and Celiac Disease 172

PLESA Alina, MAXIM Roxana, CIORTESCU Irina

Anorexia Nervosa at a Young Male Patient-Clinical and Therapeutic Approaches.

Clinical Case Presentation 177
BOLOȘ Alexandra, ȘTEFĂNESCU Gabriela, BARZU Adela,
SZALONTAY Andreea Silvana

5
Gastrointestinal Symptoms and Alcohol Withdrawal Syndrome 182
BONEA Maria, MICLUȚIA Ioana

Significance of C-Reactive Protein and Lysozyme in Crohn’s Disease

and Ulcerative Colitis Treated with Infliximab and Adalimumab 185
IONESCU Andra Consuela, GAMAN Laura, VASILESCU Alina,
ATANASIU Valeriu, STOIAN Irina, IONESCU Lucian, DICULESCU Mircea

Psychosomatic Disorders in Chronic Diffuse Liver Diseases 190

LUPASCO Iulianna, BEREZOVSCAIA Elena, DUMBRAVA Vlada-Tatiana

The Role of Fecal Calprotectin in Investigating Inflammatory Bowel Diseases 196

MĂRGINEAN Cristina, VLĂDAIA Mihai, POPESCU Marian-Sorin,
MILOTIN Nicoleta, PETRESCU Florin

Digestive Manifestations in Wilms’ Tumor 200

NEDELCUTA Ramona, POPESCU Mirela, CALIN Gigi

Collaborative Care, Teamwork, Communication and Effectiveness 205

OPREA Liviu

Psychopathological Comorbidities in Patients with Advanced Digestive

Oncologic Pathology 210
POJOGA Cristina, FADGYAS STANCULETE Mihaela,
DUMITRASCU Dan Lucian

Neutropenic Enterocolitis (Typhlitis) as a Complication of Acute

Lymphoblastic Leukemia 214
SUBOTNICU Mirabela, TRANDAFIR Laura, IVANOV Anca,
MIRON Ingrith

Pregnancy after Surgical Treatment in Ulcerative Colitis – Case Report 218

TOADER Oana, MARGINEANU Catalina, SUCIU N., VOICHITOIU A.,
CIRSTOIU Monica, BOHILTEA Roxana, VINTEA Alexandra

Fungal Dysbiosis in Inflammatory Bowel Disease – Where are We? 222

GÎLCĂ Georgiana-Emanuela, ŞTEFĂNESCU Gabriela,
CIOCOIU Manuela

The Interrelation between Gastrointestinal Microbiota and Schizophrenia 228

ISAC Andra, POP Bianca, LUPU Viorel, ANDREICA Vasile,
MICLUTIA Ioana

6
FOREWORD

This volume is covering most of the proceedings of the meeting of the Romanian Society of
Neurogastroenterology NEUROGASTRO 2017 held in Iasi, Romania, 16-18 March 2017, together
with the Rome Foundation Central and East European Meeting.

The specialists in functional gastrointestinal disorders and in digestive motility gathered together
with the Faculty of the Rome Foundation (Professor Douglas Drossman) and other experts, to discuss
the recent progress in the field. Main issue is the advent of the Rome IV criteria. The meeting was
successful and had 200 attendants. Participants had the opportunity to share experience and to design
new action directions.

This book is including many original work and several educational reviews, of interest. Beside
authors from this country, we greet the contribution of international authors as well.

The reader will find here a cross-sectional reflection of the today knowledge and research on
neurogastroenterology mainly in East Europe but also worldwide.

We wish you a pleasant and useful lecture.

Prof. Vasile Drug & Prof. Dan L. Dumitrascu

Editors

7
Functional digestive disorders – general aspects

8
Functional Gastrointestinal Disorders in Poland
MULAK Agata
Department of Gastroenterology and Hepatology, Wroclaw Medical University, Wroclaw (POLAND)
Email: agata.mulak@wp.pl

Abstract

Epidemiological data on functional gastrointestinal disorders (FGID) including irritable bowel

syndrome (IBS) and functional dyspepsia (FD) in the Polish population are limited. In a survey study
conducted in Poland, in the group of 850 subjects, the prevalence of dyspepsia in men and women
was similar (men 21%, women 25%). Surprisingly, the percentage of men and women suffering from
IBS was almost identical (13%). Recommendations on the management of IBS published in 2009 by
the Polish Society of Gastroenterology are currently being updated. Despite availability of these
recommendations, it has been shown that only 33% of Polish family doctors and internal medicine
specialists use the Rome criteria in their daily practice. The survey showed that the positive diagnosis
of IBS is still challenging since 95% of the doctors sent patients for additional tests (e.g., 75% for
fecal occult blood test, 47% for endoscopy). In Poland, FD is treated with antisecretory drugs,
prokinetics (itopride), antidepressants, as well as Iberogast® (STW 5) and melatonin.
Symptom based treatment for IBS includes osmotic laxatives, loperamide (cholestyramine is not
available), antispasmodics, antidepressants, antibiotics (mainly rifaximin) and probiotics.
Unfortunately, the most effective pharmacotherapies for IBS (i.e. serotonergic drugs, chloride
channel activators or guanylate cyclase C agonists) are still not available in Poland. The prevalence
of anxiety and depressive disorders in IBS patients hospitalized in Polish tertiary care centers amounts
to 57%. The results of genetic studies in IBS patients in Poland revealed the association of SLC6A4,
HTR2A and HTR2C polymorphisms with psychiatric comorbidity.
Keywords: functional gastrointestinal disorders, irritable bowel syndrome, functional dyspepsia

Epidemiology of FGIDs in Poland

In the Polish study conducted by Ziółkowski et al. [1] the prevalence of gastrointestinal symptoms
was assessed in the group of 850 subjects based on the face-to-face interview (510 F, 340 M, age: 21-
76 years). The study was conducted in a representative sample of a mid-sized city population (43000
inhabitants). Women comprised 60% of the sample.
Approximately 23% of participants suffered from dyspepsia, bloating was present in 31% of
subjects, and constipation as well as IBS in 13%. Of note, as the study was designed in year 2000,
the Manning criteria were used to diagnose IBS.
The prevalence of dyspepsia in men and women was similar (men 21%, women 25%).
Surprisingly, the percentage of men and women suffering from IBS was almost identical (13%).
The IBS prevalence increased with age, and it was significant in women [1].
Another Polish study aimed at determining the prevalence of IBS symptoms and the relationship
between the symptoms and physical activity in the group of 120 female students (aged 19-27 years)
at Warsaw University [2]. The BMI of investigated subjects ranged between 16.3-31.2kg/m2
(M=21.3, SD=2.7). The body mass of the majority of responders (76.6%) was within the normal
range. Abdominal pain or discomfort with concomitant changes in stool consistency and/or frequency
corresponding to IBS were observed in approximately 40% of subjects. Abdominal pain and changes
in stool consistency and/or frequency were more frequent in subjects with low physical activity.

9
 The occurrence of abdominal symptoms was influenced by nutritional habits in 81.7% of subjects
and by stress in 80.8% of them. The analysis showed that 16.9% of students reported absenteeism
from school due to their abdominal complaints.
School absenteeism due to abdominal symptoms were more frequent among subjects with low
physical activity [2].
Piotrowicz et al. [3] assessed the prevalence of FD in 230 patients (140 F, 90 M) referred to
gastroscopy due to dyspeptic symptoms. They found that FD was diagnosed in 23% of examined
subjects [3].
Currently, the Rome IV criteria are actively being disseminated in Poland [4] and there is an
ongoing study on the epidemiology of FGIDs in the frame of the global international survey
coordinated by the Rome Foundation.

Recommendations on IBS diagnosis

In 2009 the Polish Society of Gastroenterology published the recommendations on the

management of IBS [5]. They are currently being updated according to the Rome IV criteria released
in May 2016 [6]. It has been emphasized that for majority of patients, when diagnostic criteria for
IBS are fulfilled and alarm features are absent, the need for diagnostic tests is minimal. A complete
blood count (CBC) should be ordered at the first visit in elderly people and additionally C-reactive
protein (CRP) and erythrocyte sedimentation rate (ESR) – in all patients with IBS-D. Serologic tests
for celiac disease should be performed in patients with IBS-D and IBS-M. Other tests like TSH or
stool analysis (bacteria, parasites and ova, fecal occult blood test) are not indicated in all patients, but
only if it is clinically warranted. A screening colonoscopy is not recommended in patients below 50
years without alarm features, with the exception of patients with family history of colorectal cancer.
In case of colonoscopy (especially in female patients above 60 years) biopsies of different
segments of the colon are recommended to rule out microscopic colitis [5].
Despite the availability of these recommendations, it has been shown in a survey study conducted
in 122 family doctors and internal medicine specialists that only 33% of them use the Rome criteria
in their daily practice [7]. The survey showed that the positive diagnosis of IBS is still challenging
since 95% of the doctors sent patients for additional tests (e.g., 75% for fecal occult blood test, 47%
for endoscopy). Among additional tests in patients with suspected IBS, dietitian consultation was
performed in 30% and psychological consultation in 13% of patients [7]. Among participating
doctors, 83% indicated that IBS patients should be consulted by a gastroenterologist, while 54% were
giving their patients sick leaves due to IBS [7].

Treatment for functional dyspepsia and IBS used in Poland

Reassurance, education, lifestyle, and dietary recommendations constitute the basic steps of
therapeutic approach in FGIDs. The majority of patients with FGIDs do not need pharmacotherapy.
Apart from pharmacotherapy, psychological and behavioral treatments have the confirmed value
in FGIDs.
Depending on the type of FD the following options of pharmacological treatment are used:
antisecretory drugs, prokinetics, antidepressants or 5-HT1A agonists. There is evidence of a small, but
statistically significant benefit in eradicating Helicobacter pylori in patients with chronic dyspepsia
[8].
Proton pump inhibitors are recommended in epigastric pain syndrome (EPS), but are ineffective
in relieving the symptoms of postprandial distress syndrome (PDS). In PDS prokinetic drugs exert a
significant benefit. Itopride – a novel prokinetic agent working as dopamine (D2) receptor antagonist
and acetylocholinoesterase inhibitor – is used for FD, gastroesophageal reflux disease and
gastroparesis. The drug is characterized by a low rate of adverse effects. Currently itopride is available

10
in Poland under two brand names: Prokit® and Zirid® (3 times per day 50 mg) [9]. Other potentially
effective compounds in PDS are fundic relaxants including 5-HT1A agonists such as buspirone.
Antidepressants are often used as second-line drugs for epigastric pain.
In addition, an herbal mixture – Iberogast® (STW 5), with an efficacy comparable to standard
prokinetics [10], is quite popular in Poland. The induction of gastric fundus relaxation and stimulation
of antral motility may contribute to the reported therapeutic efficacy of Iberogast in FD [11].
Moreover, melatonin has been shown to alleviate epigastric pain in FD [12].
Pharmacotherapy in IBS patients depends on symptoms type and severity. For constipation
osmotic laxatives, such as lactulose or polyethylene glycol (PEG), are used. Loperamide – a synthetic
peripheral μ-opioid receptor agonist – is commonly used to treat IBS-D. A growing body of evidence
support a role of bile acids in the pathophysiology of IBS-D and the effectiveness of bile acid
sequestrants (e.g., cholestyramine, colesevelam) in improving stool passage and stool consistency
[6].
However, cholestyramine is not available in Poland. For pain antispasmodics and antidepressants
are effective. Antispasmodics used to treat abdominal pain in all IBS subtypes include mebeverine,
trimebutine and alverine. Unfortunately, the most effective pharmacotherapies for IBS such as
serotonergic drugs (5-HT4 agonists, 5-HT3 antagonists), chloride channel activators (lubiprostine),
guanylate cyclase C agonists (linaclotide) or a novel mixed μ-opioid receptor agonist/δ-opioid
receptor antagonist (eluxadoline) are still not available in Poland.
In non-constipated IBS patients with severe bloating, especially with concomitant small intestinal
bacterial overgrowth (SIBO), rifaximin is successfully used. Of note, in Poland rifaximin is registered
for SIBO, diverticular disease, hepatic encephalopathy and travelers’ diarrhea, but not for IBS. The
recommended dose for SIBO treatment (400 mg p.o. tid x 7 days) is smaller than that typically used
for IBS (550 mg p.o. tid x 14 days), but the drug can be used repeatedly [13]. Moreover, probiotics
offer also benefits for global IBS symptoms, pain, bloating and flatulence [6].
A number of clinical characteristics including the predominant bowel movement pattern, the
presence of insomnia or comorbid anxiety may influence the choice of antidepressants (i.e., tricyclic
agents vs selective serotonin reuptake inhibitors). Polish recommendations on the management of
IBS mention also about melatonin. In the Polish study conducted by Chojnacki et al. [14], the
beneficial effects of melatonin were shown especially in IBS-C postmenopausal women. In this study
melatonin was used at the dose: 3 mg fasting and 5 mg at bedtime. In IBS-C group, the intensity of
visceral pain and abdominal bloating decreased in 70% of patients (p<0.01) and constipation in 50%
of subjects (p<0.05). Beneficial effects in the IBS-D group were noted in 45% of patients, but the
results were not statistically significant [14].

Psychiatric comorbidity and genetics in IBS

In two Polish studies, the lifetime prevalence of depressive and anxiety disorders in IBS patients
hospitalized in a tertiary care center was assessed by a fully structured diagnostic instrument based
on DSM-IV and ICD-10 diagnostic criteria – the Munich version of the Composite International
Diagnostic Interview (CIDI) [15, 16]. Depressive and anxiety disorders were diagnosed in 54
participants (57%). The IBS patients were divided into 4 subgroups: with no mental disorders (n=41,
43%), with depressive disorders only (n=20, 21%), with anxiety disorders only (n=25, 26%), and
with coexisting anxiety-depressive disorders (n=9, 9%).
Furthermore, in the same group of IBS patients, genetic studies were conducted to investigate the
association of serotonin-related gene variants with psychiatric comorbidity in IBS. The results
provided evidence for the involvement of SLC6A4 rs4795541 and HTR2A rs6311 polymorphisms in
the pathophysiology of depressive disorders in IBS patients. In addition, HTR2C rs6318
polymorphism has been suggested to be associated with the susceptibility to anxiety disorders in IBS
patients. No association was found between the THP1 and HTR1A polymorphisms and the lifetime
prevalence of depressive or anxiety disorders in IBS [17, 18].

11
 Poland has been also participating in the COST action BM1106 GENIEUR (GENes in Irritable
Bowel Syndrome Research Network EURope) which has been established to address main flaws and
pitfalls in the current IBS (epi)genetic research and provide potential improvement in future
approaches in this complex field [19].

Conclusions

• Epidemiological data on IBS and other FGIDs in the Polish population are limited and further
studies in the field are required.
• Although Polish guidelines on the managements of IBS are published, they are not adequately
followed by many general practitioners.
• The most effective pharmacotherapies, including serotonergic drugs, chloride channel
activators and guanylate cyclase C agonists, are still not available in Poland.
• The prevalence of anxiety and depressive disorders in IBS patients hospitalized in Polish
tertiary care centers amounts to 57%.

REFERENCES

1. Ziółkowski BA, Pacholec A, Kudlicka M, Ehrmann A, Muszyński J. Prevalence of abdominal symptoms in

the Polish population. Gastroenterol Rev 2012; 7: 20-25.
2. Niemyjska A, Ukleja A, Ławiński M. Evaluation of irritable bowel syndrome symptoms among Warsaw
University students. Pol Przeg Chirurg 2015; 87: 252-259.
3. Piotrowicz G, Stępień B, Rydzewska G. Socio-demographic characteristics of patients with diagnosed
functional dyspepsia. Gastroenterol Rev 2013; 8: 354-365.
4. Mulak A, Smereka A, Paradowski L. Novelties and modifications in Rome IV criteria. Gastroenterol Klin 2016;
8: 52-61.
5. Bartnik W, Chojnacki J, Paradowski L, Skrzydło-Radomańska B, Tomecki R. Recommendations on the
management of irritable bowel syndrome. Gastroenterol Klin 2009; 1: 9-17.
6. Lacy BE, Mearin F, Chang L, et al. Bowel Disorders. Gastroenterology 2016; 150: 1393–1407.
7. Krawczyńska A, Maciejewska K, Pawlik M, Rydzewska G: Selected aspects of diagnosis and treatment of
irritable bowel syndrome in clinical practice of family doctors and internal medicine specialists. Gastroenterol
Rev 2012; 7: 367–373.
8. Stanghellini V, Chan FK, Hasler WL, et al. Gastroduodenal Disorders. Gastroenterology 2016; 150: 1380-
1392.
9. Mulak A: Prokinetic drugs in Poland – when and how to use them? Gastroenterol Klin 2014; 4: 148-156.
10. Ottillinger B, Storr M, Malfertheiner P, Allescher HD. STW 5 (Iberogast®) - a safe and effective standard in
the treatment of functional gastrointestinal disorders. Wien Med Wochenschr 2013; 163: 65-67.
11. Pilichiewicz AN, Horowitz M, Russo A, et al. Effects of Iberogast on proximal gastric volume,
antropyloroduodenal motility and gastric emptying in healthy men. Am J Gastroenterol 2007; 102: 1276-1283.
12. Klupińska G, Chojnacki C, Harasiuk A, et al. Nocturnal secretion of melatonin in subjects with asymptomatic
and symptomatic Helicobacter pylori infection. Pol Merkur Lekarski 2006; 21: 239-242.
13. Lembo A, Pimentel M, Rao SS, et al. Repeat Treatment With Rifaximin Is Safe and Effective in Patients With
Diarrhea-Predominant Irritable Bowel Syndrome. Gastroenterology 2016; 15: 1113-1121.
14. Chojnacki C, Walecka-Kapica E, Lokieć K, et al. Influence of melatonin on symptoms of irritable bowel
syndrome in postmenopausal women. Endokrynol Pol 2013; 64: 114-120.
15. Grzesiak M, Beszłej JA, Szechiński M, et al. Depressive disorders in patients with irritable bowel syndrome
diagnosed using the Composite International Diagnostic Interview. Adv Clin Exp Med 2010; 19: 601-605.
16. Grzesiak M, Beszłej JA, Mulak A, et al. The lifetime prevalence of anxiety disorders among patients with
irritable bowel syndrome. Adv Clin Exp Med 2014; 23: 987-992.
17. Mulak A, Waszczuk E, Beszłej JA, et al. Association of polymorphisms in 5-HT2A and 5-HT2C receptors
genes with depressive and anxiety disorders in patients with irritable bowel syndrome. Gastroenterology 2013;
144 (Suppl 1): S-725, Mo2040.
18. Mulak A, Waszczuk E, Beszłej JA, et al. Serotonin-related gene variants in patients with irritable bowel
syndrome and depressive or anxiety disorders. Gastroenterology 2016; 150 (Suppl 1): S-950, Tu1797.
19. Gazouli M, Wouters MM, Kapur-Pojskić L, et al. Lessons learned – resolving the enigma of genetic factors in
IBS. Nat Rev Gastroenterol Hepatol 2016; 13: 77-87.

12
The Prevalence of Irritable Bowel Syndrome among Gastrointestinal
Diseases in Belarus
RUSTAMOV Mirzabey
Belarusian State Medical University, Minsk, (REPUBLIC OF BELARUS)
Email: dr.rustamov@mail.ru

Abstract

Irritable bowel syndrome (IBS) is a functional bowel disorder in which recurrent abdominal pain
is associated with defecation or a change in bowel habits. IBS patients had significantly higher levels
of psychological distress, pain severity and maladaptive pain coping strategies, and lower QoL than
ulcerative colitis patients in some studies. In this retrospective data, we analyzed 6466 gastrointestinal
diseases (GI) patients’ histories of outpatients who visited the gastroenterologist in Minsk Consulting
Diagnostic Centre in 2008. 1698 patients with IBS were selected. Criteria for making a diagnosis
were Rome III criteria or the diagnosis of IBS and Manning criteria. It was revealed that IBS is a
wide spread functional bowel disorder and its proportion among GI diseases was 26,03%. IBS in
females is 2.5 times more common than in males. IBS occurred in all age groups with a small
difference in the frequency of subtypes by age, mainly at the overage age.

Keywords: irritable bowel syndrome, subtypes of IBS, gastrointestinal diseases, prevalence

Introduction

Irritable bowel syndrome (IBS) is a functional bowel disorder in which recurrent abdominal pain
is associated with defecation or a change in bowel habits. Disordered bowel habits are typically
present (ie, constipation, diarrhea, or a mix of constipation and diarrhea), as are symptoms of
abdominal bloating/distention. Symptom onset should occur at least 6 months before diagnosis and
symptoms should be present during the last 3 months [1]. IBS occurs in all age groups, including
children and the elderly, with no difference seen in the frequency of subtypes by age. However, 50%
of patients with IBS report having first had symptoms before the age of 35 years, and prevalence is
25% lower in those aged over 50 years than in those who are younger. This would suggest that
symptoms remit over time, and is contrary to the belief that IBS is a chronic lifelong condition,
because, if this were the case, then prevalence should remain constant or increase with age. Patients
aged over 50 years also report milder pain, but their overall quality of life is worse. Those aged over
65 years are also likely to have had their symptoms for longer than 1 year before they consult, whilst
those under 65 years report significantly shorter duration of symptoms [2]. IBS patients had
significantly higher levels of psychological distress, pain severity and maladaptive pain coping
strategies (catastrophization), and lower QoL than ulcerative colitis patients in two studies in Hungary
[3, 4].
IBS is classified into 3 main subtypes according to the predominant disorder in bowel habits: IBS
with predominant constipation (IBS-C): More than one-fourth (25%) of bowel movements with
Bristol stool form types 1 or 2 and less than one-fourth (25%) of bowel movements with Bristol stool
form types 6 or 7. Alternative for epidemiology or clinical practice: Patient reports that abnormal
bowel movements are usually constipation (like type 1 or 2 of Bristol stool form scale, IBS with
predominant diarrhea (IBS-D): more than one-fourth (25%) of bowel movements with Bristol stool
form types 6 or 7 and less than one-fourth (25%) of bowel movements with Bristol stool form types
1 or 2. Alternative for epidemiology or clinical practice: Patient reports that abnormal bowel

13
movements are usually diarrhea (like type 6 or 7 of Bristol stool form scale), IBS with mixed bowel
habits (IBS-M): more than one-fourth (25%) of bowel movements with Bristol stool form types 1 or
2 and more than one-fourth (25%) of bowel movements with Bristol stool form types 6 or 7.
Alternative for epidemiology or clinical practice: Patient reports that abnormal bowel movements
are usually both constipation and diarrhea (more than one-fourth of all the abnormal bowel
movements were constipation and more than one-fourth were diarrhea. The prevalence of IBS within
the community is between 10% and 25% [2]. In his systematic review study using data from PubMed
till 2012, Professor Dan L. Dumitrascu showed that the prevalence of IBS varies in different studies
from 28% in a Croatian study, to 14% in Romania [3]. Epidemiological studies on IBS exist in most
East European countries. Usually they look for self-reporting symptoms or reports from endoscopy
units.
Psychosomatic approach of IBS is taken into consideration in several countries (Poland, Hungary
and Romania) mainly by psychologists and psychotherapists than by gastroenterologists [3].
Prevalence of IBS in primary care varies in different countries and estimates of the proportion who
do attend primary care for their symptoms are between 10% and 70%. In the UK, estimates of the
proportion who consult vary from 30% to 50%. Reported consultation rates of people with symptoms
also vary in studies from Germany, between 10% and 50%. The highest proportion is in Italy, with
50% consulting; 30% consult in the Netherlands, 20% in Belgium, and 10% in Switzerland, France,
and Spain [3]. No epidemiological study was performed in Belarus. In this regard, it is necessary to
perform retrospective analysis for learning the prevalence of IBS among gastrointestinal diseases in
Belarus.

Purpose

To investigate the prevalence of IBS among gastrointestinal (GI) diseases, subtyping of IBS and
its distribution by age and gender.

Material and methods

We analyzed 6466 GI patients’ histories of outpatients who visited the gastroenterologist in Minsk
Consulting Diagnostic Centre in 2008. 1698 patients with IBS were selected. Criteria for making a
diagnosis were Rome III criteria for the diagnosis of IBS – abdominal pain and discomfort lasting at
least three days a month in the last three months, associated with two or more of following:
improvement with defecation, altered frequency of stool or altered consistency of stool) and Manning
criteria (pain relieved by defecation, having incomplete bowel movements, mucus in the stool and
changes in stool consistency). Diagnostics was based on imaging tests (Flexible sigmoidoscopy,
Colonoscopy, Abdominal ultrasonography, Esophagogastroduodenoscopy, X-ray, lower GI series,
computerized tomography scan) and Laboratory tests (Lactose intolerance tests, blood tests for Celiac
disease, complete blood count, biochemical blood analysis, stool tests for bacteria or parasites, stool
tests for gut microbiota).

Results and discussion

We performed retrospective analysis of patients’ histories of outpatients who visited the

gastroenterologist in Minsk Consulting Diagnostic Centre for learning the prevalence of IBS among
gastrointestinal diseases. It was revealed that IBS is a wide spread functional bowel disorder and its
proportion among GI diseases was 26,03% (Fig. 1).

14
 Fig. 1. Prevalence of IBS among GI diseases

Fig. 2. Subtyping of IBS

Distribution of IBS subtypes showed that majority of patients were IBS with predominant
constipation (IBS-C) – 54,77%. IBS with predominant diarrhea (IBS-D) and IBS with mixed bowel
habits (IBS-M) were 22, 03% and 23,20% respectively (Fig. 2).

Fig. 3. Distribution of IBS by age

IBS occurred in all age groups with a small difference in the frequency of subtypes by age, mainly
at the overage age.

15
 Fig. 4. Distribution of IBS by Gender

Gender distribution of IBS showed that IBS in females was 2.5 times more common than in males
and male/female proportion was 1:2,5 (Fig. 4).

Fig. 5. Distribution of IBS sybtypes by age in males

Fig. 6. Distribution of IBS sybtypes by age in females

Distribution of IBS subtypes by age in males and females had some differences depending on
subtype of IBS. IBS-C in males mainly was at the age of 41-60 and more, but IBS-D and IBS-M were
mainly at the age of 18-60 (Fig. 5). In females, all subtypes of IBS mainly occurred at the age of 41-
60 (Fig. 6).

Conclusions

1. IBS is a widespread functional bowel disorder and its prevalence among GI diseases was high
enough and consisted 26,03%.
2. IBS occurred in all age groups with a small difference in the frequency of subtypes by age, mainly
at the overage age.
3. IBS in females was 2.5 times more common than in males.

16
REFERENCES

1. Brian E. Lacy, Fermín Mearin, Lin Chang, William D. Chey, Anthony J. Lembo, Magnus Simren, and Robin
Spiller (2016) Bowel disorders. Gastroenterology 150: pp. 1393-1407.
2. Caroline Canavan, Joe West and Timothy Card (2014) The epidemiology of irritable bowel syndrome. Clinical
Epidemiology, 6, pp. 71-80.
3. Flaviu Rusu and Dan L. Dumitrascu (2015) Epidemiology of irritable bowel syndrome in the former communist
countries from Eastern Europe: a systematic review. Clujul Med. 88(2), pp. 146–151.
4. Seres G, Kovács Z, Kovács A, Kerékgyártó O, Sárdi K, Demeter P, et al. (2008) Different associations of health-
related quality of life with pain, psychological distress and coping strategies in patients with irritable bowel
syndrome and inflammatory bowel disorder. J Clin Psychol Med Settings, 15(4), pp. 287–295.

17
Ethics of Genetic Testing in Functional Gastro Intestinal Disease

GAVRILOVICI Cristina1, STARCEA Magdalena2, MIRON Ingrith2

1 Universityof Medicine and Pharmacy “Gr. T. Popa” Iasi, Medical Deontology and Bioethics
2 Universityof Medicine and Pharmacy “Gr. T. Popa” Iasi, Paediatrics
Emails: cristina.gavrilovici@gmail.com, magdabirm@yahoo.com

Abstract

The landscape of genetic testing in gastroenterology is continuously evolving, and this has been
driven primarily by the rapid advances in sequencing technology, the proliferation of genetic testing
services worldwide and ongoing investigations that identify new genetic contributions in
gastroenterology. Genetic testing in functional intestinal disorder encompasses a wide range of
techniques ranging from karyotype analysis to genome wide association studies (GWAS) and more
recently whole exome and whole genome sequencing. This paper aims to present some of the major
ethical challenges related to the current types of genetic testing applied in irritable bowel syndrome
(IBS).
Genetic testing is generally morally acceptable when the diagnosis is likely to change the
management, and improve the quality of life. Therefore, the main ethical issues involved relates to
informed consent, privacy and confidentiality of the test and stigmatization and discrimination
following test results disclosure. The development of GWAS open the pandora’s box related to the
detection of unexpected or unsolicited findings, not always easy to be managed. Whole-genome or
exome sequencing generates an enormous amount of raw data requiring complex bioinformatic
analyses to extract useful information. We are not prepared yet to envision all ethical issues that might
appear associated to “next generation sequencing methods”.
Keywords: genetic testing, GWAS, irritable bowel syndrome, ethics

The reason for which intestinal functional gastro-intestinal disorder (FGID) have become a major
public health issue is obvious: irritable bowel syndrome affects up to 20% of the Western population
(1).
According to the International Foundation for Functional Gastrointestinal disorders (FGID) 1 in 4
people in the U.S. have one of these disorders, 40% of gastro-intestinal problems being a reason for
medical consultation (2). Functional dyspepsia (FD) and intestinal bowel syndrome varies greatly
(depending on the sample size and methods of data collection) from 8,1%-20,4% for and 3,5%-19,4%
(3).
In many instances, other family members may also have bowel disturbances, thus suspecting an
important role of genes in disease development. While environmental (extrinsic) factors such as
psychological stress, diet, smoking habits, infectious gastroenteritis that results in alterations in the
gut microbiota are well known the role of intrinsic factors (genetics, epigenetics, sex hormones and
coping mechanisms) in IBS has been studied to a lesser extent. This paper aims to raise awareness on
the role of genetic testing in FGID and the related ethical issues that surround the different types of
genetic testing.

1. The role of genetics in IBS

It is not the aim of this paper to approach the genetics of FGID. However, in order to understand
why genetic testing is a valuable tool in diagnosis and management of FGID, we will underline the
major landmarks of genetics in FGID.

18
 Currently accepted genetic testing for FGID include: diagnostic testing, presymptomatic testing,
susceptibility testing, carrier testing. Usually, a genetic test recommended by a gastroenterologist will
most probably be only for diagnostic purposes, occasionally for presymptomatic testing among family
members once a genetic component is detected. Genetic testing is indicated when the diagnosis is
likely to change the management (4).
A familial clustering of IBS has been reported in several studies, therefore suggesting an inherited
component (5, 6). Waterhens et al. (7) have shown that the existence of a first-degree relative with
IBS can be predictive of IBS and that an increased risk of IBS is evident among first-degree, second-
degree, and third-degree relatives. Levy et al. (2001) analyzed 6060 twin pairs, and concordance for
IBS was significantly greater in monozygotic (17.2%) than in dizygotic (8.4%) twins, supporting a
genetic contribution to IBS. The same familial aggregation has been proved in FD patients (8).
Thus, the majority of studies have examined the effects of a few single nucleotide polymorphisms
(SNPs) in hypothesis-driven candidate approaches, whereas other studies performed a gene-naive
genome-wide association study (GWAS).

2. The genetic tests in IBS

2.1. Candidate gene studies

From all gene polymorphism studied, apparently the most common involved is 5-HTTLPR of
serotonintransporter (SERT) (3). This has been triggered because of the hypothesis that disturbances
in the 5-hydroxytryptamine (5-HT, serotonin) metabolism and/or signal transduction via the brain–
gut axis contribute to altered sensorimotor function in the gastrointestinal tract. There are also gene
variants related to neuronal function (eg. gene SCN5A encoding NaV1.5 ion channelopathy (9),
adrenergic receptor genes ADRA2A and ADRA2C (10), genes encoding catechol-O‑
methyltransferase (COMT) (11), brain-derived neurotrophic factor (BDNF), etc), gene variants
affecting intestinal barrier function (eg. genes encoding tight junction proteins (occludin, zonula
occludens 1, claudin 1, 2) (12), gene variants related to immune function. (low-grade immune
activation/dysregulation that have been proposed as underlying mechanism of IBS) (1, 13).

2.2. Next generation genetic testing

2.2.1 Whole exome sequencing

Although genetic testing includes a wide range of techniques, from karyotype analysis to whole
genome sequencing, the majority of genetic tests applicable in gastroenterology involve DNA
sequencing. This test is designed to detect the presence or absence of a specific mutation in the DNA
sequence that produce or is associated with a specific disorder (14). Specific gene sequencing or
targeted exon sequencing is the most common technique employed. These tests will sequence the
entire coding region of a gene, or the areas of the gene in which the most common disease-causing
mutations are found. Finally, whole exome sequencing, in which the coding regions of the entire
genome are sequenced, and whole genome sequencing, in which the entire genome is sequenced, are
clinically available. They remain primarily research tools at this time, though successful clinical
applications of these tests have been demonstrated.

2.2.2 Genome-wide association study (GWAS) and Whole-genome analyses (WGA)

Genome-wide association study is an examination of a genome-wide set of genetic variants in

different individuals to see if any variant is associated with a trait. Single nucleotide polymorphisms
(SNPs) are the most common type of genetic variation among people. Each SNP represents a
difference in a single DNA building block, called a nucleotide. After the revelation of whole human

19
genome sequences in 2004, it became clear that single nucleotide polymorphisms of genes were
involved in many metabolic processes. When a single nucleotide is different, translation of a protein
or function can easily be changed, and these changes may affect the development of diseases and
treatment effectiveness.
GWAS typically focus on associations between single-nucleotide polymorphisms (SNPs) and
traits (like major human diseases), but can equally be applied to any other organism (15). The entire
genome is genotyped and allele frequencies are compared between patients and control groups to find
genetic variations associated with a disease (1).

Genome-wide association study (GWAS) and Whole-genome analyses

Genomic architecture has been unravelled due to the sequencing of the human genome along with
very detailed studies exploring variation in the genome across populations. The genome-wide
association study design has a reasonable power to identify common risk factors of small effect in
large samples, but relatively low power to detect rare risk factors, even those of moderate to large
effect on disease risk. There is great interest in developing SNP profiles that might be used to
effectively screen patients to identify those disorders for which they are at greatest risk (15).
To the best of our knowledge, two major studies so far have utilized a GWAS approach to
underline the genetic substrate of IBS: 1. a small pilot GWAS conducted in a cohort of 172 patients
with IBS and identified an association of a SNP in the protocadherin-15 gene (PCDH15) on
chromosome 10 with IBS (16); 2. Secondly, Ek et al., analysed 11,326 Swedish twins, including
patients with IBS as well as asymptomatic individuals, and validated their findings in cohorts from
Europe, the USA and Australia. A significant association between one locus, at 7p22.1 encoding the
genes KDELR2 (KDEL endoplasmic reticulum protein retention receptor 2) and GRID2IP (glutamate
receptor, ionotropic, delta 2 (Grid2) interacting protein), with IBS risk was found in the index GWAS
and all replication cohorts (17).

3. Ethical issues related to genetic testing for FGID

Currently accepted types of genetic testing for FGID include diagnostic testing, presymptomatic
testing, susceptibility testing, carrier testing. For any chosen genetic testing, there are three main
ethical issues: 1. Informed consent; 2. Confidentiality and disclosure to third party and 3. Incidental
findings. It is obvious that several other ethical issues may need to be consider when talking about
genetics in IBS. However, at this point we will elaborate only on these three aspects, since these are
paramount.
3.1. Informed consent in geentic testing for FGID
Form an ethical standpoint, the most important part of a genetic testing is obtaining informed
consent. The essential elements include: a detailed explanation of the nature of the test being ordered
(the type and the aim of testing), the possible test results (including findings of unknown
significance), the implications of the test results (including altering the self-esteem or emotional
consequences, the familial relationships, impact on the health insurance, jobs, etc) the detection of
incidental findings, the risks associated with the test (including potential genetic stigmatization and
discrimination), how the test results will be communicated, the alternatives for genetic testing, the
rate of false positive, false negative or inconclusive results, the costs, the total time lengths of testing
(including the possibility of prolongation), how the results will be communicated, potential treatment
options, disclosure to third party, data storage, potential re-use of the samples and the implication that
the test results will have for the treatment plan (18).
3.2 Confidentiality in genetic testing for FGID
Genetic data must be protected from the third parties’ interests (including insurers, employers,
20
government companies, etc.). They cannot be disclosed without the written consent of the person.
Even in this case, the doctor must decide before the disclosure if the test results they are absolutely
relevant to those whom it will be revealed. How disclosure of the results will be performed must be
chosen so as to minimize the possibilities to reach unauthorized persons (19). The risk of social stigma
due to genetic disease, and discrimination in employment or health insurance, due to the breach in
genetic privacy cannot be neglected. Patients often refuse the testing because of the fear that the
results could “fall” into the “wrong hands” of an employer or insurer, and this would open the risk of
discrimination. Although today various anti-discrimination legislation specific for genetic testing
were developed in many countries, they do not sufficiently reassure the general population (20).
However, there are special situations where respecting confidentiality is questionable. The
information resulted from genetic testing are important not only for the health and the reproductive
plans of a unique patient, but also for his/her family and relatives. Thus, not to disclose the
information that may influence the life choices to a family member could be considered a violation
of his/her rights (21).
The patient should be advised and encouraged to share the information risk to his relatives or to
consent for this communication to be disclosed. If the patient categorically refuses, then another
possibility is that the patient’s relatives be contacted by the family doctor. However, this is not an
entirely and general accepted practice.
Therefore, it is currently considered that medical confidentiality is not absolute. It was proposed
that disclosure of genetic information to relatives may be performed under the following
circumstances: 1. all reasonable efforts to obtain disclosure agreement were made; 2. There is a high
probability of irreversibly “harm” to a third party; 3. Only information needed to prevent negative
side effects will be provided. These recommendations are obviously not valid for the states that have
enacted specific directives regulating the application of genetics.

3.3. Incidental findings related to genetic testing in FGID

A particular issue that may confront a geneticist is the incidental findings: the information that do
not directly relate with the initial purpose of the test (eg: unexpected discover of a non-paternity,
carrier for a particular gene, another disease etc.). Even if incidental findings may occur in any
medical discipline, until recently, incidental findings related to a genetic testing were rare. However,
due to a paradigm shift in genetics according to which untargeted genetic analysis such as exome
sequencing became a “genome first” approach to disease identification, the frequency of incidental
findings has dramatically increased.
In these cases, the counselor must explicitly distinguish between the information requested and the
other one, obtained “by chance” and then to choose the one that might be relevant to the patient’s
health and to ignore the one that is not important for any decision. The American College of Medical
Genetics and Genomics (ACMG) provided recommendations regarding when incidental findings in
whole-exome and whole-genome sequencing should be returned (22). Institutional factors can
implement procedures for disclosure, including here the possibility of incidental findings to be
discussed with participants at the time of consent (23).

4. Conclusion

Functional gastro intestinal disorders (FGID) represent today the most prevalent condition in
patients who presents to medical consultation with abdominal symptoms. Determining the etiology,
the risk factors and the mechanisms of these diseases is important to establish the treatment strategy.
In our genomic era, genetic testing for a variety of functional gastro intestinal disorders (FGID)
will be increasingly implemented. As such, apart from increasing knowledge of basic genetics as a
foundation for a better understanding of FGID, the importance of the related ethical issues is
paramount. We need to pay particular attention when informing people about the nature of genetic
testing, about the potential implication of the test results, and the associated potential risks, such as

21
stigmatization and discrimination. An increased awareness on ethics will increase the chances of a
better physician – patient relationship.

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1. Gazouli M., Wouters MM., Kapur-Pojskic L, Bengtson MB., Friedman E, Nikcevic G, Demetriou CG, Mulak
A., Santos J, Niesler B., (2016), Lessons learned – resolving the enigma of genetic factors in IBS, NATURE
REVIEWS|GASTROENTEROLOGY & HEPATOLOGY, 13, 77-87.
2. Functional GI Disorders, (2016), available at https://www.iffgd.org/functional-gi-disorders.html, last update
November.
3. Oshima T., Miwa H, (2015) Epidemiology of Functional Gastrointestinal Disorders in Japan and in the World
J., Neurogastroenterol Motil, 21 (3), 320-329.
4. Straticiuc S., Ignat A., Hanganu E., Lupu V., Ciubara AB., Cretu R (2016), Neisseria meningitidis Serogroup C
Causing Primary Arthritis in a Child Case Report MEDICINE, 95: 5, Article Number: e2745.
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of irritable bowel syndrome: a prospective study. Gut 52, 1703–1707.
6. Boeckxstaens, G. E.; Drug, V.; Dumitrascu, D.; et al., (2016), Phenotyping of subjects for large scale studies on
patients with IBS, Neurogastroenterology And Motility, 28: (8): 1134-1147
7. Waehrens, R., Ohlsson, H., Sundquist, J., Sundquist, K. & Zoller, B., (2015), Risk of irritable bowel syndrome
in first-degree, second-degree and third-degree relatives of affected individuals: a nationwide family study in
Sweden. Gut 64, 215–221.
8. Levy RL, Jones KR, Whitehead WE, Feld SI, Talley NJ, Corey LA. (2001), Irritable bowel syndrome in twins:
heredity and social learning both contribute to etiology. Gastroenterology, 121:799-804.
9. Beyder, A. et al. Loss‑of‑function of the voltage-gated sodium channel NaV1.5 (channelopathies) in patients
with irritable bowel syndrome, (2014), Gastroenterology 146, 1659–1668.
10. Choi, Y. J., Hwang, S. W., Kim, N., Park, J. H., Oh, J. C., & Lee, D. H. (2014). Association Between SLC6A4
Serotonin Transporter Gene Lainked Polymorphic Region and ADRA2A −1291C>G and Irritable Bowel
Syndrome in Korea. Journal of Neurogastroenterology and Motility, 20(3), 388–399.
11. Jiang, Y., Nie, Y., Li, Y. & Zhang, L. (2014). Association of cannabinoid type 1 receptor and fatty acid amide
hydrolase genetic polymorphisms in Chinese patients with irritable bowel syndrome. J. Gastroenterol. Hepatol.
29, 1186–1191.
12. Martínez C, Lobo B, Pigrau M, Ramos L, González-Castro AM, Alonso C, Guilarte M, Guilá M, de Torres I,
Azpiroz F, Santos J, Vicario M. (2013), Diarrhoea-predominant irritable bowel syndrome: an organic disorder
with structural abnormalities in the jejunal epithelial barrier. Gut 62, 1160–1168.
13. Öhman, L., Törnblom, H., Simren, M. (2015), Crosstalk at the mucosal border: importance of the gut
microenvironment in IBS. Nat. Rev. Gastroenterol. Hepatol. 12, 36–49.
14. Goodman R, Chung DC, (2016), Clinical Genetic Testing in Gastroenterology, Clinical and Translational
Gastroenterology 7:1-6.
15. Bulgaru-Iliescu, D., D. Botezat, and L. Oprea, THE CHRONIC CARE MODEL AND PERSONAL
RESPONSIBILITY FOR HEALTH. Revista Romana De Bioetica, 2012. 10(4): p. 78-84.
16. Holliday, E. G., Attia, J., Hancock, S., Koloski, N., McEvoy, M., Peel, R., et al. (2014), Genome-wide
association study identifies two novel genomic regions in irritable bowel syndrome. American Journal of
Gastroenterology, 109(5), 770-772.
17. Ek WE, Reznichenko A, Ripke S, Niesler B, Zucchelli M et al., (2015). Exploring the genetics of irritable bowel
syndrome: a GWA study in the general population and replication in multinational case‑control cohorts. Gut 64,
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PROCESS REQUIRED FOR ROMANIAN HOSPITALS? South African Journal of Economic and
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(2013), 15(7):565–574.
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22
How Important are Genetics in Functional Gastrointestinal Diseases?
CABA Lavinia, GORDUZA Eusebiu Vlad
“Grigore T. Popa” University of Medicine and Pharmacy, Iasi (ROMANIA)
Emails: lavinia_zanet@yahoo.com, vgord@mail.com

Abstract

Functional gastrointestinal diseases (FGID) are characterized by pain and gastrointestinal

discomfort, for which there are no specific biomarkers for diagnosis and treatment. These are
multifactorial diseases that involved genetic and environmental factors. Genetic studies have focused
on the most common FGID - Irritable Bowel Syndrome and Functional Dyspepsia. The pathogenic
pathways are numerous and interlinked: gastrointestinal dysmotility, visceral hypersensitivity, brain-
gut axis interactions, inflammation, genetic and immunological disturbances, altered microbiota,
factors related to diet. Studies identified genetic variants of the neurotransmitters (serotonin, alpha 2
adrenergic receptors, catechol-O-methyltransferase, cannabinoid receptors), inflammatory markers
(interleukin 10, tumours necrosis factor alpha, G-protein) absorption of bile acids, microRNAs,
pharmacogenetic variants involved in drug metabolism or in the genes of receptors, transporters and
enzymes involved in various physiological mechanisms.
This paper aims to synthesize genetic factors involved in various pathogenic mechanisms of
functional gastrointestinal diseases and to illustrate the practical importance of genetics in the
diagnosis and personalized management in patients with functional gastrointestinal diseases.
Keywords: genetics, functional gastrointestinal diseases, functional dyspepsia

Introduction

Phenotypic (normal/abnormal) traits are determined by genetic and environmental factors in

varying proportions. The implication of genetic factors is varying between 100% (traits determined
only by genetic factors) and 0% (non-genetic traits determined by environmental factors).
Multifactorial characters are determined by interference in varying proportions of genetic and
environmental factors. Disorders represent any major alteration of the normal structure and/or
function of the body [1]. Genetic disorders are caused or conditioned by mutations. They can be
classified into five categories: chromosomal diseases, monogenic diseases, mitochondrial diseases,
diseases produced by mutations of somatic cell DNA and multifactorial diseases. In multifactorial
diseases, the effects of the genes are polygenic and small, but additive. Thus, the phenotype is the
result of a random combination of mutant alleles and environmental factors [1, 2]. An example of
multifactorial disease is Functional Gastrointestinal Disorders (FGIDs). FGIDs are determined by
morphological and physiological abnormalities represented by motility disturbance, visceral
hypersensitivity, altered mucosa, immune function, gut microbiota, and central nervous system
processing. FGIDs could be divided in eight categories; irritable bowel syndrome (IBS),
gastroesophageal reflux disease (GERD) and functional dyspepsia (FD) are the most common
conditions [3]. Identification of genetic factors in FGID can be made by association analysis, linkage
analysis or genome-wide association studies (GWAS). The association studies use the candidate
genes and analyse the presence of a specific morbid allele in a population. Linkage analysis is based
by search of a specific non-morbid marker that is transmitted linked with a disease. In both methods,
the number of participants is limited. GWAS presents some advantages because the number of
analyzed individuals and number of specific genetic parameters (single nucleotide polymorphisms –
SNPs) are both high. GWAS studies could revealed an independent (the SNP’s effect on the

23
molecular phenotype and on the disease phenotype are independent) a causal (the SNP affect the
molecular phenotype which causes the disease) or reactive (the SNP cause the disease and the
molecular phenotype is changed by the disease) link between a particular SNP and the disease [4].
Identification of susceptibility variants by GWAS could improve the clinical practice by finding
new therapeutic targets, biomarkers, the possibility of applying an adequate prevention and
personalized management of diagnostic, prognostic and therapy [5, 6]. Application of GWAS in IBS
identified an association risk for IBS and polymorphisms in KDELR2 gene (KDEL endoplasmic
reticulum protein retention receptor 2) and GRID2IP gene (glutamate receptor, ionotropic, delta2
interacting protein) [7, 8]. Application of GWAS in GERD identified 30 GERD suggestive risk loci
[9].

Genetics in IBS

IBS is classified into three major subtypes depending on the bowel habits: constipation-
predominant IBS (IBS-C), diarrhea-predominant IBS (IBS-D), and mixed IBS (IBS-M) [3, 10].
Genetic studies in IBS have estimated a heritability ranging from 0-57% and a liability ranging
between 1-20% [11]. Positive family history of the disorder is associated with a twofold to threefold
higher risk in relatives of IBS patients [12]. Genetic variations were identified in all pathogenic
pathways: neurotransmitters, inflammation, bile acid absorption, microRNA, placebome and
pharmacogenetics.

Neurotransmitters

The most studied pathway of neurotransmitters is the serotonin one. Both receptors and serotonin
transporter genes were identified having genetic variations associated with IBS. The study of
polymorphisms in genes encoding the five families 5-hydroxytryptamine (5-HT) receptors expressed
in the intestinal mucosa showed some positive association with IBS. For example, rs1062613
polymorphism in HTR3A gene and rs62625044 polymorphism in HTR3E gene have been associated
with IBS-D in both females and males [13, 14]. The promoter region of SERT gene (serotonin
transporter) contains a polymorphism characterized by deletion (S – short variant) or by insertion (L
– long variant) of 44 bp [15, 16]. S allele was shown to be associated with the severity of symptoms
in IBS and also with depression, anxiety, increased sympathetic tone, decreased parasympathetic
tone, score increased anxiety/neuroticism, increased levels of cortisol [17, 18, 19]. Rs25531
(genotype A/G) is another SNP in SERT gene which is associated with IBS, but also with psychiatric
disorders. The polymorphisms 5HTTLPR and rs25531 are strongly linked. Their combined analysis
identified several subtypes of allele L genotypes (LG/LG, LG/LA, LA/LA). The subtype LG seems
to be similar with S allele [20, 21].

Inflammation

Among the genes involved in immune function, TNFSF15 (tumor necrosis factor superfamily
member 15) was associated with IBS. Polymorphism rs4263839 in the gene TNFSF15 was associated
with IBS-C in particular by modulating the differential proinflammatory and/or antibacterial response
and the result is an increase of cellular immune response and production of cytokines [17, 22, 23].

Endocannabinoid system

The endocannabinoid system is known to be involved in secretion, perception, motility and anti-
inflammatory activity of the gastrointestinal tract. Thus, changes of this system are associated with
development of functional gastrointestinal disorders, including IBS [15]. The A allele of rs324420

24
polymorphism in FAAH gene (Fatty acid amide hydrolase) is associated with IBS-D and IBS-M and
with the accelerated intestinal transit in IBS-D patients [24].

Bile acids absorption

Bile acids have secretor effects on the colon mucosa. One of the gene implied in bile acids
synthesis is Klotho Beta (KLB gene). The allele G of rs17618244 polymorphism in KLB gene was
associated with accelerated colon transit (increase synthesis of bile acids accelerates colon transit by
stimulating colon secretion and motility) [25]. TC or CC genotype of rs11554825 polymorphism in
bile acid receptor gene causes alteration of small intestine transit in IBS-D patients [26].

MicroRNA

MicroRNAs (miRNAs) are small regulatory non-coding RNA molecules formed by 22

nucleotides. They inhibit the expression of specific genes by cleaving the specific messenger RNAs.
More than 1000 miRNAs are known to regulate the expression of over 60% of human genes [27].
IBS studies showed the possible involvement of miR-29a, miR199a/b, miR-150, miR342-3p, miR-
16 or miR-125b in pathogenic pathway of disease [28]. IBS-D is characterized by increased intestinal
mucosal permeability (by altering the distribution of cell-to-cell adhesion proteins) associated with
aberrant visceral sensitivity [29, 30]. MiR-125b and miR-16 act as modulators of barrier function of
the intestinal mucosa and the low expression of both miRNAs determines the increase in the
expression of cingulin and claudin-2 proteins that are correlated positively with the acute stress
response and depression levels [31]. Colonic miR-199 is decreased in patients with IBS-D with
visceral pain and positive correlated with high colonic expression of transient receptor potential
vanilloid type 1 (TRPV1). TPRV1 is expressed on peripheral primary afferent sensory neurons and
when is activated by inflammatory mediators produce burning sensation and/or pain. The use of miR-
199 precursors could decrease TPRV1 expression and thus could ameliorate the symptoms in IBS,
constituting a promising therapeutic target [28]. Identification of miRNAs associated to IBS is
important because miRNAs could represent useful biomarkers in stratification of IBS subgroups and
potential therapeutic targets.

Placebome

Placebome consists of group of genome-related or derived molecules (i.e., genes, proteins, or

miRNAs) that modify the response to placebo treatment [32]. Candidate genes for placebo intervene
in the following neurotransmitter pathways: the dopamine pathway (genes for COMT – Catechol-O-
methyltransferase, MAO-A – Monoamine oxidase, DBH – Dopamine B hydroxylase, DRD3 –
Dopamine receptor 3, BDNF – Brain derived neurotropic factor), serotonin (genes for TPH2 –
Tryptophan hydroxylase-2, SLC6A4 – 5-Hydroxytryptamine transporter, HTR2A – 5-
Hydroxytryptamine receptor 2A, 5-HTTLPR – Serotonin transporter gene-linked polymorphic
region), opioid receptor (OPRM1), endocannabinoid (FAAH – fatty acid amide hydrolase) [32].
The pathogen mechanisms of the IBS/FGID involve most of these networks, and studies have been
conducted to identify the variations of placebo and their effects. Thus, the rs4680 polymorphism in
COMT gene is implied in the response to placebo treatment of patients with IBS. This polymorphism
is characterized by two possible alleles: met (with low activity) and val (with high activity).
Homozygotes for met allele have a good placebo response. Homozygotes for val allele had a bad
placebo response [33]. Heterozygotes val/met had an intermediate response and a great rate of nocebo
effects [33, 34]. The practical utility of identifying genetic variants in neurotransmitter pathways
involved in mediating placebo effects is that a genetic screening can be used to identify placebo
responders for the purpose of applying personalized therapy and specific measures for placebo
analgesia.

25
Pharmacogenetics

Pharmacogenetic variations target three aspects: gene polymorphisms involved in various

pathogen mechanisms in FGID/IBS (transporters, neurotransmitter receptors, enzymes, mediators of
inflammation), changes in the metabolism of drugs and the treatment of psychiatric comorbidities.
The first category includes variations in the metabolism of serotonergic adrenergic and opioidergic
drugs, bile acids [17]. The L/L genotype (homozygous for long variant – insertion of 44 bp) for the
SERT gene is associated with ineffective response to Tegaserod treatment and effective response to
Alosetron in IBS-D [35, 36]. The S/S genotype (homozygous for short variant – deletion of 44 pb)
shows a positive correlation with depressive episodes, requiring treatment with selective serotonin
reuptake inhibitors [37, 38]. Adrenergic polymorphisms (i.e., α2C-1291C> G) have been described
as being associated with intense response to clonidine (α2 receptor agonist) treatment. Genetic
variations in the KLB and FGFR4 genes correlate with the chenodeoxycholic acid response in IBS-C
and also with colesevelam response in patients with IBS-D [39, 40]. Among the genetic variations in
the metabolic pathway of drugs most commonly involved in IBS are variations in cytochrome
P4502D6 metabolism (CYP2D6). This enzyme is involved in the metabolism of tricyclic
antidepressants and the metabolism of serotonin reuptake inhibitors used in the treatment of IBS.
Patients could have a CYP2D6 metabolism ultra-rapid, extensive, intermediate or poor. 5-10% of
the Caucasian population has poor metabolism and 98% of these non-functional alleles are CYP2D6
* 3, CYP2D6 * 4, CYP2D6 * 5, CYP2D6 * 6 alleles. For this reason, in certain ethnic groups it is
recommended to test CYP2D6 before starting treatment with tricyclic antidepressants [29].

Genetics in FD

FD can be subdivided into two categories according to the criteria ROMA IV: postprandial distress
syndrome (PDS) and epigastric pain syndrome (EPS) [3]. Genetic association studies have identified
protective and risk genetic variants (Table 1).

Table 1. Genetic studies in FD [15]

Gene Polymorphism Role
TLR-2 Deletion 192-174 Protective for H. pylori patients
GNB3 C825T polymorphism Risk factor
Genotype CT or TT
GNB3 C825T polymorphism Risk factor for PDS
Genotype CC or TT
GNB3 C825T polymorphism Risk factor
Genotype CC
GNB3 C825T polymorphism Risk factor for EPS
Genotype TT
TRPV1 G315C polymorphism Protective
SCN10A 3218 polymorphisms Protective
Genotype CC
TLR – Toll-like-receptor, TRPV – transient receptor potential vanilloid, PDS – posprandial
distress syndrome, EPS – epigastric pain syndrome.

Conclusions

The pathogenesis in FGID includes a large variety of genetic and environmental factors.
Identification of genetic factors is required and useful for genomic medicine, because this type of
approach could offer in the future the possibility of improving of prevention and therapy in
multifactorial diseases. Thus, the medicine will become perspective, predictive, personalized,
preventive and participatory.

26
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2. Covic M, Ştefănescu D, Sandovici I. Genetică medicală, ediţia a II-a. Iaşi: Editura Polirom, 2011.
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5. McCarthy M I, Abecasis G R, Cardon L R, et al. Genome-wide association studies for complex traits: consensus,
uncertainty and challenges. Nature reviews genetics 2008; 9(5): 356-369.
6. Boeckxstaens G E, Drug V, Dumitrascu D et al. Phenotyping of subjects for large scale studies on patients with
IBS. Neurogastroenterology & Motility 2016; 28(8): 1134-1147.
7. Ek WE, Reznichenko A, Ripke S, et al. Exploring the genetics of irritable bowel syndrome: a GWA study in the
general population and replication in multinational case-control cohorts. Gut. Published Online First: 23
September 2014. doi: 10.1136/gutjnl-2014-307997.
8. Holliday E G, Attia J, Hancock S, et al. Genome-wide association study identifies two novel genomic regions
in irritable bowel syndrome. The American journal of gastroenterology 2014; 109(5): 770-772.
9. Bonfiglio F, Hysi P G, Ek W. A meta‐analysis of reflux genome‐wide association studies in 6750 Northern
Europeans from the general population. Neurogastroenterology & Motility 2016;1-10.
10. Lacy B E, Mearin F, Chang L, et al. Bowel disorders. Gastroenterology 2016; 150 (6): 1393-1407.
11. Saito Y A. The role of genetics in IBS. Gastroenterology Clinics of North America 2011; 40(1): 45-67.
12. Waehrens R, Ohlsson H, Sundquist J, et al. Risk of irritable bowel syndrome in first-degree, second-degree and
third-degree relatives of affected individuals: a nationwide family study in Sweden. Gut, 2015; 64(2): 215-221.
13. Gu QY, Zhang J, Feng YC, Dai GR, Du WP. Association of genetic polymorphisms in HTR3A and HTR3E
with diarrhea predominant irritable bowel syndrome. Int J Clin Exp Med 2015;8(3):4581-4585.
14. Kapeller J, Houghton LA, Mönnikes H et al. First evidence for an association of a functional variant in the
microRNA-510 target site of the serotonin receptor-type 3E gene with diarrhea predominant irritable bowel
syndrome. Hum Mol Genet 2008; 17: 2967-2977.
15. Vasile Drug. Tulburari functionale digestive – Actualitati. Bucureşti: Ed. Pro Universitaria, 2015.
16. Yeo A, Boyd P, Lumsden S, et al. Association between a functional polymorphism in the serotonin transporter
gene and diarrhoea predominant irritable bowel syndrome in women. Gut 2004; 53: 1452–1458.
17. Gazouli M, Wouters M M, Kapur-Pojskić L, et al. Lessons learned - resolving the enigma of genetic factors in
IBS. Nat Rev Gastroenterol Hepatol, 2016; 13(2): 77-87.
18. Farmer A D et al. Psychophysiological responses to pain identify reproducible human clusters. Pain 2013; 154:
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19. Yuan J, Kang C, Wang M, et al. Association Study of Serotonin Transporter SLC6A4 Gene with Chinese Han
Irritable Bowel Syndrome. PLoS ONE 2014 9(1): e84414. doi: 10.1371/journal.pone.0084414.
20. Kohen R, Jarrett M E, Cain K C et al. The serotonin transporter polymorphism rs25531 is associated with
irritable bowel syndrome. Dig. Dis. Sci. 2009; 54: 2663–2670.
21. Jaworska N, MacMaster F P, Foster J, Ramasubbu R. The influence of 5-HTTLPR and Val66Met
polymorphisms on cortical thickness and volume in limbic and paralimbic regions in depression: a preliminary
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22. Zucchelli, M. et al. Association of TNFSF15 polymorphism with irritable bowel syndrome. Gut 2011; 60: 1671–
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23. Czogalla, B. et al. A meta-analysis of immunogenetic Case−Control Association Studies in irritable bowel
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G13-G19.
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syndrome. Pain 2009; 146:41–46.
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dysregulation through the modulation of claudin-2 and cingulin expression in the jejunum in IBS with diarrhoea.
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33. Hall K T, Lembo A J, Kirsch I et al. Catechol-O-methyltransferase val158met polymorphism predicts placebo
effect in irritable bowel syndrome. PloS one 2012; 7(10), e48135. doi: 10.1371/journal.pone.0048135.
34. Wendt L, Albring A, Benson S, et al. Catechol-O-methyltransferase Val158Met polymorphism is associated
with somatosensory amplification and nocebo responses. PLoS One 2014; 9(9): e107665. doi:
10.1371/journal.pone.0107665.
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37. Jarrett M E, Kohen R, Cain K C, et al. Relationship of SERT polymorphisms to depressive and anxiety symptoms
in irritable bowel syndrome. Biol Res Nurs 2007; 9(2): 161-169.
38. Serretti A, Calati R, Mandelli L, De Ronchi D. Serotonin transporter gene variants and behavior: a
comprehensive review. Current drug targets 2006: 7(12): 1659-1669.
39. Rao A S, Wong B S, Camilleri M, et al. Chenodeoxycholate in females with irritable bowel syndrome-
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28
Functional Gastrointestinal Disorders and IBS in Serbia
SNEZANA Lukic1, DRĂGAN Popovic1, SOKIC MILUTINOVIC Aleksandra1,
MILOSAVLJEVIC Tomica1
1Clinic for Gastroenterology and Hepatology, Clinical Centre of Serbia, School of Medicine, University of Belgrade, (SERBIA)
Emails: lukic.snezana@gmail.com, drendo@eunet.rs, asokicmilutinovic@gmail.com, tommilos@hotmail.com

Dyspepsia and Irritable bowel syndrome (IBS) are the most common functional gastrointestinal
disorders in Serbian population. According to data from Endoscopic unit of the Clinic of
Gastroenterology and Hepatology of Belgrade prevalence of dyspepsia in patients under the age of
45 years is 22%, and of patient aged 45 years or 14% [1]. Since dyspepsia occurs more frequently in
the working population, the costs of testing and treatment of these patients are very high. Fig. 1

Fig. 1. Age distribution of the functional dyspepsia

In cross-sectional study in general population data were collected using a CATI (Computer-
assisted telephone interviewing). The study involved 3041 respondents aged over 18 years, 1464 men
and 1577 women. The gastric problems had 34.7% of respondents, 29.9% of men and 39% of women.
The most of them, 58.1% had heartburn, 44.6% had the bloating, while the pain and burning in the
stomach were reported in 40.7% of respondents. In 50% of the cases, the respondents considered that
the symptoms are due to aggravation, while 29.9% believe that alcohol drinks such as coffee and soft
drinks are responsible, 27.9% think that fast foods trigger their symptom [2]. In prospective study in
students’ population, frequency of dyspeptic complaints was higher in students than in general
population. Female students reported more symptoms than males. Stressful situations and unhealthy
dietary habits are recognized by students as the most probable cause of dyspepsia [3]. Dyspepsia- The
National Guidelines for GPs was written in 2004. According to the guidelines endoscopy should not
be performed before 55 years except in case of alarm symptoms. Treatment strategy for patients with
dyspepsia is based on the use of H2 blockers or PPI for 4 weeks. If the symptoms persist, the patient
should be tested for H. pylori [4]. Accurate data of the prevalence of IBS in the Serbian population
are not known. The Association of Serbian Gastroenterologists is part of a major EU project called
HELP EU in IBS, in addition to national associated Netherlands, Germany, Bosnia and Herzegovina,
Malta, Norway [5].

Keywords: dyspepsia, irritable bowel syndrome, project, the national guidelines

REFERENCES
1. Milosavljevic, T. (2000). Functional dyspepsia. Arch Gastroenterohepatol 19(1-2), pp 40- 45.

29
2. Milosavljevic, T. (2017). Gastroduodenal symptom in general population. Serbian Archive of Medicine (in
press).
3. Jevtovic, J. (2017). Frequency and characteristics of dyspepsia in student’s population: results from a prospective
observational study in Serbia. Vojnosanit Pregl (in press).
4. Milosavljevic, T. (2004). Dyspepsia- the National guidelines.
5. UEG LINK award project HELP EU IN IBS.

30
Esophageal motility disorders

31
High-resolution Esophageal Manometry is Superior to Conventional
Manometry in the Diagnosis of Patients with Non-Obstructive
Dysphagia and Especially Achalasia
BANCILA Ion, DIMITRIU Anca, COTRUTA Bogdan,
GHEORGHE Cristian
Fundeni Clinical Institute, Center of Gastroenterology and Hepatology (ROMANIA)
Emails: ibancila@yahoo.com, ancaborca@yahoo.com, bogdancotruta@gmail.com, drgheorghe@xnet.ro

Abstract

Conventional manometry (CM) was introduced decades ago to diagnose esophageal motility
disorders, being an inexpensive, easy to perform and accurate diagnostic procedure. Recently, high-
resolution manometry (HRM) was developed, making the procedure shorter, easier to perform and
more accurate in comparison to CM. Although HRM tends to gradually replace CM, the two
procedures were not frequently directly compared. We aimed to compare the diagnoses established
by the two manometric methods in two age- and gender-matched groups, the hypothesis being that
HRM might be superior to CM due to the more closely spaced pressure sensors and the better
identification of the lower esophageal sphincter (LES). Our results showed that HRM is superior to
CM in the diagnosis of achalasia and has a superior diagnostic yield of esophageal motility disorders.
Keywords: esophageal manometry, high-resolution manometry, esophageal motility disorders, achalasia

Introduction

Conventional manometry (CM) was a breakthrough in the diagnosis of esophageal motility

disorders several decades ago, being the gold standard in the evaluation of these conditions [1].
Unfortunately, due to the standard 5 cm distance between pressure ports and difficulty in
identifying the lower esophageal sphincter (LES) in some patients, CM failed to find abnormalities
in a significant percentage of subjects. High-resolution manometry (HRM) was recently developed
and is nowadays considered the gold standard in diagnosing esophageal motility disorders.
In comparison to CM, HRM is easier to perform, has better intra- and interobserver agreement, is
more sensitive and accurate [2, 3] but its higher costs limit for the moment its use on a large scale.
Due to more closely spaced pressure sensors (1 cm apart), extrapolation of pressure data is
possible.
Adding colour plotting to pressure data, a continuum of pressure changes through the whole
esophagus and upper and lower esophageal sphincters can be created, providing an easier to interpret
image of esophageal function [4]. HRM may be performed using water-perfused or solid-state
catheters.

Objectives

The aim of our study was to compare the diagnostic yield of CM and HRM by comparing two
age and gender-matched groups.

32
Materials and methods

We compared two cohorts of patients, the first examined by CM during a period of five years
(2005-2010) (CM group) and the second by HRM during a period of one year (March 2016 – February
2017) (HRM group). CM was performed using the Medtronic (Polygram Net™, Medtronic
Functional Diagnostics SAS, Skovlunde, Denmark) manometry system and a 4-lumen, water-
perfused catheter was used. The 4.5 mm diameter catheter has 4 side holes at 0, 5, 10 and 15cm from
the tip. Each channel was connected to an external pressure transducer and the system was perfused
continuously at a flow rate of 0.5mL/min. The catheter was introduced transnasally in the stomach
with the patient in the upright position. Then the patient was put in the supine position and the catheter
withdrawn in 1cm increments by the station pull-through technique. Intragastric pressure was used
as the zero reference-point for all pressure measurements. The mean LES pressures were assessed by
the station pull-through technique. Each patient received 9 liquid sips of 5mL each for measuring of
LES residual pressures (3 swallows for each of 3 ports) and additional 10 sips at least 30 sec. apart
for the assessment of esophageal body peristalsis. The CM pressure data were interpreted using the
Castell and Spechler classification of esophageal motor disorders [5]. The HRM examinations were
performed using the Sandhill Scientific (Highlands Ranch, USA) equipment and the Unisensor solid-
state catheter. The HRM studies consist of 2 phases: analysis during rest and during swallows. Before
administering ten 5mL water swallows, a “resting” landmark recording was measured during an
episode in which the patient did not swallow and breathed normally. In this landmark episode,
markers for the level of the UES, the upper and lower border of the LES and the stomach were placed.
HRM pressure data were interpreted using the Chicago classification version 3.0 [6].
The qualitative variables were compared using chi square test, considering a level of statistical
significance for p<0,05.

Results

CM group
During the five years period (2005-2010) 223 consecutive patients underwent CM. 191 of them
complained of non-obstructive dysphagia as main or secondary symptom. The gender ratio was
slightly in favor of male patients (f/m 90/101) and the mean age was 51,3 years (range 20-85).
The most frequently encountered diagnosis was achalasia (121 pts; 65.4%). 22 patients had
ineffective esophageal motility (IEM). 8 patients were diagnosed with nonspecific motility disorders.
2 patients had distal esophageal spasm (DES) and 1 had lower esophageal sphincter (LES)
hypotonia.
17.1% of patients had normal manometric tracings. 4 patients (1.4%) had secondary esophageal
motility disorders (2 scleroderma, 1 Raynaud syndrome and 1 pseudoachalasia).

70
65,4%
60

50 Achalasia
IEM
40
NMD
30 DES
SMD
20
17,1% Normal
9,8%
10

0
% 5,4 0,9 1,4

Fig. 1. Diagnoses of motility disorders in the CM group

HRM group
During the period March 2016 – February 2017, 57 consecutive patients underwent HRM. Of the
57 patients, 48 complained of dysphagia. The gender ratio was 1 and the mean age was 54,7 years
(range 18-80). Of the 48 patients, 36 (75%) were diagnosed with achalasia. 2 patients had

33
esophagogastric junction outflow obstruction (EGJOO), 2 had IEM, 1 had jackhammer esophagus
(JHE) and 1 had DES. 1 patient was diagnosed with jackhammer esophagus concomitant with features
of DES. 5 patients (10,4%) were considered normal, including one patient with isolated LES
hypotonia and 1 with isolated LES hypertonia, abnormalities which are not included in the Chicago
classification. In the achalasia group, type 2 was the most frequently encountered (23 pts; 63,8%),
type 1 in 12 patients (33.3%) and type 3 in only one case (2.9%).
2.1% 10.4%

4.1% Achalasia
4.1% EGJOO
IEM
JHE
75% DES
JHE+DES
Normal

Fig. 2. Diagnoses of esophageal motility disorders in the HRM group

Comparison HRM and CM groups

The two groups were matched regarding demographic data such as gender and age. Achalasia was
significantly more frequent diagnosed in the HRM group (75% vs 65,4%; p<0.05), as well as DES
(2,1% vs 0,9%; p<0.05). In contrast, IEM (9,8% vs 4,1%; p<0.05) and normal manometric tracings
(17,1% vs 10,4%; p<0.05) were more frequently diagnosed in the CM group.

Variable HRM Conventional p-value

manometry

Total no pts/ 57/48 223/191

dysphagia pts
Gender ratio (F/M) 24/24 90/101 NS

Mean age (y) 54.7 51.3 NS

Achalasia (%) 75 65.4 < 0.05

Normal (%) 10.4 17.1 < 0.05

IEM (%) 4.1 9.8 < 0.05

DES (%) 2.1 0.9 < 0.05

Table 1. Comparison between the HRM and CM groups

Discussion

The findings of our study suggest that esophageal motility disorders, especially achalasia, are more
frequently diagnosed using HRM than CM. The results are in agreement with those found by Roman
et al. [7], which also found a higher rate of achalasia cases with HRM and a lower number of normal
manometry studies with HRM. The higher rate of achalasia diagnosed by HRM may be explained by
the better identification of hiatal hernias and of the LES with HRM, this being a well-known
disadvantage of the CM procedure (upward shifting of LES during swallowing and consequent
displacement of the catheter from the high-pressure zone).
In our study IEM was more frequently diagnosed in the CM group. A possible explanation for this
situation may be the lack of synergy between the two classifications, i.e. the higher threshold (≥5/10
swallows with DCI <450 mm Hg x cm x sec) for the diagnosis of IEM in the Chicago classification
compared to the one used in the Castell and Spechler classification for CM (≥3/10 swallows with low
amplitude or non-transmitted contractions). Another explanation may be the relatively low number
of patients included in the HRM group.
Although HRM seems to be superior to CM, HRM has inherent limitations, an important one being
the fact that each HRM system has its own normative values. Moreover, thus far, despite offering

34
more insight on esophageal motility, HRM does not provide a better explanation for non-obstructive
dysphagia. Lastly, the HRM equipment is more expensive than that of CM.
Although continuously improved, the Chicago classification has also limitations, a number of
abnormalities or diagnoses not being incorporated in the Chicago classification, such as LES and UES
abnormalities and post-surgical problems. A previous study proved that up to 32% of the patients
undergoing HRM had abnormalities that were not described in the Chicago classification [8]. In our
study, we also identified two patients with isolated resting LES abnormalities, hypotensive and
hypertensive LES respectively, which we considered normal according to the Chicago classification.
In conclusion, our study showed that esophageal motility disorders in general and achalasia in
particular can be diagnosed more frequently with HRM than with CM. Due to this and to the higher
inter- and intraobserver agreement HRM should be recommended over and should gradually replace
CM in patients with non-obstructive dysphagia. Moreover, the Chicago classification, being an
ongoing process, will surely broaden in the future and encompass more situations of esophageal motor
disturbances.

REFERENCES

1. Butin JW, Olsen AM, Moersch HJ, Code CF. A study of esophageal pressures in normal persons and patients
with cardiospasm. Gastroenterology 1953; 23:278-293.
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Curr Opin Gastroenterol 2010; 26:344-351.
3. Dustin A Carlson, Karthik Ravi, Peter J Kahrilas et al. Diagnosis of Esophageal Motility Disorders: Esophageal
Pressure Topography vs. Conventional Line Tracing. Am J Gastroenterol 2015; 110: 967 – 77.
4. Clouse RE, Staiano A, Alrakawi A, Haroian L. Application of topographical methods to clinical esophageal
manometry. Am J Gastroenterol 2000; 95:2720-2730.
5. Spechler SJ, Castell DO. Classification of oesophageal motility abnormalities. Gut 2001; 49: 145 – 51.
6. International High-Resolution Manometry Working Group. The Chicago Classification of Esophageal Motility
Disorders, v3.0Neurogastroenterol Motil. 2015 February; 27(2): 160–174. doi:10.1111/nmo.12477.
7. Roman S, Huot L, Zerbib F, et al. High-Resolution Manometry Improves the Diagnosis of Esophageal Motility
Disorders in Patients With Dysphagia: A Randomized Multicenter Study. Am J Gastroenterol 2016; 111:372–
380; doi: 10.1038/ajg.2016.1.
8. Wang YT, Yazaki E, Sifrim D. High-resolution manometry: esophageal disorders not addressed by the “Chicago
classification”. J Neurogastroenterol Motil 2012; 18:365-372.

35
Correlations between Symptoms and High- Resolution Manometry
Metrics in Different Types of Achalasia

BANCILA Ion, DIMITRIU Anca, GHEORGHE Cristian

Fundeni Clinical Institute, Center of Gastroenterology and Hepatology, (ROMANIA)
Emails: ibancila@yahoo.com, ancaborca@yahoo.com, drgheorghe@xnet.ro

Abstract

Achalasia cardia is a rare motility disorder with a gradual onset of varied and subtle symptoms.
Dysphagia, regurgitation, retrosternal pain and weight loss are the cardinal symptoms, with
retrosternal pain being more frequent in younger patients. The advent of high-resolution manometry
(HRM) greatly improved the diagnostic yield for achalasia and has allowed its classification into three
subtypes. The aim of our study was to analyse correlations between symptoms and HRM pressure
data in the three subtypes of achalasia. Our results showed that dysphagia, retrosternal pain, the
integrated relaxation pressure (IRP) and distal esophageal pressure (DEP) changes were all greater in
achalasia type II compared to achalasia type I. When analysing the whole group of achalasia patients
we found significant correlations between IRP and the dysphagia, regurgitation and pain subscores,
but not with the total Eckardt score. In both achalasia types I and II, IRP correlated with retrosternal
pain, but not with dysphagia, regurgitation or weight loss. Based on our findings the subtypes of
achalasia cannot be differentiated based on symptoms alone.
Keywords: high-resolution esophageal manometry, achalasia, achalasia subtypes, dysphagia, chest pain

Introduction

Achalasia is a rare motor disorder of the esophagus characterized by absence of peristalsis and
incomplete or absent lower esophageal sphincter (LES) relaxation, with an incidence of ~1/100.000
per year. Although its etiology is unknown, the pathogenesis of the disease is due to the destruction
of the inhibitory nitrergic neurons [1, 2]. Patients present with dysphagia for both solid food and
liquids, while regurgitation of undigested food, non-cardiac chest pain, respiratory symptoms
(nocturnal cough, aspiration) and weight loss can also be present later in the course of the disease.
Esophageal manometry is the gold standard in the diagnosis of achalasia, especially early in the
course of the disease, when radiology and endoscopy may not elicit any abnormalities [3].
High-resolution manometry (HRM) has been shown to be superior to conventional manometry in
diagnosing achalasia [4] and allows the subtyping of achalasia [5]. Being a very heterogeneous
condition with insidious onset and gradual progress, outside of gastroenterology referral centers
patients with achalasia are frequently misdiagnosed with gastro-esophageal reflux disease based on
symptoms. A previous report showed that the mean duration of symptoms prior to diagnosis was 4.7
years in patients with newly diagnosed achalasia [6]. The delay in diagnosis may modify the symptom
type and severity, making regurgitation and microaspiration due to increased esophageal diameter
and heartburn secondary to stasis and fermentation of food the main symptoms. It is not clear whether
there is a correlation between the HRM metrics and symptoms. If such a correlation is present, HRM
may be useful for assessing the severity of achalasia symptoms. Therefore, our study analyzes the
correlation between HRM metrics and clinical symptoms in the different types of achalasia and
compares the achalasia subtypes in terms of symptoms and manometric data.

36
Aims
The aim of our study was to compare the three subtypes of achalasia based on demographic data,
symptoms and HRM metrics. Also, we aimed to find possible correlations between symptoms and
HRM metrics.

Materials and methods

We conducted a retrospective study on adult patients with achalasia diagnosed by HRM in a period
of 6 months. The baseline evaluation consisted of demographic characteristics, esophageal symptom
scores and the total Eckardt symptom score, and HRM data.
We included 24 adult patients diagnosed with achalasia based on HRM. For the diagnosis and
classification of achalasia we used the Chicago Classification Criteria, version 3.0. HRM was
performed in the supine position using the 4mm diameter Unisensor solid state catheter with 32
pressure sensors and 6 impedance ring pairs, introduced transnasally. The manometric protocol
included a 30 seconds baseline recording and 10 swallows of 5 ml saline solution. The HRM results
were analyzed using the Bioview™ analysis software (Sandhill Scientific). Achalasia was diagnosed
when the integrated relaxation pressure (IRP) was at least 15 mm Hg and there was no peristalsis of
the smooth muscle of the esophagus. According to the Chicago Classification criteria and based on
esophageal body peristalsis, achalasia was divided into three subtypes: type I, 100% failure of
peristalsis and no esophageal pressurization; type II, no normal peristalsis and ≥20% swallowing with
panesophageal pressurization; type III, no normal peristalsis and ≥20% swallowing with preserved
spastic contractions. For symptom evaluation at diagnosis we used the Eckardt score [7], which takes
into consideration dysphagia, regurgitation and retrosternal pain based on the frequency of occurence
(0 – none; 1 – occasional; 2 – daily; 3 – at every meal) and also quantifies weight loss (0 – none; 1 –
<5 kg; 2 – 5-10 kg; 3 - >10 kg). The scores of the variables are summed up to make a total score that
ranges from 0 to 12 points. The following variable pressure metrics were analysed: integrated
relaxation pressure (IRP; mm Hg), LES resting pressure (LESP; mm Hg), LES length (LESL; cm),
distal esophageal pressure (DEP; mm Hg).
The statistical analysis was performed using the SPSS software. Data are presented as mean ±
standard deviation. Differences in the HRM metrics and symptom scores between groups were
analyzed using the one-way analysis of variance. Relationships between the HRM metrics and
symptom scores were assessed using Pearson’s correlation coefficient analysis. A two-tailed p value
of 0.05 was considered to indicate statistical significance in all cases.

Results

24 patients were retrospectively enrolled and divided into the 3 achalasia subtypes according to
HRM findings: 9 patients with type I, 14 patients with type II, and only 1 patient with type III. Having
only one case of achalasia type III we decided to exclude this patient from the analysis, so we further
compared only patients with achalasia types I and II. There was no statistical difference regarding
gender, age at diagnosis (around 50 years of age) and symptom duration until diagnosis (around 22
months) between the patients with achalasia type I and II (Fig. 1).

Fig. 1. Demographic characteristics and symptom duration

37
 Regarding the symptoms, although dysphagia (3±0,4 vs 2,2±0,36; p = 0,016) and pain (0,75±0,8
vs 0,2±0,3; p = 0,02) were more severe in achalasia type II, there were no significant differences
regarding the regurgitation, weight loss and total Eckardt scores between the two types (Fig. 2).

Fig. 2. Symptom severity and total Eckardt scores

Taking into account the manometric data, we found significant differences between the two
achalasia types concerning mean IRP (38,57 vs 23,55 mm Hg; p = 0,011) and distal pressure values
(34,21 vs 15,88 mm Hg; p = 0,03), which were both greater in type II achalasia (Fig. 3).

DEP (mmHg)
*

LESL (cm)

Type II
Type I
LESP (mmHg)

IRP (mmHg)
*

0 10 20 30 40 50

* p < 0.05

Fig. 3. HRM data

The demographic data, symptom severity and Eckardt scores as well as the HRM data are
comparatively shown in Table 1.

Table 1. Comparative demographic data, symptom score and manometric data

We found that only IRP was positively correlated with the dysphagia, pain and regurgitation scores
for all the patients with achalasia, and also with the pain score in both achalasia subtypes. When
separately analysed, in achalasia type I and II we found no correlation between IRP and dysphagia,
regurgitation or weight loss. LESP, LESL and DEP showed no correlation with symptoms (Table 2).

38
 Table 2. Correlations between symptoms and HRM metrics

Discussion

The generation of esophageal symptoms during swallowing is a multifactorial phenomenon.

Although the pathway of the esophageal perception has been linked to mechanical and chemical
receptors in the esophageal wall, vagal and spinal nerves, and the cerebral cortex, the determinants
of perception of discomfort in the esophagus are not yet known. Previous studies have failed to find
correlations between symptoms and esophageal motor patterns [8, 9].
Achalasia is a disease with many atypical and subtle symptoms, both initially and over time, which
may delay the diagnosis. In our study, the mean duration of symptoms till diagnosis was 22 months,
showing that the diagnosis is frequently delayed due to the gradual onset of symptoms, the low
suspicion index and the misinterpretation of achalasia symptoms as gastro-esophageal reflux disease
due to regurgitation and heartburn secondary to intraesophageal fermentation of food. A recent report
showed that on average it took about 25 months until the confirmation of a diagnosis ofachalasia [10].
Although the pathophysiologic consequences of achalasia are the insufficient relaxation of the
LES with swallowing and absence of esophageal body peristalsis, the former one seems to be the
main generator of symptoms. Therefore, one would expect to find correlations between esophago-
gastric junction metrics, i.e. IRP and symptoms. In this study, we found that for all the achalasia
cases, IRP was positively correlated with the dysphagia, regurgitation and chest pain scores, but not
with the total Eckardt score. Also, IRP correlated with the chest pain scores in both type I and type II
achalasia. Chest pain is a common symptom of achalasia and predominantly affects younger patients
[11].
Similar to our findings, a study on Chinese patients with achalasia showed that IRP was positively
correlated with the Eckardt scores in achalasia patients [12]. Thus, this proves the relevance of IRP
as an important diagnostic metric in achalasia, but our findings cannot support the assumption that
the value of IRP is associated with the severity of the disease.
An older study, in which manometry was performed using the conventional technique, found on a
cohort of 115 patients that, among the main symptoms, active and passive regurgitation showed
significant correlation with LES relaxation pressure when compared to other individual symptoms
[13].
These findings indicate that the main pathophysiologic generator of symptoms in achalasia seems
to be the incomplete relaxation of the LES and that normalization of the IRP on HRM is a clinically
relevant objective of treatment for achalasia.
We did not find any correlation of LESP, LESL and DEP with the symptoms of achalasia or the
total Eckardt score. These findings are somewhat expected. In achalasia, the main pathophysiologic
mechanism at the level of the LES is the inability to relax, not the increased resting pressure. LES
resting pressure is usually normal in achalasia patients, only about 31% of patients having a
hypertensive LES [14]. Also, in the study of Agrawal et al., elevated DEP was noted in only 61.6%
of achalasia patients [14]. In type I and type II achalasia DEP is actually the result of the pressure

39
exerted by the retained intraesophageal fluid, therefore it was somehow expected that we did not find
correlations of this metric with symptoms. Similar to our findings, the study by Yurong et al. also
failed to find any correlation between LESP, LESL, DEP and symptoms [12].
In our study dysphagia and chest pain, as well as IRP and DEP were significantly greater in
achalasia type II compared to achalasia type I. Another study which compared the symptoms and
HRM metrics of the two subtypes failed to find significant differences [12]. This finding may be due
to the small patient samples and further studies on larger patient cohorts are needed to confirm this
result. On the other hand, we may hypothesize that the two achalasia subtypes may be different
evolutionary stages of the disease and not two separate types, thus explaining the differences in
symptoms and HRM metrics.
Our study has two main drawbacks. The first one is the retrospective nature of the study. Secondly,
the small number of patients and the unequal group distribution in the two achalasia subtypes (9 in
type I, 14 in type II). A larger patient sample and a prospective study are necessary for more accurate
and meaningful data.
In conclusion, in this study we found that (a) the dysphagia and chest pain scores, as well as IRP
and DEP, were greater in type II achalasia compared to type I, (b) IRP was positively correlated with
the Eckardt subscores for dysphagia, regurgitation and chest pain in the whole group of achalasia
patients, (c) IRP was positively correlated with chest pain in the achalasia subtypes I and II.

REFERENCES

1. Park W, Vaezi MF: Etiology and pathogenesis of achalasia: the current understanding. Am J Gastroenterol 2005;
100:1404-1414.
2. Castell DO: The spectrum of esophageal motility disorders. Gastroenterology 1979; 76:639-640.
3. Howard PJ, Maher L, Pryde A, et al.: Five-year prospective study of the incidence, clinical features and diagnosis
of achalasia in Edinburgh. Gut 1992; 33(8):1011-1015.
4. Roman S, Huot L, Zerbib F, et al. High-Resolution Manometry Improves the Diagnosis of Esophageal Motility
Disorders in Patients With Dysphagia: A Randomized Multicenter Study. Am J Gastroenterol 2016; 111:372–
380; doi: 10.1038/ajg.2016.1.
5. Kahrilas PJ, Ghosh SK, Pandolfino JE. Esophageal motility disorders in terms of pressure topography: the
Chicago Classification J Clin Gastroenterol. 2008 May-Jun;42(5):627-35. doi: 0.1097/MCG.0b013e31815ea291.
6. Eckardt VF, Kohne U, Junginger T, Westermeier T. Risk factors for diagnostic delay in achalasia. Dig Dis Sci
1997; 42:580-585.
7. Eckardt VF. Clinical presentations and complications of achalasia. Gastrointest Endosc Clin N Am 2001; 11:281-
292.
8. Lazarescu A, Karamanolis G, Aprile L et al. Perception of dysphagia: lack of correlation with objective
measurements of esophageal function. Neurogastroenterol Motil 2010; 22: 1292 – 7.
9. Xiao Z, Kahrilas PJ, Nicodeme F, et al. Lack of correlation between HRM metrics and symptoms during the
manometric protocol. Am J Gastroenterol 2014;109(4): 521-6.
10. Niebisch S, Hadzijusufovic E, Mehdorn M et al. Achalasia-an unnecessary long way to diagnosis Dis Esophagus.
2017 May 1;30(5):1-6.
11. Eckardt VF, Stauf B, Bernhard G et al. Chest pain in achalasia: patient characteristics and clinical course.
Gastroenterology. 1999 Jun;116(6):1300-4.
12. Yurong T, Chen X, Meifeng W, et al. Association of High-Resolution Manometry Metrics with the Symptoms
of Achalasia and the Symptomatic Outcomes of Peroral Esophageal Myotomy. PLOS ONE. DOI:
10.1371/journal.pone.0139385 September 30, 2015.
13. Yaghoobi M, Mikaeli J, Montazeri G et al. Am J Gastroenterol. 2003 Feb;98(2):278-83. Correlation between
clinical severity score and the lower esophageal sphincter relaxation pressure in idiopathic achalasia.
14. Agrawal A, Hila A, Tutuian R et al. Manometry and impedance characteristics of achalasia. Facts and myths. J
Clin Gastroenterol. 2008 Mar;42(3):266-70. doi: 10.1097/01.mcg.0000248013.78020.b4.

40
High-resolution Esophageal Manometry: Gold Standard for
Achalasia?

HERZIG Marcus1,2, CAPRARU Sandra Maria2, TUTUIAN Radu2

1Magendarmpraxis, Spital Münsingen – Inselgruppe AG, Krankenhausweg, 3010 Münsingen, (SWITZERLAND)
2Clinic for Gastroenterology, Spital Tiefenau – Inselgruppe AG, Tiefenaustrasse 112, 3004 Bern, (SWITZERLAND)
Emails: macus.herzig@insel.ch, sandra-maria.capraru@spitaltiefenau.ch, radu.tutuian@insel.ch

Abstract

Achalasia is a primary esophageal motor disease defined by aperistalsis of the tubular esophagus
in combination with impaired relaxation of the lower esophageal sphincter (LES). These changes
occur secondary to the destruction of the esophageal plexus myentericus coordinating esophageal
peristalsis and LES relaxation.
This paper reviews the use of high resolution esophageal manometry in establishing the diagnosis
of achalasia and its impact on decision making for the optimal treatment.
Keywords: Achalasia, High resolution esophageal manometry, Pneumatic dilatation, Laparscopic Heller’s myotomy

Introduction

Achalasia is a rare primary neurodegenerative motility disorder of the esophagus characterized by

esophageal aperistalsis and insufficient relaxation of the lower esophageal sphincter caused by
degeneration of the myenteric plexus. The annual incidence approximates with geographic variation
1 in 100000 persons and the prevalence is 10 in 10’000 [1]. The etiology remains poorly understood
and a multifactorial origin is suspected. Approximately 2-4% of patients with suspected achalasia are
found to have pseudoachalasia or Chagas disease. In these patients, the degeneration of the myenteric
plexus is due to neoplastic infiltration or infection with Trypanosoma cruzi [2].
The diagnostic workup of patients with dysphagia suspected to have achalasia includes an
esophagogastroduodenoscopy to rule out eosinophilic esophagitis, reflux disease, malignancy or
stenosis of the esogastric-junction (EGJ)/at the level of the lower esophageal sphincter (LES).
In patients with normal endoscopy (and histology) the next step is a barium esophagogram.
Patients with achalasia typically have a dilatation of the esophagus with a smooth tapering at the
level of the esophago-gastric junction (i.e. the “bird’s beak” appearance) and – in advanced disease –
the enlargement of the tubular esophagus can reach considerable sizes up to the level of a
“megaesophagus”. Esophageal manometry is considered the “gold standard” to diagnose achalasia
by documenting esophageal aperistalsis (condition sine qua non), poorly relaxing LES (often seen)
and hypertensive LES (can be present) [3]. In recent years, high resolution esophageal manometry
(HRM) has replaced conventional manometry in evaluating patients with non-obstructive dysphagia.
Furthermore, with respect to achalasia, HRM allows a subclassification into three subtypes which
respond different to therapies. In this review, we discuss the diagnostic modalities with an emphasis
on high resolution esophageal manometry and briefly review the treatment modalities of achalasia.

Clinical presentation of patients with achalasia

The typical symptom of achalasia is slowly progressive dysphagia for both solid and liquid foods
(79%-100%). Patients may also present with regurgitation (63%), heartburn (41%), non-cardiac chest
pain (22%), epigastric pain (15%) and odynophagia (<5%). Respiratory symptoms (cough (37%),

41
aspiration (31%), hoarseness (21%), wheezing (16%), sore throat (12%), dyspnea (10%) and weight
loss (10%) are less common symptoms in patients suffering of achalasia [4], [5].
Due to mainly non-specific symptoms, the slow progression and rarity of the disease, the diagnosis
is frequently delayed until 4-5 years [6].
The Eckardt score which includes the frequency of dysphagia, regurgitation, chest pain and weight
loss is a useful clinical tool in assessing the response to treatment but not in confirming the diagnosis
[7].
Therefore, further investigations are needed to confirm the diagnosis of achalasia. In absence of
pseudoachalasia high resolution manometry is considered the gold standard in diagnosing achalasia.

High resolution esophageal manometry (HRM)

High resolution manometry (HRM) is a catheter based method to record pressure data in the
esophagus from closely spaced pressure transducers. Data recording from HRM catheters are
displayed as esophageal pressure topography (EPT) charts (Figure 1). The key element of esophageal
manometry is the manometric catheter, a 5-6 mm PVC or silicon tube with pressure transducers
placed at predefined intervals. Esophageal manometry catheters are placed trans nasally trough the
esophagus into the stomach and then slowly pulled back (station pull-through technique) to localize
the lower esophageal sphincter (LES). Following the localization of the proximal and distal border of
the LES, the catheter provides pressure data from the pharynx, upper esophageal sphincter (UES),
esophageal body, lower esophageal sphincter and proximal part of the gastric cardia. A standard
protocol includes 10 liquid swallows of 5ml water in an interval of 20-30 seconds apart in order to
avoid deglutitive inhibition. The analysis of the recorded data follows the algorithm published in the
Chicago Classification V 3.0 by assessing the esophagogastric junction integrated relaxation pressure
(IRP), esophageal contractility and characterizing pressurization pattern [8].

Advantages and shortcomings of HRM to diagnose achalasia

In conventional esophageal manometry (CEM) absence of peristalsis of 100% of swallows in the

distal two thirds of the esophagus in conjunction with incomplete relaxation of the LES on deglutition
with absence of a structural abnormality of the esophagus establishes the diagnosis of achalasia.
Substantial variability in the peristaltic abnormalities and esophageal pressure dynamics found in
achalasia making these criteria less straightforward than they seem at first glance. As aperistalsis is
seen in 100%, poorly relaxing LES (63%) and hypertensive LES (32%) are less common, all 3 criteria
in conjunction are found in 23% only. [3].
The Chicago Classification v3.0, distinguishes three subtypes of achalasia, a sub-classification that
has both prognostic and therapeutic implications (Figure 2, Figure 3) [9]. According to treatment
outcomes, patients with type II (with pan-esophageal pressurization) achalasia and patients with type
I achalasia (classic achalasia with absent peristalsis) respond better to treatment than patients with
type III (spastic achalasia) [10]. Furthermore, while patients with type I and type II achalasia respond
equally good to pneumatic dilatation and laparoscopic Heller’s myotomy, patients with type III
achalasia respond better to laparoscopic myotomy compared to pneumatic dilatation [11]. Hence, the
classification system proposed by the Chicago group that divides achalasia in three different subtypes
helps guide therapy in these patients.
High-resolution manometry has also its limitations in diagnosing achalasia. The Chicago v3.0
classification system requires the presence of an impaired relaxation of the EGJ to diagnose achalasia
(i.e. elevated residual pressure at the level of the EGJ – integrated residual pressure (IRP4s) greater
than the upper limit of normal). Recently, Ponds et al. investigated 13 patients with typical clinical
and radiological findings of achalasia but normal relaxation of the EGJ by HRM (i.e. normal IRP4s).
When investigating the distensibility of the EGJ by means of endoscopically placed functional
luminal imaging probe (EndoFlip®) they found a reduced distensibility of the EGJ compared to a set

42
of normal volunteers [12]. Following treatment, the distensibility of the EGJ improved in this patients
to levels similar to treated patients with achalasia and initially elevated IRP4s. This study highlights
a limitation of HRM in diagnosing achalasia, underscoring the idea that HRM measures only
relaxation but not the distensibility of the EGJ.

Treatment of achalasia

A curative treatment for achalasia does not exist. Thus, the goals of treatment are to minimize
symptoms and improve quality of life. Most treatments aim to decrease the obstruction caused by the
poorly relaxing lower esophageal sphincter. Pharmacologic reduction in LES pressure with oral
calcium blockers, nitrates and 5-Phosphodiesterase inhibitors cause a reduction in LES pressure but
only with limited benefit for dysphagia and side effects are common and are therefore of minor value
[13].
Injections of Botulinum toxin into the LES have a clinical response in 80% of patients with a low
risk of perforation but repeated treatment is necessary in 60% of subjects after one year.
Therefore, Botulinum toxin injections are reserved for people not able or willing to undergo a more
invasive treatment [14].
The success rates of pneumatic dilation (PD) and laparoscopic Heller myotomy (LHM) are
comparable in achalasia. PD is easy to perform, has a short procedural time and can be done in an
outpatient setting while LHM has a mean hospital stay of 3-5 days. The complication rates are up to
5% for PD (perforations) and up to 11% for LHM (mucosal tears). Success rates are similar reaching
92% for both techniques [15].
Per oral endoscopic myotomy (POEM) is a novel endoscopic technique used in the treatment of
achalasia, originally developed as part of the concept of natural orifice transluminal endoscopic
surgery (NOTES) [16]. It is less invasive than surgical myotomy and aims to offer long lasting
symptom control. It consists of creating a submucosal tunnel in the distal esophagus by dissecting
along the muscular layer. After the EGJ is passed a minimal myotomy of the circular esophageal and
gastric muscles is performed. The mucosal entry site is then closed using endoclips. Inoue et al.
demonstrated in 500 consecutive patients after POEM an overall success rate of 91.3% after 2 months
(post-POEM Eckardt score <2 or reduction of more than 4 points from baseline) and 91% after 1 to
2 years. The complication rate was low at 3.2% [17]. The reduction of esophageal symptoms, acid
exposure and integrated LES pressure comparing POEM to Heller myotomy combined with partial
fundoplication is equal [18].
Esophagectomy is reserved for patients with end stage mega esophagus as “last resort” option.

Summary and Conclusions

Achalasia is a primary neurodegenerative disease of the esophagus with slow progressing

symptom which often lead to a delayed diagnosed. Among the investigations used in the work-up for
patients with symptoms of achalasia high resolution manometry (HRM) is currently the gold standard
for establishing the diagnosis. The most durable and effective therapeutic strategies aim at improving
the distensibility of the esophago-gastric junction. Currently available endoscopic and surgical
treatment options (pneumatic ballon dilatation, laparoscopic myotomy and more recently per-oral
endoscopic myotomy) should be regarded as equally effective in achieving sustained symptom
improvement. Regular follow-up of patients with achalasia is important in order to prevent
development of end-stage disease (i.e. megaesophagus) with the need for esophagectomy.

43
Figures:

Fig. 1. A. HRM recording of a normal swallow characterized by normotensive upper esophageal sphincter, peristaltic
progression of esophageal contraction and relaxation of the normotensive lower esophageal sphincter. HRM recording of
a swallow in patients with achalasia characteriyed by absent peristalsis, hypertensive LES with elevated residual pressure
of the lower esophageal sphincter and esophageal pressure greater than the abdominal pressure.

Fig. 2. Subtypes of achalasia: Type I – classic with absent peristalsis, Type II – with pressurisation and Type III – spastic

Subtype Pneumatic dilatation Myotomy

Achalasia Type I 85 81
Achalasia Type II 100 93
Achalasia Type III 40 86
Fig. 3. Success rate (%) following treatment of patients with different subtypes of achalasia, adapted from [10]

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1. Luján-Sanchis M et al. (2015). Management of primary achalasia: The role of endoscopy. World J Gastrointest
Endosc 7(6), pp. 593-605.
2. Kahrilas PJ et al. (1987). Comparison of pseudoachalasia and achalasia. Am. J. Med. 82(3), pp. 439-46.
3. Agrawal et al. (2008). Manometry and impedance characteristics of achalasia. Facts and myths.). J Clin
Gastroenterol 42(3):266-70.
4. Tsuboi K et al. (2012). Insights gained from symptom evaluation of esophageal motility disorders: a review of
4,215 patients. Digestion 85(3), pp. 236-42.
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6. Eckardt VF et al. (1997). Risk factors for diagnostic delay in achalasia. Dig. Dis. Sci 42(3), pp. 580-5.
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treatment--the surgeon’s viewpoint. Am Surg. 73(4), pp. 327-31.

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8. Kahrilas et al. (2015). The Chicago Classification of esophageal motility disorders, v3.0. Neurogastroenterol
Motil 27(2), pp. 160-74.
9. Ihara E et al. (2017). Diagnosis and Treatment Strategy of Achalasia Subtypes and Esophagogastric Junction
Outflow Obstruction Based on High-Resolution Manometry. Digestion 95(1), pp. 29–35.
10. Pandolfino JE et al. (2008). Achalasia: a new clinically relevant classification by high-resolution manometry.
Gastroenterology 135 (5), pp 1526-33.
11. Rohof WO et al. (2013). Outcomes of Treatment for Achalasia Depend on Manometric Subtype.
Gastroenterology. 144(4), pp. 718-25.
12. Ponds FA (2017). Esophagogastric junction distensibility identifies achalasia subgroup with manometrically
normal esophagogastric junction relaxation. Neurogastroenterol Motil 29(1), e12908.
13. Pandolfino JE et al. (2015). Achalasia: a systematic review. JAMA 313(18), pp. 1841-52.
14. Leyden JE et al. (2014). Endoscopic pneumatic dilation versus botulinum toxin injection in the management of
primary achalasia. Cochrane Database Syst. Rev.
15. Moonen A et al. (2016). Long-term results of the European achalasia trial: a multicentre randomised controlled
trial comparing pneumatic dilation versus laparoscopic Heller myotomy. Gut 65(5), pp. 732–739.
16. Grund KE et al. (2010). Transesophageal NOTES-a critical analysis of relevant problems. Minim Invasive Ther
Allied Technol. 19, pp. 252–256.
17. Inoue H et al. (2015). Per-Oral Endoscopic Myotomy: A Series of 500 Patients. J. Am. Coll. Surg 221(2), pp.
256-64.
18. Bhayani NH et al. (2014). A comparative study on comprehensive, objective outcomes of laparoscopic Heller
myotomy with per-oral endoscopic myotomy (POEM) for achalasia. Ann Surg. 259(6), pp. 1098-103.

45
Gastroesophageal reflux disease

46
Non-Cardiac Chest Pain and Gastroesophageal Reflux Disease
BARBOI Oana-Bogdana1, CIJEVSCHI-PRELIPCEAN Cristina1,2,
COBZEANU Dan1,3, FLORIA Mariana1,4, BALAN Gheorghe1,2, DRUG Vasile1,2
1 University of Medicine and Pharmacy “Grigore T. Popa” Iași, (ROMANIA)
2 Institute of Gastroenterology and Hapatology Iasi, (ROMANIA)
3 Department of Otorhinolaryngology of “Sf. Spiridon” Hospital (ROMANIA)
4 III Medical Clinic of “Sf. Spiridon” Hospital Iasi, (ROMANIA)

Emails: oany_leo@yahoo.com, cristinacijevschi@yahoo.com, cobzeanu_dan@yahoo.com, floriamariana@yahoo.com,

drbalanumfiasi@yahoo.com, vasidrug@email.com

Abstract
Non-cardiac chest pain (NCCP) is a complex and heterogeneous disease which is actually defined
as recurrent episodes of angina-like retrosternal chest pain that appears in the absence of cardiac
problems, especially ischemic heart disease. It has several known causes like musculo-skeletal,
pulmonary, psychiatric or gastro-intestinal. Of these, the majority of patients have an esophageal
source of NCCP. Gastroesophageal reflux disease (GERD) is the main underlying mechanism for
presumed esophageal origin of NCCP. The diagnosis and treatment of chest pain of GERD origin
remain challenging.
Keywords: non-cardiac chest pain, gastroesophageal reflux

Definition

Non-cardiac chest pain is a complex disease, whose definition has generated over time clinical
uncertainty. It had previously attributed to an extensive terminology from “soldiers’ heart”, “irritable
heart”, “sensitive heart” to “atypical chest pain”, “chest pain of undetermined origin”, “functional
chest pain”, “chest pain with normal coronary angiogram”, “unexplained chest pain”, “DaCosta’s
syndrome”, “X-cardiac syndrome” or “Gorlin-Likoff syndrome” (1, 3, 4). Nowadays, NCCP is
defined as recurrent episodes of angina-like retrosternal chest pain of non-cardiac origin (5).

Epidemiology

Non-cardiac chest pain is very common clinical condition in general population. It affects up to
25% of general population and though it is equally prevalent in both sexes, women have a higher
tendency to seek medical care, presenting with more severe symptoms (1, 5). NCCP can occur at any
age, from childhood to adulthood (1). Epidemiologic studies show that prevalence of NCCP is
decreasing as the population age is increasing. Patients with NCCP are younger, usually smokers and
drinkers and they associate anxiety (5, 6).
Although it affects about one quarter of the population, the mortality at 10 years is less than 1%,
but has a great impact on morbidity, generated in particular by the inability to work and the periods
of absenteeism from workplace, which reduce patients’ quality of life (7). NCCP also represents a
considerable economic burden to both patients and healthcare system because of the frequent visits
to the doctor and the great amount of material resources consumed for a correct diagnosis.
60-90% of patients that present to emergency departments with chest pain have no underlying
cardiovascular disease. Furthermore, over 30% of patients undergoing coronary angiogram for angina
like pain have normal cardiac findings. But despite these, many patients admit taking medication in
the absence of evidence for a cardiac cause (5, 7).

47
 A survey of primary care physicians (PCP) conducted by Wong et al. (8) showed that 79.5% of
patients presented with NCCP were diagnosed and treated by PCPs without being addressed to
another medical speciality. The most preferred subspecialty for initial diagnostic was cardiology
(62%), followed by gastroenterology (17%). As afterwards, for patients who needed further
management of NCCP, the favourite subspecialty was gastroenterology (76%), only 8% of patients
being ultimately referred to cardiology. These conclude that the most patients are managed by the
general practitioners rather than the gastroenterologists.

Etio-pathophysiology

Identifying the cause of NCCP continue to be very challenging in clinical practice. It is imperative
to exclude cardiac causes before pursuing non-cardiac causes, irrespective of the patients age. In order
to do that, a reasonable workup is needed. The clinician first priority is to exclude an acute life-
threatening cardiac condition like acute coronary syndrome, unstable angina, aortic dissection,
pulmonary thromboembolism or pericardial tamponade. After these have been ruled out, chronic
ischemic heart disease or pericardial disease must be excluded (9, 10).
In patients without cardiac disease, the most common causes of NCCP are musculo-skeletal,
psychological, pulmonary and gastro-intestinal: biliary, pancreatic, esophageal or gastric (5). Once
the cardiac, respiratory and chest wall causes have been excluded, esophagus remains the main source
of chest pain angina-like (60-80%). NCCP has several known causes of presumed esophageal origin,
like: gastroesophageal reflux disease, esophageal dysmotility or esophageal hypersensitivity.
Of these, by far the most common etiology of esophageal NCCP is GERD, occurring in
approximately 60% of cases (1, 5).
Epidemiological studies sustain the association between GERD and NCCP. The study of Hanizam
et al. (11) showed that about 67% of patients presenting with chest pain had an abnormal esophageal
acid exposure at ambulatory 24-hour pH monitoring. Moreover, the majority of them significantly
responded to proton pump inhibitor (PPI) therapy. Similar results were also reported by Asian trials,
GERD being diagnosed in 61.6% of chest pain patients (12). Typical GERD symptoms were found
to be significantly and independently associated with the presence of NCCP, studies showing that the
prevalence of NCCP among patients with frequent (> 1/week) typical symptoms of GERD is higher
(9, 13).
The pathophysiological mechanisms underlying chest pain of GERD substrate are not fully
elucidated. It remains unclear why esophageal exposure to refluxate in some patients determines
heartburn and in others chest pain. This is strengthened by the fact that some patients may experience
heartburn at one time and chest pain at other times (5). A possible explanation can be linked to the
duration of the sustained contractions of the longitudinal esophageal muscle as follows: a short
contraction causes heartburn, while NCCP follows a longer contraction (14).

Diagnosis

In the majority of cases it is difficult to discriminate between cardiac and esophageal origin of
chest pain based on clinical features, as the esophagus and the heart have the same innervation (vagus
nerve). Therefore, the diagnosis of NCCP of GERD substrate should be suggested by clinical
symptoms, but sustained by objective data obtained from paraclinical investigations (15-17).
The empirical trial therapy with PPI has been recently proposed as the initial diagnostic test for
GERD at NCCP patients (18, 19). Studies including patients with NCCP demonstrated the efficacy
and cost-effectiveness of double-dose PPI test in cases there is a clear evidence of GERD (typical
symptoms, esophagitis at upper gastroduodenal endoscopy or abnormal esophageal acid exposure at
pH metry) (20, 21). So, the PPI empirical trial is the first step of diagnose indicated in these patients,
with a sensitivity that ranges between 69-95% and a specificity of 67-86% (22, 23). But despite these
high values, the therapeutic test is still far from being considered perfect in the diagnosis of GERD

48
as a cause of NCCP, the more that are not clearly established the optimal dose and time of PPI
administration.
Upper gastroduodenal endoscopy has a limited value in establishing the diagnosis of pseudoangina
of presumed GERD origin. This is due to the low prevalence of the erosive esophagitis identified in
this category of patients, which has a very wide range of variation in the studies, between 2.5 to 75%
(21, 22, 24).
Esophageal manometry is not indicated as the initial diagnostic test for chest pain because of the
low specificity, but it can be useful to determine the correct position for the placement of pH
electrode. It is also the best tool for the detection of abnormal esophageal motor function, as 30% of
NCCP patients show alterations in esophageal motility (25, 26).
Ambulatory 24-hour esophageal pH monitoring is a helpful technique in patients with normal
endoscopy and in those unresponsive to an empirical PPI trial. Studies show that 28-62% of patients
with NCCP have increased esophageal acid exposure (13, 27). Using combined impedance-pH
monitoring can improve the diagnosis of NCCP of GERD origin up to 90%. Non-acid reflux may
also cause NCCP and the impedance-pH metry is the best option to assess the temporal relationship
between chest pain and reflux episodes (28, 29).

Treatment

The treatment addresses the cause that led to NCCP. The treatment of chest pain due to GERD is
a real challenge in the clinical practice. Of all therapeutical resources available for the management
of GERD, there is not clear evidence that life style modifications and diet are efficacy in the treatment
of NCCP-related GERD. Although, there is a general enthusiasm in recommended them (30).
Histamine-2 receptor antagonists proved effective in 42-52% of NCCP patients (30, 31), therefore
it is a therapy that is rarely recommended nowadays.
Most studies recommend double-dose PPI therapy until symptoms remission, followed by dose
tapering to the lowest dose that controls symptoms. It can take at least two months of PPI for an
optimal clinical response (32, 33). A meta-analysis that included 7 randomized trials showed an
improvement in symptoms with more than 50% after PPI (18) and a systematically review identified
a response rate after 3 months of PPI that varied between 75% and 92% (32).
Regarding the endoscopic therapy, only one trial evaluated the efficacy of endoluminal
gastroplication (Endocinch technique) and reported an improvement in 72% of NCCP patients (34).
Due to the high risk of perforation and the lack of information about long-term effect, this
technique is not used in current clinical practice.
Few studies have assessed the effectiveness of Nissen fundoplication in patients with GERD and
chest pain and the response rate was ranging from 48-96% (35, 36). Patients referred for surgical
treatment must be very carefully selected, as patients initially responsive to PPI and those presenting
typical GERD symptoms tend to better respond to surgery.

Conclusions

Non-cardiac chest pain represents a very common problem with high costs to the healthcare system
and significant morbidity to the patient. After ruling out life-threatening causes of chest pain, GERD
remains the most common cause of NCCP. The empirical double-dose PPI for more than 2 months is
the first line approach for the diagnosis and treatment of NCCP of presumed GERD origin,
esophageal impedance-pH monitoring being reserved for PPI refractory patients.

REFERENCES

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Gastroenterology Clinics of North America 33, pp. 1-23.

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2. Katz, PO. (2002). Diagnosis and therapy of noncardiac chest pain: A clinical dilemma. Journal of Clinical
Gastroenterology 35, pp. 292-294.
3. Kachintorn, U. (2005). How do we define non-cardiac chest pain? Journal of Gastroenterology and Hepatology 20
(l), pp. S2-S5.
4. Eslick, GD. (2001). Chest pain: an historical perspective. Internal Journal of Cardiology 77, pp. 5–11.
5. Fass, R, Achem, SR. (2011). Noncardiac chest pain: epidemiology, natural course and pathogenesis. Journal of
Neurogastroenterology and Motility 17, pp. 110-123.
6. Eslick, GD., Jones, MP., Talley, NJ. (2003). Non-cardiac chest pain: prevalence, risk factors, impact and consulting-
a population-based study. Alimentary Pharmacology and Therapeutics 17, pp. 1115-1124.
7. Eslick, GD., Talley, NJ. (2004). Non-cardiac chest pain: predictors of health care seeking, the types of health care
professional consulted, work absenteeism and interruption of daily activities. Alimentary Pharmacology and
Therapeutics 20, pp. 909-915.
8. Wong, WM., Beeler, J., Risner-Adler, S., Habib, S., Bautista, J., Fass, R. (2005). Attitude and referral patterns of
primary care physicians when evaluating subjects with noncardiac chest pain- a national survey. Digestive Diseases
Sciences 50, pp. 656-661.
9. Ford, AC., Suares, NC., Talley, NJ. (2011). Meta-analysis: the epidemiology of noncardiac chest pain in the
community. Alimentary Pharmacology and Therapeutics 34, pp. 172-180.
10. Labenz, J., Labenz, C. (2017). Gastroenterological diseases as triggers of chest pain. Der Internist Berlin 58(1), pp.
29-38.
11. Hanizam, M., Choon-Seng, Q., Choon-Heng, W., Wan, A., Khean-Lee, G. (2009). Non-cardiac chest pain:
Prevalence of reflux disease and response to acid suppression in an Asian population. Journal of Gastroenterology
and Hepatology 24, pp. 288-293.
12. Cho, YS., Choi, MG., Jeong, JJ., et al. (2005). Prevalence and clinical spectrum of gastroesophageal reflux: a
population-based study in Asian-si, Korea. American Journal of Gastroenterology 100, pp.747-753.
13. Yang, WM., Poong-Lyul, R. (2015). Noncardiac chest pain: update on the diagnosis and management. Korean
Journal of Gastroenterology 65, pp. 76-84.
14. Pehlivanov, N., Liu, J., Mittal, RK. (2001). Sustained esophageal contraction: a motor correlate of heartburn
symptom. The American Journal of Physiology: Gastrointestinal and Liver Physiology 281, pp. G743-G751.
15. Yuksel, ES., Vaezi, MF. (2012). Extraesophageal manifestations of gastroesophageal reflux disease: cough, asthma,
laryngitis, chest pain. Swiss Medical Weekly 142, w13544.
16. Oranu, AC., Vaezi, MF. (2010). Noncardiac chest pain: gastroesophageal reflux disease. Medical Clinics of North
America 94, pp. 233-242.
17. Rao, SSC. (2011). Diagnosis and Management of Esophageal Chest Pain. Journal of Gastroenterology and
Hepatology 7(1), pp. 50-52.
18. Cremonini, F., Wise, J., Moayyedi, P., et al. (2005). Diagnostic and therapeutic use of proton pump inhibitors in
non-cardiac chest pain: a metaanalysis. American Journal of Gastroenterology 100, pp.1226–1232.
19. Kahrilas, PJ., Hughes, N., Howden, CW. (2011). Response of unexplained chest pain to proton pump inhibitor
treatment in patients with and without objective evidence of gastro-oesophageal reflux disease. Gut 60, pp. 1473–
1478.
20. Faybush, EM., Fass, R. (2004). Gastroesophageal reflux disease in noncardiac chest pain. Gastroenterology Clinics
of North America 33(1), pp. 41-54.
21. Fass, R., Dickman, R. (2006). Non-cardiac chest pain: an update. Neurogastroenterology and Motility 18, pp. 408-
417.
22. Xia, HH., Lai, KC., Lam, SK. et al. (2003). Symptomatic response to lansoprazole predicts abnormal acid reflux in
endoscopy-negative patients with non-cardiac chest pain Alimentary Pharmacology and Therapeutics 17, pp. 369-
377.
23. Bautista, J., Fullerton, H., Briseno, M., et al. (2004). The effect of an empirical trial of high-dose lansoprazole on
symptom response of patients with non-cardiac chest pain - a randomized, double-bind, placebo-controlled
crossover trial. Alimentary Pharmacology and Therapeutics 19, pp. 1123-1130.
24. Dickman, R., Mattek, N., Holub, J., Peters, D., Fass, R. (2007). Prevalence of upper gastrointestinal tract findings
in patients with noncardiac chest pain versus those with gastroesophageal reflux disease (GERD)-related symptoms:
results from a national endoscopic database. American Journal of Gastroenterology 102, pp. 1173-1179.
25. Pandolfino, JE., Kahrilas, PJ. (2005). American Gastroenterological Association. American Gastroenterological
Association medical position statement: clinical use of esophageal manometry. Gastroenterology 128, pp. 207-208.
26. Dekel, R., Pearson, T., Wendel, C., De Gamo, P., Fennerty, MB., Fass, R. (2003). Assessment of esophageal motor
function in patients with dysphagia or chest pain: the Clinical Outcomes Research Initiative experience. Alimentary
Pharmacology and Therapeutics 18, pp.1083-1089.
27. Nasr, I., Attaluri, A., Coss-Adame, E., Rao, SS. (2012). Diagnostic utility of the esophageal balloon distension test
in the evaluation of esophageal chest pain. Alimentary Pharmacology and Therapeutics 35, pp. 1474-1481.
28. Karamanolis, G., Kotsalidis, G., Triantafyllou, K. et al. (2011). Yield of combined impedance-pH monitoring for
refractory reflux symptoms in clinical practice. Journal of Neurogastroenterology and Motility 17, pp. 158-163.

50
29. Karamanolis, G., Tutuian, R. (2013). Role of non-acid in patients witth non-erosive reflux disease. American Journal
of Gastroenterology 26, pp. 100-103.
30. Fass, R., Navarro-Rodriguez, T. (2008). Noncardiac chest pain. Journal of Clinical Gastroenterology 42, pp. 636-
646.
31. Fang, J., Bjorkman, D. (2001). A critical approach to noncardiac chest pain: pathophysiology, diagnosis and
treatment. American Journal of Gastroenterology 96, pp. 958-968.
32. Kahrilas, PJ., Hughes, N., Howden, CW. (2011). Response of unexplained chest pain to proton pump inhibitor
treatment in patients with and without objective evidence of gastro-oesophageal reflux disease. Gut 60, pp. 1473–
1478.
33. George, N., Abdallah, J., Maradey-Romero, C., Gerson, L., Fass, R. (2016). Review article: the current tratment of
non-cardiac chest pain. Alimentary Pharmacology and Therapeutics 43, pp. 213-239.
34. Liu, JJ., Carr-Locke, DL., Osterman, MT. et al. (2006). Endoscopic treatment for atypical manifestations of
gastroesphageal reflux disease. American Journal of Gastroenterology 101, pp. 440-445.
35. Patti, MG., Molena, D., Fisichella, PM., et al. (2002). Gastroesophageal reflux disease (GERD) and chest pain.
Results of laparoscopic antireflux surgery. Surgical Endoscopy 16, pp. 563–566.
36. Farrell, TM., Richardson, WS., Trus, TL. et al. (2001). Response of atypical symptoms of gastro-oesophageal reflux
to antireflux surgery. British Journal of Surgery 88, pp. 1649–1652.

51
Gastroesophageal Reflux Disease (GERD) and Helicobacter Pylori
(H. pylori) – A Continuing Dilemma
DIMACHE Mihaela1, ANTON Carmen2, BISTRICEANU Sandina3
1 UMF “Gr. T. Popa”, Iași; IGH, Spitalul “Sf. Spiridon”, Iași; (ROMÂNIA)
2 UMF “Gr. T. Popa”, Iași; IGH, Spitalul “Sf. Spiridon”, Iași; (ROMÂNIA)
3 IGH, Spitalul “Sf. Spiridon”, Iași; (ROMÂNIA)

Emails: mimidimache@yahoo.com, carmen_ro2008@yahoo.com, sandinabistriceanu@gmail.com

Abstract

The exact association between GERD and H. pylori infection was widely debated for the last
decades. Still, current data do not provide sufficient evidence to define the relationship between H.
pylori and GERD. Therefore, we made a review of the most recent studies and meta-analyses
published during 2014-2017 and tried to draw some conclusions in order to help us in our daily
medical practice.

Keywords: H. pylori infection, GERD, controversy

The relationship between GERD and H. pylori infection has been widely debated over the years,
but the problem is still controversial. On this background, we made a review of the most recent studies
and meta-analysis which have followed this subject for the last 3 years.

H. pylori status and GERD

One major question regards the relationship between H. pylori status and GERD.
The studies of Grande et al. (2014) and Grossi et al. (2015) found no statistical differences between
H. pylori-positive and H. pylori-negative status in patients with GERD (1, 2).
Also, a large study of Bor et al. (2017) made on 3214 patients established a global prevalence of
H. pylori infection of 75,7%, with no statistical differences between patients with GERD (71,4%) and
those without reflux symptoms (77,1%) (3, 4).
On the contrary, the study of Chandramohan et al. (2017) made on 79 patients found that the
prevalence of H. pylori infection is lower in GERD patients compared to general population,
suggesting a protective role of H. pylori against GERD (5).
Furthermore, a large study of Ribeiro et al. (2016) on 9576 patients evaluated the relation between
H. pylori and reflux esophagitis and found that among patients with reflux esophagitis, only 13,16%
were H. pylori-positive, and 86,83% were H. pylori-negative (6). These results suggest once again a
possible protective role of H. pylori against GERD.

H. pylori and the clinical pattern of GERD

A very interesting problem concerns the relationship between H. pylori infection and the clinical
presentation of GERD.
The study of Grossi et al. (2015) analysed whether the H. pylori infection could affect the quality
of symptoms in GERD patients (2).
For this purpose, GERD patients were stratified according the quality of their symptoms in typical
patients (affected by heartburn and regurgitation) and atypical patients (with chest pain, respiratory
and ears, nose and throat features).

52
 Furthermore, patients were also classified in H. pylori-positive and H. pylori-negative; if they had
a previous diagnosis of H. pylori infection, they were considered as “recently eradicated” (less than
6 months from eradication) or “eradicated” (more than 6 months).
The results of the study showed that the presence of H. pylori infection in GERD patients is
associated with a greater frequency of atypical extraesophageal symptoms; GERD patients without
H. pylori infection are preferentially affected by typical heartburn and regurgitation (2).
Moreover, the symptoms of H. pylori-positive patients (atypical) were similar to those of cases
with very recent eradication (< 6 months); clinical aspects of patients treated for H. pylori infection
long time earlier (> 6 months) were similar to those of H. pylori-negative patients.
These findings made the authors to conclude that the presence of bacterial infection with H. pylori
may have an action on GERD clinical pattern, which is progressively reduced by the time the infection
is eradicated (2).

H. pylori and the severity of GERD

Another important question is that of the relation between H. pylori infection and the severity of
GERD, which means the degrees of reflux esophagitis.
The results of the study of Grande et al. (2014) show a role of H. pylori infection neither in the
development of GERD nor in the pathogenesis of reflux esophagitis (1).
In this regard, no statistical difference was found between patients with H. pylori infection and
those without H. pylori infection, concerning the presence and the severity of reflux esophagitis.
On the contrary, the study of Chandramohan et al. (2017) found another result: as the severity of
GERD increases (on endoscopy findings), H. pylori positivity decreases, suggesting a negative
association between H. pylori infection and endoscopic parameters of GERD (5).
A recent European population-based study concluded that H. pylori infection did not decrease the
risk of GERD (7); but the low prevalence of gastric atrophy (only 1,8%) in the study population may
offer an explanation for this result.
The situation appears to be different for study populations with higher prevalence of atrophic
gastritis (4).
Thus, there is evidence from a Korean study made on more than 5000 patients that H. pylori
seropositivity was associated with a reduced risk for erosive esophagitis (8).
Likewise, the data from a large Japonese study concluded that the association of H. pylori and
erosive esophagitis is only possible in patients without gastric atrophy (9).
Reviewing these data, it seems that the relation between H. pylori infection and GERD differs
according to the geographical affiliation of the patient and to the prevalence of atrophic gastritis in
that population.

H. pylori and the pHmetric/manometric parameters of GERD

The authors were also concerned about the relationship between H. pylori infection and the
pHmetric or manometric parameters of GERD.
The study of Grande et al. (2014) evaluated the relation between H. pylori infection and GERD,
in patients with reflux symptoms and showed two aspects:
a. The manometric data found no statistical difference between H. pylori-positive and H. pylori-
negative patients, regarding lower esophageal sphincter (LES) pressure, esophageal wave
length and esophageal wave height;
b. The pHmetric data found no correlation between H. pylori infection and the total time of
acidification or the mean value of the DeMeester score.
In conclusion, both the clinical, endoscopic and the manometric and pHmetric data show a role of
H. pylori neither in the development of GERD nor in the pathogenesis of reflux esophagitis (1).

53
 The study of Grossi et al. (2015) which analysed the relation between the clinical pattern of GERD
(typical/atypical) and the presence of H. pylori infection also showed no difference between H. pylori
status positive versus negative and either the number of reflux episodes or the percentage of time with
pH values < 4,0 (2). Plus, clinical signs in patients with recent H. pylori eradication were similar to
those of H. pylori-positive (atypical); patients with ancient H. pylori eradication showed a clinical
pattern similar to that of H. pylori-negative subjects (typical).

H. pylori eradication and GERD

In 2012, a meta-analysis of 10 randomized controlled trials showed that the eradication therapy
was associated neither with the incidence of reflux symptoms nor with reflux esophagitis (10).
Other meta-analysis found no effect of successful eradication therapy on GERD symptoms or
erosive esophagitis.
Furthermore, it appears that eradication therapy did not aggravate preexisting GERD symptoms
(11, 12).
In 2015, a study from China investigated the effect of eradication therapy on the healing rates of
erosive esophagitis. Thus, there was no difference in the healing rates of esophagitis, neither between
H. pylori-positive and H. pylori-negative patients nor between eradication and non-eradication groups
(13).
These results are in agreement with the Maastricht IV-Florence Consensus report: H. pylori
infection and eradication appear to have no influence on the success of reflux esophagitis therapy
(14).
Also, the Korean guideline for H. pylori infection states that H. pylori eradication does not affect
the development or clinical course of GERD.
Besides, a meta-analysis from a Chinese group reviewed 16 cohort studies and concluded that H.
pylori eradication had no significant effect on the development of GERD in the long term (15).
Though, they recommended eradication therapy because H. pylori infection is known to be cause
of peptic ulcer and gastric cancer.
Likewise, a German review concluded that in areas with a high prevalence of H. pylori-induced
atrophic gastritis, the “protection” that the infection might offer against GERD was not comparable
to the risk that H. pylori poses for the development of gastric cancer (16, 17).

Conclusion

Summarizing all these information, some important conclusions may be done.

The possible relation between H. pylori and the clinical presentation of GERD, as the results of
the study of Grossi showed, may be of great importance for the treatment of GERD; maybe the
patients with atypical GERD must have a new approach, concerning the evaluation of H. pylori
infection and the bacterial eradication.
We also must look at the therapeutic approach in GERD patients who are H. pylori-positive. Even
if the subject belongs from a populational group with a high prevalence of H. pylori-induced atrophic
gastritis, most of the authors believe that the infection must be eradicated, because the risk of gastric
cancer is much higher than the possible “protection” against severe esophagitis.
Because there are yet a lot of contradictory opinions, new large and prospective studies are needed
to evaluate the special relation between H. pylori and GERD, in order to solve the present debates
and give us complete answers.

REFERENCES

1. Grande M., Lisi G., De Sanctis F., et al. Does a relationship still exist between gastroesophageal reflux and
Helicobacter pylori patients with reflux symptoms? World Journal of Surgical Oncology 2014, 12: 375.

54
2. Grossi L., Ciccaglione A.F., et al. Typical and atypical symptoms of gastroesophageal reflux disease: Does
Helicobacter Pylori infection matter? World J of Gastrointestinal Pharmacology and Therapeutics 2015, 6(4):
238-243.
3. Bor S., Kitapcioglu G., Kasap E. Prevalence of gastroesophageal reflux disease in a country with a high
occurrence of Helicobacter pylori. World J Gastroenterol 2017; 23(3):525-532.
4. Chirilă I., Morariu I.D., Bărboi O. B., et al. The role of diet in the overlap between gastroesophageal reflux
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population-based study (The HUNT Study). Helicobacter 2007, 12: 16-22.
8. Chung S.J., Lim S.H., Choi J., et al. Helicobacter pylori serology inversely correlated with the risk and severity
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2011, 16: 255-265.
12. Yaghoogi M., Farrokhyar F., et al. Is there an increased risk of GERD after Helicobacter pylori eradication? a
meta-analysis. Am J Gastroenterol 2010, 105: 1007-1013.
13. Xue Y., Zhou L.Y., et al. Effect of Helicobacter pylori eradication on reflux esophagitis therapy: a multicenter
randomized control study. Chin Med J (Engl), 2015, 128: 995-999.
14. Malfertheiner P., Megraud F., et al. Management of Helicobacter pylori infection – the Maastricht IV/Florence
Consensus Report. Gut, 2012, 61: 646-664.
15. Tan J., Wang Y., Sun X., et al. The effect of Helicobacter pylori eradication therapy on the development of
gastroesophageal reflux disease. Am J Med Sci 2015, 349: 364-71.
16. Kandulski A., Malfertheiner P. Helicobacter pylori and gastroesophageal reflux disease. Curr Opin Gastroenterol
2014, 30: 402-7.
17. Vasapolli R., Malfertheiner P., Kandulski A. Helicobacter pylori and non-malignant upper gastrointestinal
diseases. Helicobacter 2016; 21 (Suppl. 1): 30–33.

55
Heart Rate Variability in Patients with Gastroesophageal Reflux
Disease – A Prospective Study

FLORIA Mariana1,2, BĂRBOI Oana1,3, BOCÎNCĂ Cristina1, DÎRZU Iulia3,

ŞAVLOVSCHI Dumitriţa3, CIJEVSCHI-PRELIPCEAN Cristina1,3,
BĂLAN Gheorghe1,3, DRUG Vasile Liviu1,3
1 Grigore T. Popa University of Medicine and Pharmacy Iași (ROMANIA)
2 III Medical Clinic of Sf. Spiridon University Hospital Iași (ROMANIA)
3 Hepatology and Gastroenterology Institute of Sf. Spiridon University Hospital Iași (ROMANIA)

Emails: floria_mariana@yahoo.com, oany_leo@yahoo.com, savlovschi_dumitrita21@yahoo.com, dirzuiuliaioana@yahoo.com,

cristina.cijevschi@yahoo.com, balan.gheo@yahoo.com, vasidrug@email.com

Abstract

Background
Sympatho-vagal balance seems to be disturbed in patients with gastro-oesophageal reflux disease
(GERD). We aimed to assess time (SSDN) and frequency domain (LF/HF ratio) parameters of heart
rate variability (HRV) in patients with GERD.

Material and methods

Patients were prospectively included by a joint team consisting of gastroenterologist and
cardiologist. GERD diagnosis was clinically assessed by gastroenterologist. In addition, all patients
underwent upper gastrointestinal endoscopy and 24-hour ECG Holter monitoring. All patients were
in stable sinus rhythm, with no history of arrhythmias.

Results
Sixty patients were included in 2 groups: 25 patients with GERD (study group: 52% men, 64±10
years, BMI 29±5 kg/m2) and 35 patients without GERD (control group: 39% men, 59±11 years, BMI
29±5 kg/m2); all p>0.05. None statistically significance differences between cardiovascular risk
factors of the 2 groups were obtained. Esophagitis was diagnosed in 56% of patients with GERD and
14% of patients without GERD (p=0.001). Hiatal hernia was present in 16% of patients with GERD
and 20% of patients without GERD (p=0.94). Heart rate variability in time (SSDN value of 88±53ms
versus 146±33ms; p=0.001) and not in frequency (LF/HF ratio value of 0.76±0.24 versus 0.72±0.17;
p=0.749) domain parameters were statistically significant different between patients with GERD
versus without GERD.

Conclusions
In this small prospective study, lower value of SDNN in patients with GERD suggests lower HRV
and implicitly an increased risk for arrhythmias. Sympatho-vagal balance seems to be disrupted in
patients with GERD.
Keywords: Gastro-oesophageal reflux disease, sympatho-vagal imbalance, heart rate variability

Introduction

The anatomic position of the oesophagus behind of left atrium and the same innervation of these
structures in addition to the autonomic nervous system imbalance could explain the association
between gastro-oesophageal reflux disease (GERD) and atrial fibrillation (AF) [1]. Sympatho-vagal

56
imbalance is incriminated in the pathogenesis of both, GERD and AF. Vague nerve activity plays an
important role in physiological oesophageal sphincter functions (avoiding reflux disease) and also
could promote triggers occurrence in the pulmonary vein antrum with subsequent electrical atrial
myocardium instability [2]. Heart rate variability (HRV) is a non-invasive tool for autonomic tone
imbalance assessment in clinical practice [3]. We aimed to assess time (SSDN) and frequency domain
(LF/HF ratio) parameters of HRV in patients with GERD.

Materials and methods

Study population
Patients were prospectively included during 12 months by a joint team consisting of
gastroenterologist and cardiologist. We compared prospectively HRV parameters, in time (SSDN)
and frequency (LF/HF ratio or low frequency/high frequency ratio) domains, in patients with and
without GERD assessed by 24 hours electrocardiogram (ECG) Holter monitoring. GERD diagnosis
was clinically assessed by gastroenterologist. In addition, all patients underwent upper
gastrointestinal endoscopy. All patients were in stable sinus rhythm, with no history of
supraventricular or ventricular arrhythmias. Proton pump inhibitors were stopped 8 weeks before
inclusion in the study.
Inclusion criteria: patients older than 18 years, without any prior gastroenterological
evaluation (naïve patients), with symptoms suggesting GERD, defined as mild symptoms of
heartburn and/or regurgitation at least 2 times per week or moderate/severe symptoms occurring more
than 1 day a week, perceived as “troublesome” by patients (according with Montreal definition) [4].
Exclusion criteria: patients <18 years; patients with any type of documented valvular AF or
under anticoagulation treatment; patients with chronic gastrointestinal diseases; patients with any
valvular disease more than mild, thyroid disorders, previous myocardial infarction, transient ischemic
attack or stroke; patients who refused to be included. The treatment with proton pump inhibitors was
interrupted 8 weeks before the inclusion in the study. Antiarrhythmic drugs in patients with AF were
not stopped during the study (due to the ethical reasons).
Gastro-oesophageal reflux disease was diagnosed by gastroenterologist clinically. The
diagnosis of GERD was determined on the basis of clinical symptoms (according to the Montreal
Consensus) [4]: mild symptoms of heartburn and/or regurgitation at least 2 times per week or
moderate/severe symptoms occurring more than 1 day a week, perceived as “troublesome” by
patients. All patients underwent gastroenterological and, after that, cardiologic assessment. They
underwent upper gastrointestinal endoscopy and 24 hours ECG monitoring, even if they were
asymptomatic.
After a detailed medical history, the following clinical parameters were noted: age, sex, the
presence of obesity (defined as BMI – body mass index – higher than 30 kg/m2), dyslipidemia,
hypertension, diabetes mellitus, heart failure, ischemic heart disease and peripheral arterial disease.
Upper gastrointestinal endoscopy was made by only one experienced gastroenterologist
(Endoscope Olympus Exera CV-160) in 48-72 hours before or after ECG Holter monitoring. The
presence of hiatus hernia (as favoring condition of GERD) esophagitis and Barrett’s esophagus, was
noted.
HRV parameters were registered by 24 hours ECG Holter monitoring, using a two-channel
tracker (EC-2H 2-Channel, Cardiospy, Labtech Holter ECG System, Hungary). Individuals went
about normal daily activities. All HRV data were collected and interpreted by an experienced
electrophysiologist.
This study was approved by Hospital and University Ethics Committee (approval number
2005/2014). Informed consent was obtained from each patient before the inclusion in the study. This
study conforms to the Declaration of Helsinki.

57
Statistical analysis
Categorical data are presented as frequencies and percentages; continuous variables are
expressed as mean ± standard deviation. Categorical, ordinal and numerical variables were compared
between groups using χ2, Cochran and Wilcoxon rank sum tests, Kruskal-Wallis and Anova test
respectively. All statistical tests were two-tailed and performed with SPSS 15.0 (SPSS Inc., Chicago,
IL, USA). A p-value <0.05 was set as statistical significance.

Results

We prospectively included: 25 patients with GERD (52% men, 64±10 years, BMI 29±5 kg/m2)
and 35 patients without GERD (39% men, 59±11 years, BMI 29±5 kg/m2); all p>0.05.
None statistically significance differences between cardiovascular risk factors of the 2 groups were
obtained: (obesity, defined as body mass index – BMI higher than 30 kg/m2; dyslipidemia;
hypertension; diabetes mellitus; heart failure; peripheral arterial disease; aortic atheroma, defined as
the presence of atherosclerotic plaque at the level of ascending aorta or aortic cross in transthoracic
echocardiography. Heart rate variability (Table 1) in time (SSDN) and not in frequency (LF/HF ratio)
domain parameters were statistically significant different between patients with GERD and without
GERD. Mean SSDN value in patients with GERD was lower than that in patients without GERD.
Mean value of LF/HF ratio was non-significant statistically greater in patients with GERD
comparing with those without GERD. Esophagitis was diagnosed in 56% of patients with GERD and
14% of patients without GERD (p=0.001). Hiatal hernia was present in 16% of patients with GERD
and 20% of patients without GERD (p=0.94).
Table 1. Comparative data of heart rate variability and upper gastrointestinal endoscopy parameters in patients with
GERD (group I) versus without GERD (group II)
PARAMETER GROUP I GROUP II P value
(n=25) (n=35) (Student’ t test)
ECG HOLTER
SDNN+ (ms) 88±53 146±33 0.001
LF/HF ratio++ 0.76±0.24 0.72±0.17 0.749
UPPER GASTROINTESTINAL ENDOSCOPY
Esophagitis (%) 56 14 0.001
Hiatus hernia (%) 16 20 0.94
++
LF/HF ratio=low frequency/high frequency ratio; +SDNN=the standard deviation of normal to normal N-N intervals.

Study limitations
It is a small prospective study. Non-erosive GERD was not possible to be assessed in these
patients. The assessment of HRV before and after proton pump inhibitors not only in the absence of
this treatment could bring new information’s because therapy with proton pump inhibitors may have
proarrhythmic or antiarrhythmic effects.

Discussion

Sympatho-vagal imbalance is the main theory envolved in the association of AF with GERD; it
acts as trigger for AF occurrence in patients with GERD (5). Arrhythmia risk is usually assessed by
HRV. In this study, lower value of SDNN in patients with GERD suggests lower HRV and implicitly
an increased risk for arrhythmias.
The impairment of parasympathetic function seems to be more congruent to GERD.
The mechanism of impairment of parasympathetic function of the patients with GERD is not
completely clear, but in all autonomic neuropathies, the first stage of dysfunction is damage of
parasympathetic neurons, possibly because the general function of the autonomic nervous system
depends on vagal activity.

58
 In this study, LF/HF ratio (a marker of sympathetic and parasympathetic system imbalance) had
has a greater value in patients with GERD; this signifies a domination of sympathetic nervous system.
However, it was statistically non-significant. This result could be explained by the greater number
of patients with esophagitis in patients with GERD. In addition, non-erosive GERD was not assessed
in these patients. It seems that LF/HF ratio is significantly lower in the non-erosive compared with
erosive GERD patients [6]. However, in comparison with non-erosive GERD patients, autonomic
tonus in patients with endoscopic confirmed esophagitis (even without symptom) is lower.
The association between gastrointestinal symptoms and cardiac dysrhythmias, as one of the
autonomic system impairments in GERD patients, has been described as cardio-gastric syndrome [7].
This imbalance between autonomic nervous system components assessed by heart rate variability
in not so simple to be studied in these patients [8, 9].
Clinicians should be aware of the possible cardio-gastric interaction with GERD being associated
with AF [8-10]. Identification and appropriate treatment of GERD, especially esophagitis, may help
to reduce AF-onset and symptoms and can facilitate conversion from AF to sinus rhythm in a subset
of patients. Treatment of GERD to avoid AF or to reduce AF burden might represent a future
treatment perspective [10].

Conclusions

In this small prospective study, a lower value of SDNN in patients with GERD suggests a lower
HRV and implicitly an increased risk for arrhythmias. Sympatho-vagal balance seems to be partially
disrupted in patients with GERD.

REFERENCES

1. Roman, C, Bruley des Varannes, S, Muresan, L, Picos, A, Dumitrascu, D.L. (2014). Atrial fibrillation in patients
with gastroesophageal reflux disease: A comprehensive review. World J Gastroenterol 20, pp. 9592-9.
2. Haissaguerre, M, Jais, P, Shah, DC, et al. (1998). Spontaneous initiation of atrial fibrillation by ectopic beats
originating in the pulmonary veins. N Engl J Med 339(10), pp. 659–666.
3. Task Force of the European Society of Cardiology and the North American Society of Pacing and
Electrophysiology (1996). Heart rate variability: Standards of measurement, physiological interpretation and
clinical use. Eur Heart J 17, pp. 354–381.
4. Vakil, N, van Zanten, SV, Kahrilas, P, Dent, J, Jones, J. (2006). Global Consensus Group. The Montreal
Definition and Classification of Gastroesophageal Reflux Disease: A Global Evidence-Based Consensus. Am J
Gastroenterol 101, pp.1900-20.
5. Bunch TJ, Packer DL Jahangir A, et al. (2008). Long-term risk of atrial fibrillation with symptomatic
gastroesophageal reflux disease and esophagitis. Am J Cardiol 102(9), pp. 1207-11.
6. Chen CL, Orr WC, Yang CC, Kuo TB. (2006). Cardiac autonomic regulation differentiates reflux disease with
and without erosive esophagitis. Scand J Gastroenterol 41(9), pp. 1001-6.
7. Patcharatrakul T, Gonlachanvit S. (2014). Gastroesophageal reflux symptoms in typical and atypical GERD:
roles of gastroesophageal acid refluxes and esophageal motility. J Gastroenterol Hepatol 29: 284-290.
8. Floria M, Drug VL. (2015). Atrial fibrillation and gastroesophageal reflux disease: From the cardiologist
perspective. World J Gastroenterol 21(10), pp. 3154-6.
9. Floria M, Bărboi O, Grecu M, et al. (2017). Atrial fibrillation and sympathovagal balance in patients with
gastroesophageal reflux disease. Turk J Gastroenterol 28(2), pp. 88-93.
10. Linz, D, Hohl, M, Vollmar, J, Ukena, C, Mahfoud, F, Bohm, M. (2017). Atrial fibrillation and gastroesophageal
reflux disease: the cardiogastric interaction. Europace.
19(1), pp. 16-20.

59
Gastroesophageal Reflux Disease and Coronary Heart Disease – From
Pathophysiology to Treatment Controversies

FLORIA Mariana1,2, BARBOI Oana1,3, BOCINCA Cristina1,

CIJEVSCHI-PRELIPCEAN Cristina1,3, BALAN Gheaorghe1,3,
DRUG Vasile Liviu1,3
1 Grigore T. Popa University of Medicine and Pharmacy Iași (ROMANIA)
2 III Medical Clinic of Sf. Spiridon University Hospital Iași (ROMANIA)
3 Hepatology and Gastroenterology Institute of Sf. Spiridon University Hospital Iași (ROMANIA)

Emails: floria_mariana@yahoo.com, oany_leo@yahoo.com, cristina.cijevschi@yahoo.com, balan.gheo@yahoo.com,

vasidrug@email.com

Abstract

Chest pain experienced by patients with coronary heart disease (CHD) can be of non-cardiac
origin, and symptoms frequently related to gastro-oesophageal aetiologies. Gastro-oesophageal reflux
disease (GERD) and CHD can cause chest pain and frequently co-exist. It seems that GERD is a
frequent condition in patients with CHD. Coexistence of GERD may predispose to the myocardial
ischemia. In humans, chemical, electrical, and mechanical stimulation of the oesophagus modifies
the sympatho-vagal balance. Gastro-oesophageal reflux disease may cause the shift of sympatho-
vagal balance towards its parasympathetic component. One of potential mechanisms explaining the
influence of oesophageal disturbance on the appearance of coronary hypo-perfusion may be their
common neurological control of the functions, which include oesophageal-cardiac reflex. Short-term
proton pump inhibitors therapy in patients with GERD that restores normal oesophageal pH
significantly reduces myocardial ischemia, possibly due to elimination of acid-derived oesophageal-
cardiac reflex compromising coronary perfusion. Long-term proton pump inhibitors interfere with
the clearance of asymmetrical dimethyl-arginine, the endogenous antagonist of nitric oxide synthase.
However, mechanisms by which the proton pump inhibitors may increase the risk of major adverse
cardiovascular events in CHD patients are still controversial.
Keywords: Gastro-oesophageal reflux disease, sympatho-vagal balance, oesophageal-cardiac reflex

Introduction

The anatomic position of the oesophagus behind of left atrium and the same innervation of these
structures in addition to the autonomic nervous system imbalance seem to explain the association
between gastro-oesophageal reflux disease (GERD) and some cardiovascular disease like atrial
fibrillation and coronary heart disease (CHD). There is the normal coronary artery appearance in 20-
30% of coronarographies, made in patients with chest pain and/or positive non-invasive cardiologic
tests [1]. This could be explained by the presence of diseases which may affect coronary perfusion
via mechanism independent to the diameter of main coronary arteries. One of them seems to be
GERD.

Prevalence of Gastro-oesophageal Reflux Disease in Coronary Heart Disease Patients

The presence of GERD symptoms in general population concerns about 30-40% of individuals,
while non-physiological reflux is stated in 50 to 85% of patients with CHD [1]. That means, that
GERD is twice more frequent in patients with CHD than in general population [2]. However, there is

60
substantial overlap between the prevalence of CHD and GERD. CHD might be found although a
patient was referred to the hospital with a complaint of GERD symptoms. The prevalence of GERD
in patients with CHD is higher, ranging from 40% to 78% [2]. In patients with GERD symptoms and
electrocardiographic signs of coronary artery ischemia, the prevalence of linked angina is about 0.4%
[3].

Gastro-oesophageal Reflux Disease and Coronary Heart Disease: Pathophysiologic

Considerations

Gastro-oesophageal reflux disease is a frequent condition in patients with angiographically

confirmed CHD. Coexistence of GERD may predispose to the myocardial ischemia. In humans,
chemical, electrical, and mechanical stimulation of the oesophagus modifies the sympatho-vagal
balance [4]. The distal oesophagus and the heart share a common afferent nerve supply, suggesting
that location and radiation of perceived pain may be identical.
One of potential mechanisms explaining the influence of oesophageal disturbance on the
appearance of coronary hypo-perfusion may be their common neurological control of the functions
(Fig. 1). There are three aspects of it: vagal reflexes (oesophageal-cardiac reflex), the disturbances of
autonomic nervous system balance and changes in visceral pain perception threshold [5].

Fig. 1. From oesophageal disturbance to potential mechanisms of coronary hypo-perfusion

Visceral reflex can combine GERD and CHD with mechanism of vicious circle (Fig. 2): acid
gastro-oesophageal reflux via vagal reflex may cause coronary hypo-perfusion, and the products of
anaerobic metabolism of cardio-myocytes may cause relaxation of lower oesophagus sphincter,
facilitating reflux.
Oesophageal stimulation amplifies respiratory-driven cardiac vago-afferent modulation, while
decreasing sympathetic modulation which is associated with an increase in vagal activity [4].
Acid refluxes could cause a local inflammatory process that may directly alter the autonomic
innervations of the oesophageal mucosa and may also penetrate the oesophageal wall and stimulate
the adjacent vagal nerves. Injury of the distal oesophagus can further impair vagal nerve responses,
particularly nerve sensitization of the afferent pathways [4].

61
 Fig. 2. Association of GERD and CHD as result of visceral reflex

Oesophageal acid stimulation can cause angina attacks and significantly reduce coronary blood
flow in patients with CHD [6]. The lack of any significant effect in heart transplant recipients, in
whom the heart is denervated, suggests a neural reflex [6, 7].
GERD is frequently established in patients with either epicardial or microvascular coronary artery
disease or with coronary spasm [8]. The oesophageal-cardiac reflex seems to be more frequently in
patients with coronary spasm.
Patients with prolonged gastro-oesophageal acid reflux episodes, erosive esophagitis and coronary
spasm may be at higher risk for the development of linked-angina [8].
Another explanation of the increased frequency of GERD appearance in patients with CHD is the
adverse effect of drugs used in treatment of cardiologic diseases [1].
Additional mechanism connecting GERD and CHD is inflammation caused by Helicobacter pylori
infection [1]. The relationship between digestive tract pathology and evolution, as well as progression
and complications of atherosclerosis together with similarity of clinical presentation imply the
necessity of precise diagnosis of chest pain causes and caution in interpretation of laboratory
examination results.
The combination of oesophageal acid perfusion test and trans-oesophageal Doppler
echocardiographic coronary flow measurement could be a useful method for the detection of this
reflex. Pathological GERD that induce myocardial ischemia could be also determined by analysis of
ST depression during 24-hour monitoring of electrocardiogram [9]. Patients with GERD seem to have
significantly higher number of ST-segment depression episodes and total ischemic burden, compared
to patients without GERD [10].
Short-term proton pump inhibitors therapy in patients with GERD that restores normal
oesophageal pH significantly reduces myocardial ischemia, possibly due to elimination of acid-
derived oesophageal-cardiac reflex compromising coronary perfusion [11]. Short-term proton pump
inhibitors therapy reduces myocardial ischemia and significantly improves the general health-related
quality of life of patients [11].

Proton Pump Inhibitors Treatment and Associated Cardiovascular Risk

Proton pump inhibitors are gastric acid–suppressing agents widely prescribed for the treatment of
GERD. They irreversibly bind to the gastric proton pump and inhibit acid secretion. Most proton
pump inhibitors are now available, increasing their general use in the absence of medical supervision.
Recently, several studies in patients with acute coronary syndrome have raised the concern that
use of proton pump inhibitors in these patients may increase their risk of major adverse cardiovascular
events. It seems that proton pump inhibitors interfere with the clearance of asymmetrical dimethyl-

62
arginine, the endogenous antagonist of nitric oxide synthase. Proton pump inhibitors might increase
plasma asymmetrical dimethyl-arginine levels, reduce vascular nitric oxide levels and endothelium-
dependent vasodilation, and impairs vascular-protective mechanisms [12]. Proton pump inhibitors
increase asymmetrical dimethyl-arginine because they bind to and inhibit dimethyl-arginine
dimethyl-amino-hydrolase, the enzyme that degrades asymmetrical dimethyl-arginine [12].
Endothelium-derived nitric oxide inhibits thrombosis, inflammation, and abnormal vascular wall
thickening and contributes significantly to endothelium dependent vasodilation. Increased levels of
plasma asymmetrical dimethyl-arginine and impaired endothelium-dependent vasodilation seem to
be associated with increased cardiovascular morbidity and mortality. By inhibiting activity of the
nitric oxide synthase pathway, proton pump inhibitors may interfere with vascular homeostasis. These
changes may explain the increased major adverse cardiovascular events and mortality associated with
the prolonged use of proton pump inhibitors in patients with acute coronary syndrome [13].
Elevated plasma asymmetrical dimethyl-arginine is associated with a 50-fold increased risk for
CHD and a 5-fold increase in the prevalence of hypertension [13]. In addition, a large population-
based study demonstrates an association between GERD and future development of acute myocardial
infarction; however, proton pump inhibitors use only achieved marginal significance in reducing the
occurrence of acute myocardial infarction in GERD patients [14].
GERD seems to be associated with an increased risk of developing CHD, and proton pump
inhibitors use for more than 1 year might increase the risk of CHD [15], although this drug seems to
not significantly influence vascular endothelial function [16]. Therefore, data on proton pump
inhibitors are controversial.
Proton pump inhibitors may reduce the benefit of antiplatelet agents in patients with acute coronary
syndromes [17]. This could be explaining for example by reduced benefit of clopidogrel, because the
inhibition by proton pump inhibitors of the hepatic enzyme (CYP2C19), which is required for
activation of clopidogrel. In addition, the proton pump inhibitors also diminish the benefit of
ticagrelor, another antiplatelet drug that does not require hepatic activation.
Proton pump inhibitors seem to have a pro-arrhythmic by decreasing heart rate variability but also
an anti-arrhythmic effect in patients with atrial fibrillation [18, 19]. However, a mechanism by which
the proton pump inhibitors may increase the risk of major adverse cardiovascular events in CHD
patients is still in debate. The appearance of multidisciplinary care team focused on promoting the
agency of health care professionals might help to understand better this issue [20].

Conclusions

GERD is frequently established in patients with either epicardial or microvascular CHD or with
coronary spasm. The oesophageal-cardiac reflex is more frequently observed in patients with
coronary spasm. However, it seems that proton pump inhibitors may increase the risk of major
adverse cardiovascular events in CHD patients.

REFERENCES

1. Pulkowski, G, Majer, M, Budzyński, J, Swiatkowski, M. (2006). Gastroesophageal reflux disease and coronary
heart disease--coexistence or interrelationship? Pol Merkur Lekarski. 20(115):104-8.
2. Liuzzo JP, Ambrose JA. (2005). Chest pain from gastroesophageal reflux disease in patients with coronary artery
disease. Cardiol Rev 13(4), pp. 167-73.
3. Kato, H, Ishii, T, Akimoto, T, Urita, Y, Sugimoto, M. (2009). Prevalence of linked angina and gastroesophageal
reflux disease in general practice. World J Gastroenterol 15(14), pp. 1764-8.
4. Linz, D, Hohl, M, Vollmar, J, et al. (2017). Atrial fibrillation and gastroesophageal reflux disease: the
cardiogastric interaction. Europace 19(1), pp. 16-20.
5. Dobrzycki, S, Skrodzka, D, Musiał, WJ, et al. (2004). Relationship between gastroesophageal reflux disease and
myocardial ischemia. Effect of reflux on temporary activity of autonomic nervous system. Rocz Akad Med
Bialymst 49, pp. 93-7.

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6. Chauhan, A, Mullins, PA, Taylor, G, Petch, MC, Schofield, PM. (1996). Cardioesophageal reflex: a mechanism
for “linked angina” in patients with angiographically proven coronary artery disease. J Am Coll Cardiol 27(7),
pp.1621-8.
7. Chauhan, A, Petch, MC, Schofield, PM. (1996). Cardio-oesophageal reflex in humans as a mechanism for
“linked angina”. Eur Heart J 17(3), pp.407-13.
8. Rosztóczy, A, Vass, A, Izbéki, F, et al. (2007). The evaluation of gastro-oesophageal reflux and
oesophagocardiac reflex in patients with angina-like chest pain following cardiologic investigations. Int J Cardiol
118(1), pp. 62-8.
9. Dobrzycki S, Baniukiewicz A, Musiał WJ, et al. (2002). Ischemic heart disease and gastro-oesophageal reflux
disease--simultaneous 24 monitoring of ECG and oesophageal pH. Przegl Lek 59(9), pp. 675-7.
10. Mehta, AJ, de Caestecker, JS, Camm, AJ, Northfield, TC. (1996). Gastro-oesophageal reflux in patients with
coronary artery disease: how common is it and does it matter? Eur J Gastroenterol Hepatol 8(10), pp. 973-8.
11. Dobrzycki S, Baniukiewicz A, Korecki J, et al. (2005). Does gastro-esophageal reflux provoke the myocardial
ischemia in patients with CAD? Int J Cardiol 104(1), pp. 67-72.
12. Ghebremariam, YT, LePendu, P, Lee, JC, et al. (2013). Unexpected effect of proton pump inhibitors: elevation
of the cardiovascular risk factor asymmetric dimethylarginine. Circulation 128(8), pp. 845-53.
13. Maggio, M, Corsonello, A, Ceda, GP, et al. (2013). Proton pump inhibitors and risk of 1-year mortality and
rehospitalization in older patients discharged from acute care hospitals. JAMA Intern Med 173, pp. 518–523.
14. Valkonen VP, Tuomainen TP, Laaksonen R. (2005). DDAH gene and cardiovascular risk. Vasc Med 10 (suppl
1), pp. S45–S48.
15. Lei WY, Wang JH, Wen SH, et al. (2017). Risk of acute myocardial infarction in patients with gastroesophageal
reflux disease: A nationwide population-based study. PLoS One. Mar 20;12(3): e0173899.
16. Chen CH, Lin CL, Kao CH. (2016). Association between gastroesophageal reflux disease and coronary heart
disease: A nationwide population-based analysis. Medicine (Baltimore) 95(27): e4089.
17. Ghebremariam, YT, Cooke, JP, Khan, F, et al. (2015). Proton pump inhibitors and vascular function: A
prospective cross-over pilot study. Vasc Med 20(4), pp. 309-16.
18. Goodman, SG, Clare, R, Pieper, KS, et al. (2012). Platelet Inhibition and Patient Outcomes Trial Investigators.
Association of proton pump inhibitor use on cardiovascular outcomes with clopidogrel and ticagrelor: insights
from the Platelet Inhibition and Patient Outcomes Trial. Circulation 125, pp. 978–986.
19. Floria M, Drug VL. (2015). Atrial fibrillation and gastroesophageal reflux disease: From the cardiologist
perspective. World J Gastroenterol 21(10), pp. 3154-6.
20. Floria M, Bărboi O, Grecu M, et al. (2017). Atrial fibrillation and sympathovagal balance in patients with
gastroesophageal reflux disease. Turk J Gastroenterol 28(2), pp. 88-93.
21. Bulgaru-Iliescu D, Botezat D, Oprea L. (2012). the chronic care model and personal responsibility for health.
Romanian Journal of Bioethics 10(4), pp. 78-84.

64
Gas Reflux in Children

GALOȘ Felicia1,2, BOBOC Cătălin2, STOICESCU Mihai1,2, MUNTEANU Mihai2,

BĂLGRĂDEAN Mihaela1,2
1University of Medicine and Pharmacy Carol Davila Bucharest (ROMANIA)
2Marie Curie Children’s Emergency Hospital Bucharest (ROMANIA)
Emails: felicia_galos@yahoo.com, catalin.boboc@hotmail.com, stoima@gmail.com, munteanusen@yahoo.com,
mbalgradean@gmail.com

Abstract

Background
Multichannel intraluminal impedance (MII) recording allows the assessment of flow through the
oesophagus and the differentiation between liquid and gas contents.

Aim
We aimed to evaluate the role of gas reflux in children diagnosed with pH-metry associated with
MII (MII-pH).

Methods
We performed a retrospective study, examining all of our recordings of patients suspected of
gastro-oesophageal reflux (GOR) evaluated with MII-pH and selected the ones with pathological gas
reflux. The lowest value for pathological gas reflux was 72. The following parameters were evaluated:
reflux index, the number of acid reflux episodes detected with pH-metry, the total number of reflux
episodes detected by impedance, the number of acid reflux episodes, the number of weakly acidic
reflux episodes, the number of weakly alkaline reflux episodes and the composition of the reflux:
liquid, mixed or gaseous.

Results
32 children (18 male) were selected for the study, according to protocol regulations, aged between
4 months and 16 years (mean age of 3 years and 5 months). Using MII, 3586 gaseous reflux episodes
and 3970 liquid and mixed reflux episodes were identified. Predisposing conditions for gaseous reflux
were identified in 24 children: 20 children were diagnosed with alimentary allergies (17 non IgE
mediate) and 4 children with small intestinal bacterial overgrowth detected through glucose breath
test. 11 patients were treated with proton pump inhibitors for acid RGE.

Conclusions
MII allows the detection and characterization of GOR, including gaseous reflux. The majority of
children with gaseous reflux in our study were allergic (62.5%).
Keywords: gas reflux, child

Introduction

Gastro-oesophageal reflux (GOR), defined as the passage of the gastric content in the oesophagus,
is a physiological event found in infants, children and healthy adults in the postprandial period.
Physiological GOR episodes are characterized by the absence of symptomatology, short duration
and limited extension of the distal oesophagus. [1] Transient lower oesophageal sphincter relaxation

65
(TLOSR) is the main underlying mechanism of GOR in healthy volunteers and patients with GOR
disease in all age groups. [2], [3] This has been shown for both liquid and gas GOR. [4]
Multichannel intraluminal impedance measurement (MII) was recently introduced for the
detection of flow of liquids and gasses throughout the oesophagus. Conductive fluids within the
oesophagus, such as saline or refluxate, will lower baseline impedance values, while gases are non-
conductive and will increase impedance values. [5] Oesophageal impedance monitoring is a technique
for determining the physical characteristics (liquid, gas, or mixed) of refluxate, and combining
impedance monitoring with pH recording (pH) makes it possible to assess whether reflux is acid or
non-acid. MII-pH is the only method with high sensitivity for detecting all types of reflux. [6]
The role and normal values of gaseous reflux are debated issues. [6], [7], [8], [9] It has been
reported that gas or gas-containing reflux which reaches the proximal oesophagus are important
causes of symptoms in GOR disease patients. [10]
Whether lower oesophageal sphincter (LOS) motility could also be affected by exposure of the
colon to malabsorbed carbohydrates or gas production of small intestinal bacterial overgrowth is
presently unknown. Piche et al. [11] shows that colonic fermentation, through the production of short-
chain fatty acids (SCFAs), exerts a controlled feedback on LOS motor function. SCFAs production
may result in decreased gastric tone and delayed emptying, conditions known to be associated with
GOR disease. Whether the mechanism of this phenomenon is of hormonal nature, neural nature, or
both remains to be determined. Their data suggest that hormonal pathways are involved in the
observed chances in LOS motility. Some regulatory peptides such as glucagon-like peptide 1 (GLP
1) and peptide YY (PYY), which are colocalized in the endocrine L cell of the distal intestine, have
been proposed as ileocolonic mediators of upper gastrointestinal inhibition under several conditions
[12].
Allergy and intestinal dysmotility are certainly fellow-travellers and conditions as diverse as infant
colic, gastro-oesophageal reflux, delayed gastric emptying, visceral hyperalgesia, irritable bowel
syndrome and constipation have all been linked at some stage with dietary allergies [13].
The aim of our study was to evaluate the role of gas reflux in children evaluated with MII-pH
monitoring. Furthermore, we aimed to identify favouring causes of gaseous reflux, to help the
clinician in treating these patients.

Materials and Methods

Subjects
We performed a retrospective study, examining all of our MII-pH recordings of patients who were
referred to Marie Curie Children’s Emergency Hospital of Bucharest for gastro-oesophageal reflux
assessment. Patients were selected on the basis of the presence of at least 72 gas reflux episodes.
32 children (mean age 3 years and 5 months; range 4 months – 16 years, 18 male) were identified.

Oesophageal pH-Impedance Measurements

Oesophageal impedance-pH monitoring was performed using an ambulatory system (Digitrapper
pH-Z Monitoring Given Imaging). The system included a portable data logger with impedance-pH
amplifiers and MII-pH catheter with an outer diameter of 2.13 mm (6.4 F), containing one pH-
measuring electrode and seven impedance sensors. Different age appropriate impedance catheters
were used: infant (height < 75 cm), paediatric (height >75 cm and < 150 cm), and adult (height >150
cm).
The distance between impedance rings was 1.5 cm in infantile MII-pH catheters, and 2 cm for the
paediatric and adult catheters. The pH electrode was localised in the middle of the last MII channel
in infant and paediatric catheters, and the one immediately proximal to it, in adult catheters. [14], [15]
On the day of MII-pH monitoring, infants fasted for at least 3 hours, and children for at least 6
hours. Before the procedure, the pH electrode was calibrated using pH 4 and pH 7 buffer solutions.

66
 The MII-pH catheter was introduced through the nose and fluoroscopically positioned so that the
pH measuring electrode was over the second vertebral body above the diaphragm at the level of the
vertebral column. Strobel formula was used to estimate the appropriate probe location. Each
participant ate a regular diet. Parents and older children were instructed to keep a diary, recording
meal times, body position (upright or recumbent), daily activities, and timing of any symptoms.

Data Analysis
We analysed data by specific software, and them all the MII-pH studies were manually reviewed
for each patient. Meals were excluded from analysis.
Regarding impedance, reflux events were classified as liquid mixed or gas containing. Liquid
reflux events were defined as a retrograde drop in impedance of at least 50% of the baseline in at least
2 distal impedance channels. Gas-only refluxes were defined by an increase in impedance > 3000
Ohm in any 2 consecutive impedance sites. Mixed reflux events are a combination of both liquid and
gas reflux patterns. According to the corresponding pH changes, reflux episodes were classified as
acidic (pH<4.0), weakly acidic (pH 4-7) and weakly alkaline (pH>7). [13], [14], [15]
The following parameters were evaluated: reflux index, the number of acid reflux episodes
detected with pH-metry, the total number of reflux episodes detected by impedance, the number of
acid reflux episodes, the number of weakly acidic reflux episodes, the number of weakly alkaline
reflux episodes, the composition of the reflux: liquid, mixed or gaseous.

Statistical Analysis
All data are expressed as mean± standard deviation of the mean unless otherwise stated. Single
comparisons were made an unpaired Student t test (parametric data) or Mann-Whitney U test
(nonparametric data) where appropriate. Correlations were tested by using the Spearman and Pearson
tests. The Fisher exact test was used to test proportional differences. Significance was declared at
p<0.05.

Results

Thirty-two children (mean age 3.5 years, range 0.4-16 years, 18 male) were enrolled in the study.
Of this, twelve had failure to thrive, nine, eating disturbance, six extraoesophageal symptoms,
represented especially by chronic chough, recurrent wheezing, and five, respectively four had
recurrent abdominal pain and chronic vomiting. (Fig. 1)

Chronic vomiting 4

Recurrent abdominal pain 5

Extraoesophageal symptoms 6

Eating disturbance 9

Failure to thrive 12

0 5 10 15
Fig. 1. Sign and symptoms at diagnosis

MII-pH monitoring detected 3970 reflux episodes. Of those, 954 (24.03%) (mean 29.81±22.36)
were classified as weakly acidic as detected only by impedance sensors, and 3016 (75.97%) were
classified as acid reflux. Of the acidic events, 954 (24.03%) were detected by both impedance and
pH sensors (mean 26.65±22.11) where 2062 (51.96%) by pH sensor alone and classified as pH-only
reflux episodes. Impedance analysis showed that 63.40% of the total reflux episodes were liquid

67
(mean 37.78±24.44), and 36.60% (mean 15.03±11.66) were mixed. No weakly alkaline reflux was
found (Fig. 2).

Fig. 2. Reflux episodes detected by MII-pH monitoring

Impedance analysis detected 3586 gas reflux episodes (mean 112.06±43.21). Underline that the
patients were selected on the basis of the presence of at least 72 gas reflux episodes.
Pathological acid GOR was noted in 11 (34.37%) subjects, and these benefited from proton pomp
inhibitors treatment. No statistical correlation was found between acid GOR and the nutritional status
of children, but statistical correlation was found between allergic status and failure to thrive (p=0.02)
(Fig. 3).
12
p=0.02
10

6 Normal weight
Failure to thrive
4

0
Allergic Non-allergic
Fig. 3. Corelation between allergic status and failure to thrive

Twenty children (62.50% of the total number of patients) (seven infants) were diagnosed with food
allergy; of these 17 with non-Ig E mediated food allergy.
Four children were diagnosed with SIBO (12.50%), and two children were constipated and treated
accordingly.

Discussion

Because it is ethically not possible to perform MII-pH recording in asymptomatic health children,
real normal ranges are not available. The abnormal MII study if the measurement fulfils the following
criteria: high number of reflux episodes (arbitrarily defined as >70 episodes in 24 hours in patient
aged 1 year or older and >100 episodes in those younger than 1 year. [14], [15] If the number of acid
or non-acid reflux episodes in children was obtained with the expert’s consensus, the normal range
of gas reflux in the adult population and children is not known. Therefore, there is a need for evidence
based criteria, which can more reliably detect gas GOR episodes. We used arbitrarily the abnormal
value for gas reflux over 72, according with available data [6], [7], [8], [9].
It was important to use MII-pH monitoring, because we established that there was no air
swallowing. Aerophagia in childhood is defined by the Rome IV criteria [16]. Multichannel

68
intraesophageal impedance resulting in a specific pattern characterizes aerophagia. An air swallow is
defined as a peak superior to 1000 ohms above baseline moving in the antegrade direction and
measured in the most distal impedance segment [17], [18], [19]. Air swallowing during eating and
drinking is a normal physiological event. In healthy children, each swallow transports a certain
quantity of air to the stomach. The stomach protects itself against excessive distension through
belching. Transient lower oesophageal sphincter relaxation (TLOSRs), triggered by gastric
distension, is the main mechanism underlying reflux events. It has been shown that TLORSs are
generated in response to gastric distension in both health and GORD and they occur more frequently
after meals. The activation of mechano-sensitive receptors in the proximal stomach, by stimuli such
as air, meal intake, starts a vago-vagal reflex arc that involves central processing and the circuit is
completed via a short burst of inhibitory vagal input to the lower oesophageal sphincter (LOS) [20].
Patients with aerophagia present supragastric belches more specifically, due to excessive air
swallowing [17]. With multichannel impedance recording we were able to demonstrate the two
different types of belching. The first type is characterized by an increment of intraluminal impedance
moving in the oral direction, representing venting of gas from the stomach and can be referred to as
gastric belching. The second type, characterized by a rapid antegrade impedance rise followed by a
rapid retrograde return to baseline represents esophageal air ingestion followed by immediate
expulsion. Whereas gastric belches were found both in patients and healthy children, supragastric
belches were only seen in patients with excessive aerophagia [19].
It is important to realize that not all gas GOR episodes (retrograde flow of gas from the stomach
into esophagus) fall under the definition of a belch (a subjective perception, which is assumed to be
the result of gas GOR episodes and is often accompanied by airflow from the mouth [19]. Belching
occurs occasionally and is regarded as normal behavior. In a patient with excessive belching, gastric
and supragastric belches are distinguished and this distinction has consequences for therapy.
Excessive belching is a behavioral disorder and should be treated as such.
After excluded air swallowing with MII recording, we focused on the favouring conditions for gas
reflux. We analysed small intestinal bacterial overgrowth (SIBO) by breath glucose test (LactoFAN)
and food allergy.
Piche et al [11] shows that colonic fermentation, through the production of short-chain fatty acids
(SCFAs), exerts a controlled feedback on LOS motor function. SCFAs production may result in
decreased gastric tone and delayed emptying, conditions known to be associated with GOR disease.
Whether the mechanisms of this phenomenon are of hormonal nature, neural nature, or both
remains to be determined. Their data suggest that hormonal pathways are involved in the observed
chances in LOS motility. Some regulatory peptides such as glucagon-like peptide 1 (GLP 1) and
peptide YY (PYY), which are colocalized in the endocrine L cell of the distal intestine, have been
proposed as ileocolonic mediators of upper gastrointestinal inhibition under several conditions [12].
In our study, 12.50% of children were diagnosed with SIBO, but, we use the glucose breath test
only for older children capable of collaboration.
With surprise, we found the majority of our children had food allergy (62.50%). We have not
found another study about this argument (gas reflux and food allergy) to compare the results. We
suppose the intestinal dysmotility to be the cause, with all the mechanisms which involve food allergy,
which involve T cell mediated responses, mast cell mediated responses and eosinophil mediated
responses. Gut flora has bi-directional effects. Flora may modulate motility and vice versa [13].

Conclusion

The type of reflux and the presence of gas in the refluxate could be relevant in the pathogenesis of
symptoms. In this sense, we recommended using pH-metry associated with multichannel intraluminal
impedance when we suspected gastro-oesophageal reflux disease in order to detect all types of reflux
and their composition: liquid, mixed and gas. The majority of children with gaseous reflux in our
study were allergic (62.5%).
This article is one of the first to debate gas reflux in children and the favouring conditions for it.
69
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(NASPGHAN) and the European Society Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN). J
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2. Dent j, Holloway RH, Toouli J, et al. Mechanisms of lower oesophageal sphincter incompetence in patients with
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70
IBS

71
Markers of Inflammation in IBS: Road Still Open?
CHIRA Alexandra1, CHIRA Romeo Ioan2, DUMITRASCU Dan Lucian1
1 2nd Medical Clinic, Department of Internal Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy Cluj-Napoca,
(ROMANIA)
2 1st Medical Clinic, Department of Internal Medicine, Div. Gastroenterology, “Iuliu Hatieganu” University of Medicine and

Pharmacy Cluj-Napoca, (ROMANIA)

Emails: alexandra_rusu_22@yahoo.com, romeochira@yahoo.com, ddumitrascu@umfcluj.ro

Abstract

Irritable bowel syndrome (IBS) one of the most frequent functional gastrointestinal disorders is
highly prevalent across the globe. We aimed to review the available data on the markers of
inflammation in IBS, those assessed from blood and that could be useful for a positive diagnosis.
In order to find the appropriate data, we screened the studies that responded to our questions and
those were selected.
Multiple biomarkers (BM) have been proposed and investigated in IBS. Pro-inflammatory and
anti-inflammatory cytokines were assessed in various components of the blood. Some of the
cytokines, like: interleukin (IL) IL-6, IL-8, IL-1β, transforming growth factor-β had higher blood
levels in IBS than controls, for others like tumour necrosis factor-α, interferon-γ, IL-10 or IL-12
results are discordant.
After numerous years of research, we are still in search for a reliable biomarker or a set of
biomarkers for IBS. A restricted number of markers of inflammation are available and though some
were assessed, their use is still missing. There is still an open road in discovering a specific and
reliable BM in IBS.

Keywords: IBS, inflammation, biomarker

Introduction

Irritable bowel syndrome (IBS) is a frequent gastrointestinal disorder, highly prevalent worldwide
[1-3].
Since diagnosis still relies on clinical criteria [4, 5] efforts have been made to identify a biomarker
(BM) specific for IBS. During several decades we have expected a reliable biomarker, since
researchers have assessed multiple biomarkers, starting from the pathways that were investigated in
IBS [6, 7].
The study of IBS has already a long history, and still there are many unknowns.
Various medical specialities investigate the mechanism of IBS, as this could lead to the
development of a specific biomarker for IBS. The ethiopathogenesis of IBS is now considered to be
multifactorial [6, 8, 9] with various pathways that are dysregulated such as: the gastrointestinal
motility [10], the balance of pro- or anti-inflammatory systems [11, 12], brain-gut interactions [13,
14].
One of the first hypothesised cause that would lead to IBS was inflammation [15]. After this was
proves, the concept of a “low-grade inflammation” was sustained [16-18]. BM proposed in IBS were
assessed from various biological samples: blood, faeces and even exhaled air [19-21].
Our purpose was to review data available on the markers of inflammation assessed from blood in
IBS, the current status of knowledge and their clinical applicability, focusing on the new potential
BM. In order to find the appropriate data, we performed several types of search using PubMed motor.

72
Cytokines
Various cytokines have been investigated in IBS. Cytokines are soluble mediators, proteins or
glycoproteins with various functions, which are secreted by a broad range of cells, such as:
macrophages, T- and B-lymphocytes, mast cells [22, 23]. Cytokine balance is highly important for
our immune system [11, 16]. Regarding the altered balance of pro- and anti-inflammatory cytokines
there are already systematic reviews and meta-analysis available just for some of the cytokines [12].
Many of the authors assessed multiple BM, considering the various pathways that lead to IBS [6,
7, 24].
If some assessed just 1-3 BM [25-28], other proposed complex strategies [6, 7, 24].
A lot of the studies assessed a combination of pro- and anti-inflammatory [25, 27-31].
Despite their efforts, there is still an ideal BM to be found.
Pro-inflammatory cytokines
Some pro-inflammatory cytokines have been assessed in IBS. Of these cytokines, more data are
available on in interleukin (IL): IL-6, tumour necrosis factor (TNF)-α, interferon (IFN)-γ.
IL-6 was assessed by multiple studies [23, 29, 31-33]. The studies reported significantly statistic
higher levels in IBS patients versus healthy controls, as concluded also by a systematic review [34].
Another IL, IL-8 was studied [29]. Statistic higher levels of IL-8 were found in IBS patients versus
healthy controls. Some of the studies assessed though IL-8 only in IBS-D [25, 35].
There are few data regarding blood levels of IL-1β [6, 29, 33], more data being reported regarding
mucosal levels. Available data on blood levels, indicate higher levels in IBS patients than healthy
controls [29, 33].
IL-12 was also studied. If in a study IL-12 had lower levels in IBS than in controls [36], other
studies reported higher IL-12 levels in patients with IBS than in healthy children [37].
TNF-α is another pro-inflammatory cytokine that was intensively researched [11, 31, 32, 38-40].
As result of a systematic review and meta-analysis authors concluded that serum or plasma TNF-
α levels had a trend of higher levels in IBS versus controls [12]. If data included in the meta-analysis
indicated higher levels in IBS, concordant with results of Darkoh et al.[11], a study published later –
in 2015, reported no difference of TNF-α levels in IBS patients versus controls [37].
IFN-γ was determined in IBS [11, 29, 41]. No differences were observed between IBS patients
and controls in one study [29], while other authors reported that IFN-γ tended to have lower levels in
IBS patients [41], or others found significantly higher levels in IBS patients [11].
There are also other types of studies, those that assessed gene polymorphisms in IBS:
polymorphisms of IL-8, IL-10, TNF-α were also investigated in IBS [42-46], or others that assessed
various SNPs [44, 47] or genome-wide association studies [48]. Also, other studies assessed some of
the cytokines after some type of interventions, such as the changes induced in the cytokine level after
a certain diet [49]. IL-8, -10 haplotypes were studied, IL-8 and IL-10 ACC were associated with a
susceptibility to develop IBS [42].
A recent review appraises the potential role of IL-10, as a therapeutic target in IBS [50].
Anti-inflammatory cytokines
IL-10 is the most studied anti-inflammatory cytokine in IBS [28, 31, 32, 38-40] Bashashati et al.
[12] found in the meta-analysis of the studies that assessed IL-10 that blood levels of IL-10 were not
significantly statistic different between IBS patients and controls and statistical significance was
reached only in male patients with IBS compared to male controls. Another study though, reports
levels significantly statistic higher in healthy volunteers than in IBS patients [11]. Most recent data
reported lower levels of IL-10 in IBS patients versus controls [37]
Few data are published on transforming growth factor (TGF)-β, another anti-inflammatory
cytokine, which was found to be significantly statistic higher in IBS patients [37]. Also, TGF-β gene

73
polymorphisms study has been conducted [47]. In view of the importance of TGF-β pathway in
regulating stem cells and mucosal immunity [51], we expect more data regarding TGF-β in IBS.
Regarding other anti-inflammatory cytokines, such as IL-4 and IL-13, these were also less studied
[11, 28].

Conclusions

After numerous years of research, we are still in search for a reliable biomarker or a set of
biomarkers for IBS. Limited markers of inflammation are available, of which some were assessed,
but their application is still missing. Although there is evidence of an imbalanced inflammatory status,
still these markers are not approved for diagnosing IBS. There is still an open road in discovering a
specific and reliable BM in IBS. Rigorous studies with a higher number of study population are
mandatory to validate existing BM or to detect new ones.

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Diet in IBS: Old Problems. New Solutions?
IOAN Chirila1,2

1 NationalInstitute of Public Health – RCoPH Iasi (ROMANIA)

2 Universityof Medicine and Pharmacy “Grigore T. Popa” – Iasi (ROMANIA)
Email: chirilaioan@yahoo.com

Abstract
Irritable Bowel Syndrome (IBS) is a common digestive disease and have a clear impact on patient’s
quality of life. The role of diet in the pathophysiology and management of IBS is still under evaluated.
Food may precipitate the symptoms, acting through several mechanisms, depending on food
composition, intestinal microbiota and reaction of the body (abnormalities in gut hormones,
controlling gastrointestinal motility and visceral hypersensitivity). The dietary approach includes
lifestyle changes, elimination of certain food (e.g. dairy products or fermentable carbohydrates) or
supplementation with others (fiber, pre-, pro-biotics).
Keywords: irritable bowel disease, food, diet,

Prevalence of IBS
Irritable Bowel Syndrome (IBS) is a common cause for medical referral and has a clear impact on
the patient quality of life and also on the medical system spending, needing a chronic care and a
personal responsibility for health [1, 2]. During years, definition criteria for IBS have evolved from
Manning and Kruise criteria’s to Roma I and Roma IV criteria’s [3] and it is difficult now to have
clear conclusions when we are comparing studies with different definitions for IBS. The worldwide
prevalence of IBS varies according to location and design of the study from 1.1% [4, 5] – to 22% [6].
Most western studies revealed figures between 15-20% [7]. IBS seems to be more prevalent in
women, independent of age [8], and ethnic groups. However, IBS is somehow more frequently
present in western European countries than in Asia Pacific [9] and in white population compared with
Afro-Americans [10].
The studies conducted in Romania revealed IBS prevalence of 14.49% (8.4% man and 17.7%
women), on the general population from Romania, using Rome I criteria [11], and 19.17% (19.47%
for females and 18.75% for males) using Rome 3 criteria [12].
IBS is a complex condition with multiple etiological and pathophysiological factors: genetics,
environment and lifetime events with changes in motility, central processing, visceral sensitivity,
immunity, epithelial permeability and gastrointestinal microflora [13]. Clinical investigations in IBS
involve many difficult methodological and ethical issues, especially when dietary trials are required
[14, 15].

IBS and food

Although many patients recognize the impact of specific food in symptom occurrence, very few
population-base studies evaluated the importance of diet in IBS and its role remains uncertain and
under-studied [16, 17]. Even many patients report that food may precipitate or aggravate their
symptoms, only one population-based study evaluated its role in IBS and the results suggested that
food sensitivity rather than different diet composition may be related to IBS [6].
Food and IBS relationship
Although it has been shown an association between diet and all functional digestive disorders [18],
the most obvious relationship is for IBS. 2/3 of IBS patients associated symptoms with certain foods;

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28% describe the appearance of symptoms in 15 minutes after the meal and 93% up to 3 hours. Foods
that have a trigger role are milk and dairy, meat products, bread (wheat), beans/peas, cabbage, onions,
spicy, fried, smoked foods, coffee, alcohol. Dietary restrictions (which occurred in 62% of IBS
patients) may lead to nutritional deficiencies (in 12% of cases) – for example, a supposed “lactose
intolerance” lead to consumption of small amounts of milk and dairy, with low intake of calcium,
vitamin B2 (riboflavin), phosphorus [19].
Compared with healthy subjects, in IBS patients occurred some diet changes: low consumption of
vegetables (cabbage, broccoli, peppers, onions, leeks, garlic, tomatoes, mushrooms and green beans),
grains (pasta, rice, millet, couscous), dairy, alcoholic beverages and a high consumption of fruits
(grapes, pears, peaches, mango, peas, plums and cantaloupe) and milk-alternatives (soy, rice, oats
milk) [20].
In North-East Romania, the subjects IBS are eating significantly more frequent than general
population the following foods: canned food (p<0.001), processed meat (p<0.01), beef meat
(p<0.001), milk (p<0.05), pulses (legumes)(p<0.05), cereals or grain bread /pasta (p<0.01), cafeteria
products (p<0.01), fruits compotes (canned or not) (p<0.001), herb teas (p<0.001) [12].
Food and physiopathology of IBS
Certain categories of food (canned food, processed meat, milk, high carbohydrates vegetables,
pulses, whole cereals, confectionary, compotes or herb teas) were significantly related to IBS. Food
may contribute to symptom onset through several mechanisms including food allergy and intolerance.
Also, certain food may alter the composition of the luminal milieu, either directly or indirectly
through effects on bacterial metabolism. Finally, IBS symptoms may develop following exposure to
food-borne pathogens [17].
Specific food intolerance (for example, lactase deficiency) may explain the symptoms for a part
of the patients [21-25].
Food composition and IBS
Depending on the intraluminal content of proteins, carbohydrates, fats, some intestinal hormone is
released into the interstitial spaces and will act about endocrine/paracrine as a
neurotransmitter/neuromodulator on neurons in the enteric nervous system. (CCK, cholecystokinin;
GIP, gastric inhibitory polypeptide; NPY, neuropeptide Y; PP, pancreatic polypeptide; PYY, peptide
YY)
Restrictive diets in fructose and sorbitol together with other fermentable carbohydrates can lead to
improvement of symptoms of IBS. Challenge tests with lactose, fructose, sorbitol, fructo-
oligosaccharides cause IBS-like symptoms – bloating, abdominal pain, nausea, abnormal transit.
Fermentable Oligo-saccharides Di-saccharides Mono-saccharides and Polyols (FODMAPS) and
insoluble fiber increase the osmotic pressure in the large-intestine lumen and provide a substrate for
bacterial fermentation, with consequent gas production, abdominal distension and abdominal pain or
discomfort [26, 27].
Increased intake of insoluble fiber in patients with IBS increased symptoms of abdominal pain,
bloating and distension and does not improve symptoms compared with placebo or a low-fiber diet,
while intake of soluble fiber is effective in improving general symptoms of IBS in relation to
consumption of insoluble fiber [28, 29].
Fibers and FODMAP effects on IBS symptoms are strongly associated with intestinal flora. IBS
patients’ intestinal flora contains a lower population of Lactobacillus spp. and Bifidobacterium spp.
flora than healthy individuals. If Clostridium spp. are dominant in the intestinal flora, then fibers and
FODMAP are decomposed with production of gas and bowel distension (causing abdominal
discomfort or pain) [30]. Food supplements with beneficial bacteria (Lactobacillus spp. and
Bifidobacterium spp.) lead to greater tolerance to fiber and FODMAP (no fermentation gases) [31].
Prebiotics are food ingredients, fermentable, allowing modifications in composition and/or activity
of gastrointestinal microflora. They are natural (eg. inulin) from leek, asparagus, chicory, artichokes,

78
garlic, onions, wheat, oats and soybeans or added (inulin, galacto-, fructose-oligosaccharides) in
yogurts, cereals, bread, cakes, ice creams, beverages, supplements [32].
Food intolerance and allergy and the presence of food additives may play a role in the occurrence
of the IBS-like symptoms – 60% of patients with IBS had at least one positive dermal test and 27%
reported symptomatic improvement if avoid additives/food for which had a positive reaction [33].
Nutrition-based interventions in IBS patients
Despite the difficulty to conduct a dietary trial and to prove the efficacy of a dietary intervention
[34], the dietary approach seems to have acquired recognition as a valid therapeutic alternative [35].
Also, comparative studies with pharmacotherapy are needed, although the mechanisms of action
might be different – usually pharmacotherapy in IBS (e.g. Mebeverine) is oriented mainly towards
symptom control [36].
British Dietetic Association proposed evidence-based guidelines for the dietary management of
irritable bowel syndrome in adults including eliminate dairy (in lactase deficiency proven by lactose
breath test and in cow’s milk protein allergy), use of non-starch polysaccharides (avoiding wheat bran
supplementation and additional flaxseeds for 3 months in IBS-C), remove and re-introduction in the
diet of fermentable carbohydrates (FODMAP), use of probiotics (one product once – assessing the
effects of 4 weeks) and also empirical/elimination diet (for 2-4 weeks, following the triggers
symptoms of SII- D) [37].
Probiotics are an effective pharmacological therapy in IBS patients. In diarrhea-predominant IBS
patients, single probiotics with a short treatment duration appear to be more effective in improving
symptom response and quality of life, but in IBS-C subjects’ multispecies probiotic supplementations
are more effective inducing a different composition of intestinal microbiota [38-40].
Some nutraceutical products were tested successfully for the treatment of IBS: peppermint
essence, curcumin (from turmeric, decreased abdominal pain intensity and improved quality of life),
anethole (from fennel seeds oil, similar to dopamine, reduced crampiform abdominal pain) [41].
A practical dietary approach to IBS may be conducted in 3 steps: first, improving lifestyle and
eating habits, second, specific changes in diet for constipation, diarrhea or meteorism and third,
elimination diets for food intolerance or FODMAP.

Conclusion

Food plays an important role both in the pathophysiology and in the treatment of Irritable Bowel
Syndrome. The dietary approach has acquired recognition as a valid therapeutic alternative but still,
there are needed clarifications of the underlying mechanisms of action and long-term and comparative
studies with the pharmacological approach to IBS.

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Fecal Calprotectin – Can Differentiate IBD from IBS?

DRANGA Mihaela1,2, MIHAI Cătălina1,2, MIHAI Bogdan1,3, GAVRILESCU Otilia1,2,

CIJEVSCHI PRELIPCEAN Cristina1,2
1 University of Medicine and Pharmacy “Grigore T. Popa”(ROMANIA)
2 Institute of Gastroenterology and Hepatology Iasi (ROMANIA)
3 Clinic of Diabetes, Nutrition and Metabolic Diseases, St Spiridon Hospital Iasi (ROMANIA)

Emails: mihaela_dra@yahoo.com, catalinamihai@yahoo.com, bogdanmihai2003@yahoo.com, otilianedelciuc@yahoo.com,

cristinacijevschi@yahoo.com

Abstract

There are many common features between inflammatory bowel disease (IBD) and irritable bowel
syndrome (IBS). Clinical assessment, laboratory tests, endoscopy and various imaging modalities has
been the main methods for diagnosis for many years. Accurate diagnosis is established by
colonoscopy, but the method is invasive and expensive. Laboratory markers have low sensitivity and
specificity. The presence of inflammation in the colon can be detected by fecal markers, especially
by fecal calprotectin. The aim of the study was to analyze the role of fecal calprotectin in
differentiating beetween IBD and IBS. Material and methods. We conducted a prospective study that
include 2 groups: 58 patients with IBD and 46 patients with IBS. For all the patients we analiyzed the
biological profile and the values of faecal calprotectin – by semiquantitative immunochromatographic
rapid test. Results. 1. There was significant differeces of the values of albumin, erythrocyte
sedimentation rate (ESR), C-reactive protein (CRP) and fecal calprotectin between the two groups
studied. 2. The sensitivity and specificity of studied markers for IBD are the following: albumin
53.38% and 50.56%; ESR 55.17% and 54.42%; PCR 74.27% and 63.67%, faecal calprotectin 86,54%
and 95.8%. Conclusions. Fecal calprotectin proved a good diagnostic power for differential diagnosis
between IBS and IBD.

Keywords: fecal calprotectin,semiquantitative rapid test, irritable bowel syndrome, inflammatory bowel disease

Introduction

The Irritable Bowel Syndrome (IBS) is a functional bowel disorder defined exclusively by clinical
criteria: change in bowel habits and abdominal pain and discomfort in the absence of detectable
organic lesions or biochemical modification [1]. The clinical picture is heterogeneous, as the
symptoms include diarrhoea, constipation, bloating or abdominal pain. Generally, the patients’
symptomatology evolves within years, and in some cases even in decades [2].
Three forms of IBS are described: diarrhoea-predominant, constipation-predominant, or
abdominal-pain predominant [3].
The prevalence of IBS has been estimated to be in between 10% and 20% of the adult population
and it is twice more frecquent in women than in men. Althought only 30% of the patients seek medical
help, representing 20-50% of consultations, the costing reports in USA are up to 30 million dollars
per year [4].
Ulcerative colitis (UC) and Crohn disease(CD) are the two most common forms of IBD. They are
being remitting and relapsing conditions with a variable course of progression.
For a certainty diagnosis, colonoscopy is necesary. But these is a costly procedure, with risks and
discomfort for the patient. Because of the significance of making a diagnosis of IBD versus IBS, there
has been significant interest in developing biomarkers that can aid diagnosis.

82
 Serologic markers, such as C-reactive protein (CRP) and the erythrocytes sedimentation rate
(ESR) have a reduced sensitivity and specificity for the diagnosis of inflammatory bowel diseases
[5].
Validated on large study samples, the faecal calprotectin proved to be effective in the differential
diagnosis between IBD and IBS [6, 7].
The great advantage of faecal calprotectin is that is not influenced by other extraintestinal
conditions [8]. it can be detected for small values of the inflammation, insufficient to cause an increase
in ESR or CRP.
Within this context, the present study aims to analyze the role of fecal calprotectin in
differentiating beetween IBD and IBS.

Material and methods

We conducted a prospective study between january 2016 and Decembre 2016. The study included
two groups: the first group consisted of 46 patients with IBS, while the second group consisted of 58
patients with IBD.
For all patients, we determined the following parameters: haemoglobin, hematocrit, red cell
indices, leucocytes, platelets, ESR, fibrinogen, CRP, total protein, serum albumin.
Colonoscopy was used for certify the diagnosis of IBD and to exclude other conditions in patients
with IBS.
The fecal calprotectin was determined through the semiquantitative rapid test CalDetect® SOFAR
prior to colonoscopy.
The control line appears immediately and shows the viability of the test. The results are read after
2-3 minutes. The first band occurs in the calprotectin concentration that is lower than15μg/g and it
shows the absence of inflammation. The second band appears at a concentration comprised between
15μg/g and 60μg/g, in the presence of acute inflammation. The third band shows a high degree of
mucous inflammation and occurs at a value of calprotectin that is higher than 60μg/g.
The data was centralised in SPSS 18.0 databases and interpreted by means of the corresponding
statistical functions, for a confidence interval of 95% (CI 95%). The assessment of sensitivity and
specificity was carried out by drawing the ROC (Receiver Operator Characteristic) curve.

Ethical considerations

The protocol was approved by the local ethics committee. All participants signed an informed
consent.

Results

The two groups were matched in order of gender, age and area of rigin so there were no significant
differences between the two groups. The patients in the IBS group were predominantly female, while
the IBD group was predominantly male (61.7% vs. 58.3%; p=0.068).
The mean age was higher in the IBS group, compared to the age recorded in the IBD group (49.22
vs. 1.23 years; p=0.053).
In both study samples, the patients’ area of origin was predominantly urban (83% vs. 84.9%;
p=0.082).
The abdominal pain was recorded in approximately two thirds of the patients in both groups.
Eightysix percent of the patients with IBD and 65.9% of the patients with IBS have diarrhoea. The
most significant difference was recorded in the patients presenting rectorrhagia. These were met in
more than half of the patients with IBD, but also in a quarter of the patients with IBS.

83
 Analysing the biological parameters, it can be noticed that the significant differences between the
two group have: serum albumin, inflammatory markers (ESR, CRP) and calprotectin in patients with
IBD (Tab. I).

Table I. Average values of the laboratory markers compared on the study samples
IBS group (n=46) average±SD CD group (n=58) P values for
Biological marker
(extreme) average±SD (extreme) FANOVA test
Serum albumin (g/l) 47.64±5.19 37.87±8.72 0.001
(30.66-58.40) (19-54.9)
ESR (1 mm/h) 3.75±2.65 20.26±18.84 0.001
(1-14) (1-89)
CRP (mg/dl) 0.59±0.46 3.0±5.78 0.001
(0.04-1.62) (0.04-25.61)
Calprotectin, n (%)
T1
T2 45 (95.7%) 36 (66.0%) 0.001
T3 1 (4.3%) 12 (20.8%)
- 8 (13.2%)

The analysis of the Receiver Operating Characteristic (ROC) curve points to a sensitivity of
54.38% and a specificity of 50.56% for albumin. ESR sensitivity was 54.87% and ESR specificity
was 55.12%, while the values for CRP were 73.77% in sensitivity and 64.87% specificity, when
distinguishing between IBS and IBD. The best values for sensitivity and specificity were those
recorded for faecal calprotectin, namely 96.54%, and 95.83% (Tab. II, Fig. 1).

Table II. Balance sensitivity/specificity for serum albumin, ESR, CRP and calprotectin in patients with IBD
Biological VPP (%) VPN (%) Sensitivity (%) Specificity (%) Accuracy p
marker
Albumin 66.80 40.84 53.38 50.56 52.47 0.001
ESR 95.74 50.19 55.17 54.42 55.00 0.001
CRP 95.74 69.81 74.27 63.67 69.32 0.001
Calprotectin 95.74 46.79 86,54 95.83 96.19 0.001

1.2

0.8
sensibilitate

0.6

0.4

0.2 Calprotectina
PCR
VSH
albumina
0
0 0.1 0.2 0.4 0.6 0.8 1

1-specificitate

Fig. 1. ROC curve for serum albumin, ESR, CRP and Calprotectin level in patients with CD

Discussions

Because of the similarity of symptoms, it is sometimes difficult to differentiate between IBS and
IBD. This can lead to delayed IBD-specific treatment and progression to more complicated forms.
On the other hand, in order to exclude major lesions in patients with abdominal pain or diarrhea,
it is necessary to perform colonoscopy, most of the result being negative.

84
 On the other hand, the presence of clinical manifestations, such as diarrhea or abdominal pain,
requires colonoscopy to rule out the existence of organic lesions. Often the result of colonoscopy is
negative. Rectorrhagia is an alarm signal that requires colonoscopy. However, it may be present up
to 20% of patients with IBS [9], similar to our study.
ESR and CRP are markers of inflammation that grow during acute phase periods with reduced
sensitivity and specificity for inflammatory bowel disease [5].
A recent meta-analysis of 30 prospective studies compared the diagnostic strength of calprotectin
with histopathological diagnosis. Calprotein sensitivity was 95% and the specificity was 91%, with
an ROC under the curve of 0.95 for a calprotectin value of 100μg/g [10].
In a recent study, Chang et al demonstrated that ESR and CRP as well as faecal calprotectin have
significant differences between IBS and IBD patients. However, the sensitivity of faecal calprotectin
was much higher compared to that of the other parameters studied [11]. The same aspects we
encounter in our study.
A recent meta-analysis shows that CRP and calprotectin of ≤0.5 or 40, respectively, essentially
excludes IBD in patients with IBS symptoms. The addition of CRP and calprotectin to symptom-
based criteria may improve the confident diagnosis of IBS. In conclusion, it can be considered that
for a normal value of calprotectin, in the absence of alarming symptoms in patients meeting the
criteria in Rome, patients are unlikely to present IBD [12].
All of these studies are based on the Elisa method for the determination of faecal calprotectin. It
is a costly, time-consuming and non-ambulatory method to quickly examine patients requiring
colonoscopy.
Otten et al. (2008) conducted a study using the semi-quantitative immunochromatographic rapid
test that we used in this study. In their study, Otten et al determined 100% sensitivity and 94.5% fecal
calprotectin for IBD diagnosis [13].
Tursi A et al., In a study conducted in 2014 in patients treated with antiTNF alpha agents,
demonstrated that in IBD patients, faecal calprotectin was able to detect the presence of endoscopic
lessions with a sensitivity of 73.5% and a specificity of 96.0% [14].
To conclude, although presenting statistically significant differences between the samples, the
laboratory markers studied revealed a limited diagnosis capacity for distinguishing between the IBS
and CD. Nevertheless, the immunochromatographic rapid test for faecal calprotectin turned to be a
rapid, easy to conduct test, cost-efficient and well-performing in CD diagnosis. Further study is
required in order to recommend its use in patients displaying symptoms that suggest colorectal
disorders, in order to distinguish between the functional and organic pathology.

REFERENCES

1. National Institute for Health and Clinical Excellence. NICE diagnostic guideline 11. London UK: 2013. Faecal
calprotectin diagnostic tests for inflammatory diseases of the bowel.
2. Hungin A.P.S. (2005). Irritable bowel syndrome in the United States: prevalence, symptom patterns and
impact. Aliment Pharmacol Ther 21, pp. 1365–1375.
3. Holten K.B. (2003). Diagnosing the Patient with Abdominal Pain and Altered Bowel Habits: Is It Irritable
Bowel Syndrome? Am Fam Physician 67, pp. 2157-2162.
4. NICE, Irritable bwel syndrome, in Costing report implementing NICE gidence, F (2008). Editor 2008: NICE
clinical guidelines.
5. Vermeire S. (2006). Laboratory markers in IBD: useful, magic, or unnecessary toys? Gut 55, pp. 426–431.
6. Langhorst J. (2008). Noninvasive markers in the assessment of intestinal inflammation in inflammatory bowel
disease: performance of fecal lactoferrin, calprotectin, and PMN-elastase, CRP and clinical indices. Am J
Gastroenterol 108, pp.162–169.
7. Sutherland A.D. (2008). Review of fecal biomarkers in inflammatory bowel disease. Dis Colon Rectum 51,
pp.1283–1291.
8. Tibble J.A. (2002). Use of surrogate markers of inflammation and Rome criteria to distinguish organic from
non-organic intestinal disease. Gastroenterology 123, pp. 450–460.
9. Akhtar A.J. (2006.) Organic colonic lesions in patients with irritable bowel syndrome (IBS). Med Sci Monit
12(9), pp.363-367.

85
10. Von Roon A.C. (2007). Diagnostic precision of fecal calprotectin for inflammatory bowel disease and
colorectal malignancies. Am J Gastroenterol 102, pp. 803-813.
11. Chang MH, Chou JW, Chen SM, et al. (2014). Faecal calprotectin as a novel biomarker for differentiating
between inflammatory bowel disease and irritable bowel syndrome. Mol Med Rep.10(1), pp 522-6.
12. Menees S, Powell C, Kurlander J, et al. (2015). A Meta-Analysis of the Utility of C-Reactive Protein,
Erythrocyte Sedimentation Rate, Fecal Calprotectin, and Fecal Lactoferrin to Exclude Inflammatory Bowel
Disease in Adults With IBS. Am J Gastroenterol 110, pp 444–454.
13. Otten C.M.T. (2008). Diagnostic performance of rapid tests for detection of fecal calprotectin and lactoferrin
and their ability to discriminate inflammatory from irritable bowel syndrome. Clin Chem Lab Med 46(9), pp.
1275–1280.
14. Tursi A, Elisei W, Picchio M, et al. (2015). Accuracy of Rapid Fecal Calprotectin Test in Monitoring
Inflammatory Bowel Diseases Under Treatment with TNFa Antagonists. Dig Dis Sci 60, pp 1406–1413.

86
Irritable Bowel Syndrome Versus Crohn Disease – Impact on Quality
of Life

GAVRILESCU Otilia1,2, DRANGA Mihaela1,2, CARDONEANU Anca1,2,

MIHAI Cătălina1,2, CIJEVSCHI-PRELIPCEAN Cristina1,2
1University of Medicine and Pharmacy, “Grigore T. Popa” (ROMANIA)
2Institute of Gastroenterology and Hepatology (ROMANIA)
Emails: otilianedelciuc@yahoo.com, mihaela_dra@yahoo.com, cardoneanu_anca84@yahoo.com, catalinamihai@yahoo.com,
cristinacijevschi@yahoo.com.

Abstract

Background
The inflammatory bowel disease (IBD) and the irritable bowel syndrome (IBS) are both chronic
diseases, associated with fluctuating gastrointestinal symptoms, altered bowel habits, and a
significant impact on a patient’s health-related quality of life (QoL) (1). The aim of this study was to
assess and compare the impact of Crohn disease (CD), an organic disorder, and that of IBS (functional
disorder), on the patients’ QoL.

Material and methods

A prospective study was conducted over a period of 12 months (January 2016 - December 2016).
The study included 93 patients, divided into 2 groups: group A consisted of 45 CD patients and
group B of 43 IBS patients. The patients’ QoL was assessed by means of the SF-36 questionnaire, a
generic instrument used for measuring the physical and mental state.

Results
According to the results of the SF-36 questionnaire, the patients with CD presented a significantly
lower score of the QoL physical component (p<0.001), compared to the IBS patients. Three of the
subscale scores reflecting the physical state of the QoL (physical state, general health, vitality) were
significantly lower in the patients with CD, compared with those with IBS (p<0.001). The values of
the score reflecting the social activity were also lower compared with the IBS-d group (p<0.001).

Conclusions
Regardless of the nature of the disorder – organic or functional – the impact on the QoL is negative.
In both cases, the assessment of QoL reflects the therapeutic response and it contributes to identifying
the patients requiring specialized support.
Keywords: quality of life, Crohn disease, irritable bowel syndrome

Introduction

The inflammatory bowel disease (IBD) and the irritable bowel syndrome (IBS) are both chronic
diseases, associated with fluctuating gastrointestinal symptoms, altered bowel habits, and a
significant impact on the patient’s health-related quality of life (QoL) (1).
IBS is a functional disorder that affects approximately 11.2% of the population (2), occurring more
frequently in patients aged between 20 and 50 years old (2-4) with a prevalence that is 3 to 4 times
higher in females (3). IBS patients may present recurrent abdominal pain or discomfort, bloating or
visible distension, improved with defecation, associated with a change in the frequency or the form

87
(appearance) of stool. According to the Roma III criteria, there are three types of IBS: diarrhea-
predominant IBS (IBS-d), constipation-predominant IBS (IBS-c), or mixed IBS (IBS-m), manifested
through periods of constipation alternating with diarrhea (4).
IBD represent a preponderant pathology, with a rising prevalence over the last decades. IBD,
including Crohn’s disease (CD) and ulcerative colitis (UC) are chronic immune mediated diseases of
unknown etiology. These disorders are defined by the chronic intestinal inflammation, with a
fluctuating, unpredictable clinical course characterized by exacerbations and remissions (5). The peak
age-specific incidence occurs between 15 and 25 years of age, and a second smaller peak occurs
between 55 and 65 years old. Males and females are equally affected but there is a slight female
predominance (5).
Patients affected by these diseases experience diarrhea, abdominal pain, bloody stools, weight loss,
fever or subfebrility and extraintestinal manifestations (cutaneous, articular, ocular, hepatic or renal)
(6).
The early onset, the periods of exacerbation, associated pathologies and the treatment of these
diseases are likely to impact the patients not only physically, but also by limiting their social and
emotional life, their educational and professional activity. These diseases can eventually have a
negative impact on the patients’ QoL, even leading to major psychic disorders.
Consequently, both IBD – an organic disorder, and IBS – a functional disorder, can have a negative
impact on patients, leading to impaired QoL.
The present study aims to assess and compare the impact of CD (organic disorder), and that of IBS
(functional disorder), on the patients’ QoL.

Material and method

A prospective study was conducted over a period of 12 months (January 2016 - December 2016)
at the Institute of Gastroenterology and Hepatology, Iași. The study included 93 patients, divided into
2 groups: group A was represented by 45 CD patients and group B by 43 IBS patients. The CD
diagnosis was supported by complete hematologic-biochemical tests, diagnostic imaging, endoscopy
and it was histopathologically confirmed. The disease activity was quantified through the CDAI
score.
The IBS diagnosis was supported by the ROMA III criteria, excluding organic disorders (complete
blood count, stool tests and colonoscopy – normal).
QoL was assessed by means of the SF-36 questionnaire (Short Form-36). This questionnaire uses
eight scales, grouped into two generic concepts: physical and mental health. Physical health was
assessed by the first 4 scales (physical function, physical activity reduction, somatic pain, general
health state, vitality), while mental health was assessed by the last 4 scales (general health state,
vitality, social function, emotional function and mental health state). The scores vary from 0 to 100,
in such a way that the higher the score, the better the patient’s functioning in the respective field.
The interpretation was carried out both on each dimension individually, and based on the two
general scores: the physical and the general component.

Results

In statistical terms, there were no significant differences in the demographic parameters between
the patients in the CD group and those in the IBS group (Table 1). Most patients with CD and IBS
came from the rural environment and were married. The sex distribution was approximately equal in
the sample of patients with IBS, while in the sample of patients with CD, the number of female
patients prevailed (58%). The average age was 38.50±12.24 years old in the patients with CD and
37.46±11.01 in the patients with IBS. The non-smoking status was preponderant in both groups.

88
 Table 1. Structure of samples based on demographics
Characteristics Group A – CD Gropu B – IBS Statistical
(n=45) (n=48) differences
(p)
Female n (%) 26 (57.7%) 26 (54.1) 0.853
Average age 38.50±12.24 37.46±11.01 0.972
(min-max) (18-58) (19-50)
Urban environment 29 (64.4%) 30 (62.5%) 0.803
N (%)
Married n (%) 20 (44.4%) 31 (64.5%) 0.049
Smoker n (%) 18 (45%) 21 (43.7%) 0.351

Most patients with CD presented mild and moderate forms of disease; only 24% were in remission
and 7% of the patients had severe forms of the disease.
IBS subtypes were found in approximately equal proportions: IBS with predominant constipation
(IBSc) – 29%, IBS with predominant diarrhea (IBSd) – 35,38%, IBS with mixed bowel habits (IBSm)
– 35,40%.

SF-36 Score

According to the results of the SF-36 questionnaire, the patients with CD presented a significantly
lower score of the physical component (p<0.001), compared to the IBS patients (Table 2).
Three of the subscale scores reflecting the physical state of the QoL (physical state, general health,
vitality) were significantly lower in the patients with CD, compared with those with IBS (p<0.001) –
Fig. 1/Table 2. The disorder these patients suffer from seems to limit their physical activities that
suppose moderate or high effort. The values of the score reflecting the social activity were also lower
compared with the IBS-d group (p<0.001) – Fig. 1.
As regards the QoL depending on the disease activity, the patients in remission presented higher
scores compared to the patients with severe disease forms (p<0.001).
The age and sex distribution, the smoker/ non-smoker status and the area of origin (urban/rural)
did not present statistically significant differences. The disease extension did not have a statistically
significant influence on the QoL.
For the patients with IBS, the mental component of the QoL was more deeply influenced (Table
2).

Table 2. QoL in patients with CD compared with patients with IBS

SF-36 Group A - CD (n=72) Group B – IBS (n=63) P values for
Functions Average score Average FANOVA test
±SD(extreme) score±SD(extreme)
SF-physical component 61.25±5.00 (54-66) 68.95±5.27 (63-75) 0.001
SF-mental component 60.03±3.56 (57-65) 60.81±1.85 (58-63) 0.120

The scores of the subscales assessing the mental component of QoL (vitality, social function,
emotional role and mental health) were significantly lower compared with the patients in the UC
group (p<0.001) – Fig. 1.

89
 30
Group A (CD) Group B (IBS)

25

20
Average SF-36 Score

15

10

0
Physical Physical Somatic General Vitality Social Emotional Mental
functions role pain health functions role health
Fig. 1. QoL in patients with CD compared with patients with IBS

Depression and anxiety, feelings such as sadness, loss of hope, tension, and irritability, as well as
the diminishing of positive feelings (calmness, happiness) contributed to a decrease in activities, as
well as in the effectiveness and the quality level of these activities. The patients in this group seem to
be more prone to the psychological effects of gastrointestinal symptoms. The age and sex distribution,
the smoking/non-smoking status and the area of origin (urban/rural) did not present statistically
significant differences.

Discussion

The results of the present study confirm the importance of estimating QoL, both in the patients
with CD – organic disorder, and in those with IBS – functional disorder, both diseases having a
negative impact on all the aspects related to the patients’ QoL.
In our study, the QoL of CD patients was affected more by the physical component of the disease,
compared to the IBS patients, whose QoL seems to be more prone to the impact of gastrointestinal
symptoms on the psychosocial variables. The data obtained in the present study corresponds to the
data from the studies applying the same test, or various other tests designed to assess QoL. One study
demonstrated that patients with IBS show health‐related QoL, psychological distress and recent
occurrence of stressful life events of severity at least comparable with age‐matched IBD patients (7).
Another study showed that patients with IBS have a higher level of anxiety and irritability
compared to the patients IBD (8). Other studies have shown that IBS has a stronger impact on QoL
compared to obesity; the scores obtained for QoL in all fields, except for the physical function and
the physical role, were lower in subjects with IBS, compared with the group of subjects with obesity
(body mass index ≥ 30) (9). These results confirm once again the magnitude of the impact these
functional disorders have on the QoL.
Although psychic stress and disease severity constitute the most important parameters likely to
affect QoL, there are additional psychological variables, such as somatisation – which has an
important role in the final score (10). Moreover, it was noticed that some patients with IBD present
affected QoL despite the fact that they are in clinical remission (11).
Irrespective of the type of disorder – organic or functional – the favorable perception of the patient
on the state of health constitutes the target of therapeutic success. Several studies have demonstrated
the existence of discrepancies between the patient’s and the doctor’s perception as regards the results
of the medical and surgical treatment (12). Therefore, even though most of the times the improvement
in symptoms prevails over the disease cure, the estimation of therapeutic success is essential through
the assessment of the improvement in the patient’s QoL.

90
Conclusions

The present study shows that QoL is affected in both the patients with IBS and those with CD.
Compared to IBS, which influences more the mental QoL component, in the studied groups, CD had
higher impact on QoL through the reduction of physical activities.
To conclude, regardless of the nature of the disorder – organic or functional – the impact on QoL
is negative. In both cases, the assessment of QoL reflects the therapeutic response and it contributes
to identifying the patients requiring specialized support. Additionally, it has an important role in
understanding the real impact of the disease on the patients, as well as in redefining the strategies for
improving QoL in both the patients with IBS and those with IBD.

REFERENCES

1. Naliboff BD, Kim SE, Bolus R et al. (2012). Gastrointestinal and psychological mediators of health-related
quality of life in IBS and IBD: a structural equation modeling analysis. Am J Gastroenterol 107(3), pp.451-459.
2. Canavan C, West J, Card T. (2014). The epidemiology of irritable bowel syndrome. Clinical Epidemiology 6,
pp.71-80.
3. Weber FH, McCallum RN. (1992). Clinical approaches to irritable bowel syndrome. Lancet 340, pp.1447–1452.
4. Jung, H-K. (2011). Rome III Criteria for Functional Gastrointestinal Disorders: Is There a Need for a Better
Definition? Journal of Neurogastroenterology and Motility 17(3), pp.211-212.
5. Sarid O, Slonim-Nevo V, Pereg A, et al. (2017). Coping strategies, satisfaction with life, and quality of life in
Crohn’s disease: A gender perspective using structural equation modeling analysis. Green J, ed. PLoS ONE
12(2), e0172779.
6. Burisch J, Weimers P, Pedersen N et al. (2014). Health-related quality of life improves during one year of
medical and surgical treatment in a European population-based inception cohort of patients with Inflammatory
Bowel Disease – An ECCO-EpiCom study. J Crohns Colitis 8 (9), pp. 1030-1042.
7. Pace F, Molteni P, Bollani S. et al. (2010). Inflammatory bowel disease versus irritable bowel syndrome: a
hospital‐based, case‐control study of disease impact on quality of life. Scandinav J Gastroenterol 38 (10),
pp.1031-1038.
8. Tkalcić M, Hauser G, Stimac D.(2010). Differences in the health-related quality of life, affective status, and
personality between irritable bowel syndrome and inflammatory bowel disease patients. Eur J Gastroenterol
Hepatol 22(7), pp.862-827.
9. Amouretti M, Le Pen C, Gaudin AF et al. (2006). Impact of irritable bowel syndrome (IBS) on health-related
quality of life (HRQOL). Gastroenterol Clin Biol 30(2), pp.241-246.
10. Vidal A, Go´mez-Gil E, Sans M, et al. (2008). Health-related quality of life in inflammatory bowel disease
patients: the role of psychopathology and personality. Inflamm Bowel Dis 14(7), pp.977– 983.
11. Fuller-Thomson E, Sulman J. (2006). Depression an inflamatory bowel disease: findings from two nationally
representative Canadian surveys. Inflamm Bowel Dis 12, pp.697-707.
12. Groll D, Vanner SJ, Depew WT et al. (2002). The IBS-36: a new quality of life measure for irritable bowel
syndrome. Am J Gastroenterol 97(4), pp. 962-971.

91
Useful Tools to Differentiate Irritable Bowel Syndrome from
Inflammatory Bowel Disease

GOLDIS Adrian, GOLDIS Ramona, LAZAR Daniela

Department of Gastroenterology and Hepatology, University of Medicine and Pharmacy, Timişoara (ROMANIA)
Emails: goldisadi@yahoo.com, amalia_goldis@yahoo.com, lazar_daniela@yahoo.com

Abstract

There is no simple algorithm used to define specific conditions clinically expressed by chronic
diarrheic syndrome or the best management approach in each of these patients. This paper presents
most recent data regarding the diagnostic tools used to differentiate irritable bowel syndrome
associated with chronic diarrhea from other organic disorders such as microscopic colitis, celiac
disease and inflammatory bowel diseases. Furthermore, the paper tries to reveal if there is a benefit
from categorizing chronic diarrhea by using fecal biomarkers and their accuracy in defining specific
conditions.
Keywords: chronic diarrhea, irritable bowel syndrome, microscopic colitis, celiac disease, inflammatory bowel disease, fecal
biomarkers

Introduction

Chronic diarrhea is a condition affecting up to 5% of the population. Patients may describe diarrhea
as loose stool consistency, increased bowel frequency, stool urgency or incontinence. The diagnosis
of chronic diarrhea indicates an increased frequency of defecation/stool weight, symptoms usually
present for more than 4 weeks [1]. Irritable bowel syndrome can be distinguished from other
etiologies of chronic diarrhea using Rome III criteria. In order to categorize chronic diarrhea into a
specific etiology, history and physical examination of the patients, sometimes associated with blood
and stool testing, endoscopic and imaging study, or histological changes may be needed.
This paper proposes to review the most prominent entities manifested with chronic diarrhea, and
to define the most useful tools currently available for differentiating functional from organic causes
of diarrhea.

Microscopic colitis

Literature data reveal a prevalence of microscopic colitis (MC) that exceeds 20 cases in a
population of 106 [2-4]. This condition is found in ~10–15% of patients that undergo endoscopy with
biopsy for investigation of chronic watery diarrhea, higher rates being encountered in the elderly [5-
6].
By definition, MC is characterized clinically by chronic watery diarrhea in patients with a
macroscopically normal mucosa, associated with specific histological changes in the colonic bioptic
specimens. [7]
Rasmussen J. et al. [8] have established a regional Danish database comprising a complete, non-
selected population of patients diagnosed with MC, in order to determine incidence rates in that
population, describe the persistence of histological changes in patients undergoing subsequent
endoscopies, and investigate whether pre-diagnostic microscopic aspects could be associated with
later development of this entity.
The study has defined three histological subtypes: collagenous colitis (CC), lymphocytic colitis
(LC) and incomplete microscopic colitis (MCi) [9], with similar clinical symptoms but different

92
histology, as follows: CC comprises lamina propria inflammation along with the presence of a
collagenous subepithelial band of ≥10μm; LC, lamina propria inflammation with ≥20 intraepithelial
lymphocytes/100 epithelial cells; MCi, slight lamina propria inflammation associated with either a
subepithelial collagenous band of 5–9μm or an increased number of intraepithelial lymphocytes (>5
and <20).
This retrospective study collected data from 2000-2014 and found 1055 MC patients: 468 with
CC, 361 with LC and 226 with MCi. Several patients with a later diagnosis of MC had an endoscopy
with biopsy prior to the diagnosis. This study highlights the fact that the existence of lamina propria
inflammation in patients presenting chronic watery diarrhea should lead the clinician to evoke a
certain diagnosis of MC or rise the suspicion that these clinical and histological changes represent the
initial stages in developing MC. Literature data are sparse regarding the long-term prognosis of
patients with MC, high rates of relapse being noted in some clinical trials [7].
The results from retrospective studies are controversial, showing both high rates of recurrence [10]
and resolution [11].
Post-diagnostic histologies demonstrated that MC persisted for up to one year in 77% patients with
CC, 64% with LC and 45% with MCi. In accordance to previous reports, Rasmussen et al. show that
histology normalizes in only a small proportion of patients in which symptoms continue/reappear
[12].
Their results indicate that histology appears to normalize more often in patients with MCi,
suggesting that MCi represents an early form of MC. The histological changes persisted beyond the
first year in a significant proportion of patients with persistent symptoms. However, such changes
also persisted in patients with resolution of symptoms, suggesting that there is no direct relation
between histological changes and pathophysiology of this condition. The study showed also that the
changes of CC appear more persistent in post-diagnostic endoscopies, reflecting either a more
persistent disease, a more recognizable histological diagnosis [13] or the fact that the collagenous
band is less reversible compared with other microscopic changes.
The results of this paper confirm the fact that MC may be ruled out using biopsies from any
segment of the colon situated proximally to the rectum. Therefore, normal histological aspects
obtained from the descending and sigmoid colon biopsies in patients with chronic watery diarrhea
have high negative predictive value for this condition, but do not completely rule out this diagnosis
at a repeat endoscopy. Assessment of the right colon by colonoscopy in these patients is indicated in
order to rule out other diseases.

Irritable bowel syndrome vs. Microscopic colitis

Irritable bowel syndrome (IBS) represents a chronic functional disorder of the digestive tract
characterized by abdominal discomfort and altered bowel habit, affecting approximately 10% of the
general population [14]. Numerous mechanisms for the pathophysiology of IBS have been proposed,
such as visceral hypersensitivity, mild inflammation of the intestinal mucosa, bacterial overgrowth
and altered intestinal microbiota. The diagnostic gold standard for IBS is the Rome III criteria, but
their performance in predicting IBS seems to be modest. Data revealed that IBS symptoms may co-
exist with other organic gastrointestinal diseases, such as inflammatory bowel diseases, bile acid
diarrhea or celiac disease. Moreover, microscopic colitis and IBS may share similar clinical features
and both conditions present with normal mucosa at colonoscopy.
The meta-analysis performed by Kamp E et colab [15], examined the prevalence of IBS in
individuals with histologically confirmed MC, as well as the prevalence of MC in patients with IBS.
There were four studies including 1056 patients that assessed the prevalence of IBS in patients
with MC [16-19]. These four studies investigated 420 patients with histologically confirmed MC, the
pooled prevalence of IBS being 33.4% (range 13.8%-55.7%). However, when comparing the
prevalence of IBS in patients with MC vs. without MC, two of these studies didn’t show a
significantly higher OR for IBS in association with MC.

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 Furthermore, the meta-analysis included 1758 patients from 3 cross-sectional surveys that reported
the prevalence of MC in patients with IBS vs. patients without IBS [16, 20, 21]. All studies used
Rome III criteria for diagnosing IBS and all patients underwent colonoscopy; 144/1758 patients
(8.2%) presented histologically confirmed MC. These surveys showed a pooled prevalence of MC
among patients with IBS of 7.4% (range 2.4%-11.5%). Two of the 3 studies including 1655 patients
reported the prevalence of CC and LC in individuals with IBS vs. without IBS [16, 20]. The pooled
prevalence of CC in patients with IBS (659 individuals) was 2.7% and for LC it was 3.2%. The pooled
OR for CC in patients with IBS vs. non-IBS was 1.34 (95% CI, 0.59-3.02) meanwhile the pooled OR
for LC was 0.49 (95 CI, 0.26-0.93).
There were 4 case-control studies including 604 subjects- 365 patients with IBS (60.4%) fulfilling
Rome III criteria and 239 controls represented by asymptomatic individuals [22-25]. These studies
showed a pooled prevalence of MC in patients with IBS of 7.1% (range 1.4%-23.3%); the pooled OR
for MC was significantly higher in patients with IBS vs. controls (5.16; 95% CI 1.32-20.2). When
only patients with IBS manifesting with diarrhea were considered (IBS-D), the OR increased further
(9.2%; 95% CI, 2.7%-19.1%).

Celiac disease

Celiac disease is a condition triggered by exposure to gluten in genetically predisposed patients

that can develop changes of inflammation and villous atrophy in the proximal small intestine,
associated with signs of malabsorption. Unfortunately, because the asyptomatic, paucisymptomatic
or non-classic presentation of this disease nowadays, more than 80% of cases remain undetected [26,
27].
Celiac disease was linked to irritable bowel syndrome in outpatient clinics; a recent systematic
review suggested that the prevalence of biopsy-proven celiac disease in patients presenting IBS-like
symptoms was significantly higher vs. controls (4-fold higher) [28].
For this reason, a large US population-based study (Olmsted County, including Minnesota
residents) was conducted in order to determine whether positive results from serologic tests for celiac
disease are associated with IBS and other functional gastrointestinal disorders [29]. There were 3202
individuals included who completed the bowel disease questionnaires (BDQs) and had serum
available for celiac disease testing. IBS was diagnosed in 13.6% of these subjects and any
gastrointestinal symptom occurred in 55.2%. The prevalence of celiac disease diagnosed on the basis
of positive serologic markers such as tissue transglutaminase IgA and anti-endomysial antibodies was
1%. IBS proved to be less prevalent in patients with celiac disease vs. non-celiac disease (3% vs.
14%), although this different didn’t reach statistical significance. The results of this study suggest
that testing for celiac disease in IBS patients will not have a significantly increased yield over
population-based serologic screening.

Fecal biomarkers

The most widely studied serological markers in inflammatory bowel disease (IBD) patients are
perinuclear anti-neutrophil cytoplasmic antibodies (pANCAs) and anti-Saccharomyces cerevisiae
antibodies (ASCAs). According to ECCO IBD guidelines 2016 [30], pANCAs may be found in up
to 65% of patients with ulcerative colitis (UC) and in less than 10% of patients with Crohn’s disease
(CD).
Due to the limited sensitivity of these two serological markers, their routine uses for the diagnosis
of UC/CD and for therapeutic decisions in IBD patients is not justified.
There are several neutrophil-derived proteins such as calprotectin, elastase, lysozyme, and
lactoferrin that have been investigated as markers of intestinal inflammation in IBD patients [31, 32].
Heretofore, the most studied stool markers are faecal calprotectin and lactoferrin, though other
markers such as elastase and S100A12 have also demonstrated high accuracy at detecting colonic
inflammation [33-36].
94
 Fecal calprotectin is a protein binding Ca and Zn derived from neutrophils and monocytes with
antimicrobial and antiproliferative activities. It may be detected in liquid samples and stool and its
value is increased in intestinal inflammation. It has a high discriminative capacity of distinguishing
the non-inflammatory causes from inflammatory diarrhea. Studies assessing the role of fecal
calprotectin were made in colon cancer screening and inflammatory bowel disease monitoring.
On the other hand, as the rest of fecal tests, calprotectin lacks the specificity to discriminate
between different types of inflammation [37].
Calprotectin appears to be the most sensitive fecal biomarker [38], numerous studies
demonstrating its value in selecting UC patients for diagnostic investigation, in the assessment of
disease severity (in correlation with endoscopic indices), in the diagnosis of disease recurrence and
response to treatment [39-41]. Doubling of calprotectin levels was associated with an increased risk
of relapse (hazard ratio [HR]: 2.01; 95% confidence interval [CI]: 1.52–2.65). It has been
demonstrated an excellent correlation between calprotectin and the severity of endoscopic and
histological changes in acute pouchitis.
Calprotectin proved to be a useful non-invasive marker in the follow-up of UC patients [42].
International guidelines suggest that home-based calprotectin assessment represents an easy
method to measure gut inflammation and a convenient alternative to enzyme-linked immunosorbent
assay (ELISA), therefore a new modality of monitoring IBD patients by eHealth [43].
Current recommendations suggest that fecal markers, such calprotectin or lactoferrin can be used
to guide therapy and short-term follow-up and also to predict clinical relapse in CD patients [44].
Furthermore, fecal calprotectin can help to differentiate CD from IBS.
Mucosal healing is considered a surrogate marker of sustained controlled CD [45], still evaluated
by means of endoscopy, an invasive and expensive method. The fecal level of calprotectin and
lactoferrin mirrors the migration of neutrophils through the inflamed bowel wall to the mucosa and
can be easily measured in stools using ELISA method [46]. Recent meta-analyses demonstrated that
both adult as well as pediatric CD patients present high calprotectin levels vs. IBS patients [47] and,
conversely, that normal calprotectin levels could exclude IBD in adult patients with high accuracy
[48].
Therefore, fecal levels of calprotectin or lactoferrin are emerging as surrogate markers of mucosal
healing.
Data showed that in CD patients fecal calprotectin has a >90% positive predictive value for
endoscopically active disease. The accuracy of fecal markers is limited, because some CD patients
may have endoscopically active disease with normal fecal protein levels, especially in ileal disease.
Despite this limitation, the 60–70% sensitivity of increased level of fecal markers for indicating
endoscopically active disease proved to be superior to both serum CRP and CDAI [49, 50]. Moreover,
fecal calprotectin may predict relapse in CD patients [51]. The drawbacks of its value in CD patients
include its diminished sensitivity in patients with CD limited to the small intestine, a non-linear
correlation with transmural inflammation and the absence of clear cut-offs [49].
Currently, fecal calprotectin in IBD represents a strong indicator of mucosal healing if normal
values are reached, is a useful tool in monitoring patients, assessing treatment response and predicting
relapse of inflammatory bowel diseases. The negative predictive value for exclusion of organic
disease of the lower gastrointestinal tract surpasses 95%.
Measuring lactofferin and calprotectin in stool was also shown to be superior to CRP in the
prediction of postoperative disease recurrence of CD. Calprotectin level three months after surgery
(cutt-off 200 µg/g of stool) demonstrated to be superior to diagnostic ultrasound in predicting disease
reccurence [52, 53]. Patients with ileal CD may have large ulcers in the absence of markedly elevated
fecal calprotectin levels and the cut-off values for ileal CD may differ from those with ileo(colonic)
disease, a possible explanation for these results being a less extensive ulcerated surface in the ileum,
resulting in lower mucosal and systematic inflammatory load.
False-positive results of fecal calprotectin may be encountered in infectious causes (giardia
lamblia, bacillary dysentery, viral gastroenteritis, Helicobacter pylori positive gastritis), malignancies

95
(colorectal cancer, gastric cancer, lymphoma), medications (NSAI, PPI) and other gastrointestinal
causes (gastro-oesophageal reflux disease, celiac disease, diverticular disease, juvenile polyps,
microscopic colitis, liver cirrhosis, food allergy).
The meta-analysis of van Rheenen et colab [48], has evaluated whether including a test for fecal
calprotectin in the investigation of suspected inflammatory bowel disease reduces the number of
unnecessary endoscopic procedures. The results have shown that screening by measuring faecal
calprotectin levels would result in a 67% reduction in the number of adults requiring endoscopy.
In addition, 65 children and teenagers instead of 100 would undergo endoscopy.

The results of our own study

We have included a cohort of 113 patients, out of which 71 patients (35 men and 36 women) were
evaluated in a tertiary referral gastroenterological clinic from Timisoara, Romania for suspicion of
IBS with diarrhea predominance (IBS-D) (the infectious pathology was ruled out) and 38 patients
with IBD (with/without treatment), during September 2012 – May 2013.
Mean age was 38.2 years in IBS-D patients versus 35.6 years in patients known with IBD. We
obtained a mean fecal calprotectin level in IBD patients of 184.2±12.3 microg/g versus 79.3±9.2
microg/g in patients with chronic diarrhea syndrome-IBS-D (p<0.03). From IBS cases 38 had a value
of fecal calprotectin <30 microg/g. IBD cases with mild disease or in remission had a mean value of
85.3 microg/g, in comparison with the value of 291 microg/g found in moderate/severe cases
(p<0.001).

Conclusions

The results presented by this paper confirm the fact that MC may be ruled out using biopsies from
any segment of the colon situated proximally to the rectum. MC was encountered in significantly
higher proportion in patients with IBS (especially IBS-D vs. controls). In addition, recent studies
suggest that testing for celiac disease in IBS patients will not have a significantly increased yield over
population-based serologic screening.
Fecal calprotectin performed in subjects with chronic diarrhea syndrome allows a clear distinction
between irritable bowel syndrome and inflammatory bowel disease. We should bear in mind that
there are cases of false positive results to be taken into account. Testing for faecal calprotectin seems
to be a useful screening tool for identifying patients who are most likely to need colonoscopy for
suspected inflammatory bowel disease. Usefulness of fecal calprotectin has proved as a non-invasive
method of monitoring inflammatory bowel diseases.

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Connections Between Systemic Inflammation and Pathophysiologic
Mechanisms of Irritable Bowel Syndrome
HALIGA Raluca Ecaterina, MORARASU Bianca Codrina, SORODOC Laurentiu
Second Internal Medicine Clinic, “Saint Spiridon” Emergency Clinical Hospital Iasi, (ROMANIA)
Emails: ralucahaliga2017@gmail.com, morarasu.bianca.codrina@gmail.com

Abstract

Irritable bowel syndrome (IBS) accounts for many gastrointestinal (GI) functional symptoms
which diminishes quality of life. The exact cause for IBS is yet to be discovered, but there is evidence
that enhanced immune activity impairs gut-brain axis communication at different levels. We have
reviewed current literature that inquired about immunological altered activation which may cause GI
and systemic low-grade inflammation, thought to be one of the underlying pathophysiologic cause
for IBS. Furthermore, it might be a strong interaction between gut microbiota, altered intestinal
permeability and local inflammation, from which the latter might be a cause or an effect.
Inflammation seems to play a key role. Firstly, an increased number of activated T cells have been
found in the biopsy samples from GI tract of the IBS patients, although their circulating levels seem
to be unaltered. Secondly, increased baseline plasma levels of proinflammatory cytokines, such as
TNF-α, IL-1β, IL-6 may be the expression of chronic low-grade systemic inflammation. These
cytokines act as immune messengers promoting neural activation within the GI tract and correlates
with IBS symptoms. Further research is needed in order to establish what triggers intestinal and
systemic inflammation, if it holds a key role in IBS pathophysiology, either as a cause or as a
consequence and if inflammatory cytokines may be used as biomarkers in diagnosis and follow-up
of IBS patients.
Keywords: irritable bowel syndrome; systemic inflammation; pathophysiology

Introduction

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder which presents with altered
bowel habits, chronic abdominal pain and other heterogeneous symptoms including bloating,
abdominal distension and altered defecation. Taking into consideration stool consistency, IBS has
been classified with either predominantly constipation (IBS-C), diarrhea (IBS-D), both (IBS-M) or
unsubtyped (IBS-U). It is estimated that approximately 11% of the global population is affected by
IBS [1]. In Europe, prevalence is ranging from 6.2% to 12%, with variations depending on the type
of diagnostic criteria used: Manning 6.5%, Rome I 4.2% and Rome II 2.9% [2]. Drug et al. showed
that in Romania the prevalence of IBS symptoms in the general population is around 14.4%, with a
distribution of 8.4% in males and 17.7% in females [3]. Epidemiologic results differ due to several
factors, which may be dependent on the patient or due to lack of gold standard diagnostic criteria.
This issue emerges as a result of IBS heterogeneity with poorly defined diagnostic tests and
multiple underling pathophysiologic mechanisms, including mucosal inflammation, systemic low-
grade inflammation, alteration of microbiota and intestinal permeability, genetic, nutritional and
environmental factors. In addition, the concept that IBS is a gut-brain axis disorder has become
increasingly apparent.

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Gut-brain axis

It is increasingly recognized that gut-brain axis is a complex system that ensures the
gastrointestinal (GI) homeostasis and modulates the responses of the organism to different stressors.
Communication between the main components is assured by the enteric and autonomic nervous
system and the hypothalamic pituitary adrenal (HPA) axis through endocrine, neurologic and immune
mediators. The nervous system transmits both afferent and efferent signals from gut to brain and
backwards, and the HPA axis coordinates the responses to different factors. One of these might be
systemic inflammation, which activates the corticotropin releasing factor, stimulates the pituitary
gland to secrete adrenocorticotropic hormone which, in turn, leads to secretion of cortisol. Cortisol is
a stress hormone which increases absorption of water in the colon and rectum. Therefore, both
hormonal and neural pathways combine and permit the brain to influence autonomic, motor, sensory
and secretory functions of the GI tract and allow gastrointestinal mediators to influence brain
function, which are also under microbiota control [4].
Appropriate intestinal bacterial colonization is required for the normal development of the HPA
axis.
Microbiota might be able to interact with central nervous system through gastrointestinal
epithelial, immune and nerve cells [5] generating neurotransmitters and neuromodulators such as
noradrenaline, dopamine or acetylcholine. The administration of probiotics such as Lactobacillus
acidophilus seems to induce expression of cannabinoid and opioid receptors in the gastrointestinal
tract, which contributes to modulation of the normal perception of visceral pain. Furthermore, it seems
that murine exposure to the pathogen free fecal microbiota increases the expression of tight junctions’
proteins from intestinal wall and decreases the permeability of blood-brain barrier. The interaction
between gut flora, intestinal permeability and inflammatory molecules might be of high importance,
because the latter seem to affect mood and cognition. Several studies showed that stress-induced
alteration of microbiota is associated with changes in cytokine levels, whereas, maternal separation
in early life leads to significant decrease in fecal Lactobacillus numbers. To our knowledge, the
sequence of the process is poorly understood, if increased intestinal permeability induces and
maintains mucosal inflammation which, in turn, alters the epithelial permeability or systemic
inflammation raises intestinal permeability and allows translocation of bioactive molecules.
For example, patients with depression seem to exhibit high levels of IgA and IgM LPS-induced of
several commensal gut bacteria, bacterial DNA and higher expression of Toll-like receptor-4 (TLRs)
on peripheral mononuclear blood cells [6]. TLRs may serve as a molecular connection between
microbiota and immune homeostasis in the gastrointestinal tract. They are transmembrane proteins
which recognize microbial components and their activation triggers activation of innate immune
system and guides development of acquired immunity. They can be found on several numbers of
immune cells like dendritic cells, neutrophils, macrophages, T cells, as well as endothelial and
epithelial cells of the gastrointestinal tract. Therefore, excessive TLRs activation results in chronic
inflammatory response which may decrease epithelial resistance, as well as thinning of the mucus
layer [7]. In addition, a large number of mast cells leading to increased release of preformed
molecules, such as histamine, proteases and eicosanoids in the intestine of IBS patients have also
been related to alteration in gut permeability through direct mechanism or indirect, by stimulation of
enteric nervous system [8].

Intestinal microbiota

The microbiome is a fundamental component of the gut-brain axis. It has a key role in several
physiologic functions, being involved in digestion, immune cell development and activation,
resistance to pathogens, metabolism, brain development and function. There is evidence that
alteration in the intestinal microbiota is involved in IBS. Microbiome composition varies within
specific IBS subgroups in contrast with healthy subjects, with IBS-D subtypes having a lower density

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of Bifidobacteria in comparison with C-IBS, while others found decreased number of Lactobacilli
and Bifidobacteria with higher number of aerobes in contrast with anaerobes irrespective of the IBS
subtype [9].
Another key role of the microbiota is to assure the balance between inflammation and
immunosupression, patients with IBS exceeding an activation of intestinal immune system leading to
increased density of lymphocytes and mast cells. Treatment with Heligmosomoides polygyrus shifted
the composition of gut microflora in an IBD murine model which ameliorated the colonic
inflammation, leading to the hypothesis that some luminal antigens might play a role in development
of mucosal low-inflammatory state. Evidence from patients with post-infectious IBS (PI-IBS) seems
to support the theory that an infective trigger may alter the intestinal flora, between 7 and 32% of
subjects developing IBS symptoms after an episode of acute gastroenteritis [10]. There is a strong
interaction between microbiota and external factors, such as diet [11] or use of antibiotics, that may
cause IBS symptoms, but this is still poorly defined and it needs further research [12]. Another factor
would be the relationship between gut microbiota and behavior or mood. A predominance of
Firmicutes over Bacteroides has been found in some IBS patients and it seems to correlate with
anxiety and depression, while the treatment with prebiotic in a patient with IBS and anxiety led to
significant reduction in anxiety score and improvement of the quality of life. All these factors have a
common consequence which impacts the microbiota function leading to interference with gut-brain-
axis [13].

Inflammation

Clearly, IBS is not a disease with typical mucosal inflammation as it may be observed in
inflammatory bowel disease, although there is a mild inflammatory activity that seems to determine
abnormal functional responses within enteric and sensory nerves, as well as increased intestinal
permeability [14].
The human gastrointestinal tract has a high density of mast cells in the lamina propria mucosae,
with a lower density in the submucosa. Multiple stimuli have the ability to trigger mast cells
activation, for example, neuropeptides, hormones, neurotransmitters or bacteria components, which
leads to release of preformed and newly synthesized bioactive molecules that can modulate intestinal
nerve activity [15]. In IBS, the number of mast cells homing the small and large bowel seems to be
increased, with variations regarding the gender, intestinal segment or IBS subgroup [16]. However,
the data are conflicting, other authors indicate that mast cell number is unchanged in IBS patients
[17] and there is disparate correlation with symptoms when the density is higher [18].
Notwithstanding, it has been shown that increased rate of mast cell activation and degranulation is
more significant from a pathophysiologic perspective, since the simple presence of these cells in the
digestive tube is not necessarily pathologic [19]. Activation of mast cells impacts the digestive
functions at different levels. Firstly, it seems that activated mast cells release a number of
inflammatory molecules, such as interleukin-6 (IL-6), interleukin-8 (IL-8), TNF-α, interleukin-3 (IL-
3), interleukin-5 (IL-5), interleukin-13 (IL-13) which leads to recruitment of different immune cells,
such as neutrophils, macrophage and chemokines. This inflammation produced by mast cells may
contribute to intestinal mucosal barrier dysfunction [20]. Secondly, due to their position in the closer
proximity of the colonic nerve endings, the products of degranulation lead to activation of splanchnic,
vagal, and mesenteric nerve tracts which are involved in visceral hypersensitivity [21].
In addition, the molecules released have been associated with altered intestinal motility by
increasing bowel contraction of longitudinal and circular smooth muscle, high mioelectric spike
activity and duodenal intense contractions [22].
Macrophages and dendritic cells are antigen-presenting cells which play a central role in regulation
of immune response and establish a connection between allergen uptake, intestinal inflammation and
clinical manifestation. Macrophages are able to secrete cytokines and chemokines which enhance
local inflammation. The number of CD68+ macrophages has been found to be decreased in the

101
intestinal biopsies of IBS patients compared with healthy subjects, suggesting an altered response
capacity to antigens [23].
T cells have also an important role in mucosal immune activation of the gastrointestinal tract.
Studies showed an increased density of T cells at different levels of the digestive tract such as
rectum, rectosigmoid colon, colon, cecum, jejunum and duodenum [24]. Furthermore, T lymphocytes
seem to be in an activated state, because they have high expression of activation markers, CD25,
CD69 and HLA-DR. Biopsies with increased number of T-cells from the descending colon have been
found to be in direct connection with the motility-related symptoms in some IBS patients [25].
Attention has increasingly been focused on the immune systemic activation in IBS. In order to
prove it, quantitative assessment of pro-inflammatory cytokine IL-6 and sIL-6R (soluble receptor IL-
6) showed increased blood levels in IBS patients, while the levels of anti-inflammatory IL-10 proved
to be reduced [26]. Another study showed significantly higher baseline levels of TNF-α, IL-1β, IL-6
in peripheral blood mononuclear cells, as well as increased LPS-induced IL-6 levels. All cytokines
were found elevated predominantly in D-IBS subgroup, whereas LPS-induced IL-1β levels were
higher in the constipation predominant IBS [27]. Darkoh et. al., found high levels of TNF-α and IL-
1β in serum and fecal sample in patients with IBS, while Scully et al found high plasma levels of IL-
6 and IL-8, but no changes in TNF-α, IL-13, IL-10 or IL-1β in 21 IBS patients compared with healthy
control [26], [28]. There is considerable divergence regarding the Th cytokine profile present in the
blood. Kindt et al. found that patients with IBS have a predominating Th2 phenotype (IL-5, IL-10,
IL-13 and low TNF-α), whilst others showed a shift toward Th1 phenotype (TNF- α, IL-1β, IL-12,
IL-6 and decreased IL-10). The lack of orientation towards Th1 or Th2 shows that activation of
immune system involves different cell types, being a complex phenomenon. On the other hand, some
other studies found no alteration in Th2 blood levels, but they did observe high IL-10 mRNA
expression in the colon, suggesting that IBS patients might have an exaggerate immune response to
different stimuli. Although IBS patients have unaltered circulating number of T cells, it seems they
express with higher frequency markers of activation, such as CD-69 and integrin beta7/HLA-DR [29]
which leads to B-cell activation through secretion of cytokines involved in this process. Activated B-
cells produce antibodies (Ig) which are directed against an antigen, with increase of Ig-positive B
cells in IBS subjects in comparison with healthy subjects. Furthermore, there might be elevated levels
of autoantibodies against neuronal channels from the digestive system leading to a potential
autoimmune gastrointestinal neural dysfunction which is yet to be determined. Hypothesis that
systemic increased cytokines might derive from the intestine has not yet been demonstrated, with lack
of correlation between cytokine levels and analysis of colonic tissue. On the other hand, high plasma
levels of pro-inflammatory cytokines seem to be associated with psychological physical stressors,
like depression or heavy exercise. Furthermore, blood levels of TNF-α, IL-6 and IL-1β correlate with
IBS symptoms and they might be used as potential diagnostic biomarkers. Fecal biomarkers are also
of high interest. Human beta-defensin 2, marker of intestinal barrier function, is an antimicrobial
peptide which has been found more elevated than healthy subjects but lower when compared with
patients with ulcerative colitis [30].

Conclusion

More evidence involves the immune system as a key factor in IBS, and associated with gut-brain
axis, builds up a circle that activates and perpetuates the condition having major implications both in
diagnosis and therapeutic aspects. Quantitative measurement of systemic pro-inflammatory cytokines
previously mentioned above might be used to differentiate patients from healthy subjects, but due to
the data inconsistency, larger studies are needed for further research. It is still difficult to differentiate
IBS based only on this measurement because other numerous conditions associate a grade of low
systemic pro-inflammatory state. Nevertheless, validation of specific biomarkers in IBS needs further
investigation.

102
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Trust in Doctor Patient Relationship in the Context of IBS
ROTARU Tudor-Ștefan1
1University of Medicine and Pharmacy Gr. T. Popa Iași (ROMANIA)
Email: tudor.rotaru@umfiasi.ro

Abstract

Trust in the doctor-patient relationship is vital for patients’ adherence to doctors’ recommendations
despite the little knowledge with respect to how trust builds up in this relationship. In this paper, we
present the philosophical grounds for trust in medicine and we synthesize the main aspects of the
doctor-patient trust. We also discuss the specifics of trust in the context of IBS patients and we focus
on the main findings of quantitative and qualitative endeavours in the study of trust. We also present
the result of a qualitative research on fifteen interviews of irritable bowel patients from Iasi Area,
Romania, focused on their trust-related experiences. In this latter study, we identified several
pathways embedded in the communication process that instilled trust and several that generated
distrust. In the end, we sum up the main coordinates for further research in this area.
Keywords: IBS, trust, doctor-patient communication

Introduction
Irritable bowel syndrome [IBS] affects around 10–15% of adults and is a common diagnosis to be
found in both primary care practices and gastroenterology [1], [2], [3]. Individuals with chronic
diseases have a poorer quality of life and activity impairment [4], [5], [6], [7]. Societies also suffer
directly through increased health care costs and indirectly through decreased productivity [8].
Several studies have shown that evidence-based health care for chronic conditions is not the rule
in most health care systems [9]. This evidence-practice gap is thought to be caused by socio-economic
factors and by individual doctor and patient factors [10]. There is a consensus on the fact that a
thorough communication is the foundation of a successful encounter in the medical practice [11].
However, some findings suggest the need for extensive research and specific strategies tailored to
each specific population to promote healthy behaviours [12]. Therefore, mutual trust in doctor-patient
relationship plays an important role amongst the variables responsible for the evidence-practice gap
[13].
It appears to be the vehicle, through which evidence-based recommendations get implemented.
Patients’ trust in their doctors seems to be associated with patients’ propensity to seek care and to
comply with therapeutic recommendations [14].

Philosophical grounds in trust

Trust is important because it allows us to form relationships with people and to depend on them
especially when we know that no exterior force compels them to give us help or support. Trust also
involves the risk that people we trust will not have our best interest at heart: if there were some
guarantee that they would take care of our interests, then we would have no need to trust them in the
first place. Therefore, trust is also dangerous because we risk the loss of the things that we entrust to
others [15].
It’s uncontroversial that trusting requires making ourselves vulnerable to others, think well of the
people we trust, at least in certain domains and be optimistic that they are competent in certain

105
respects related to our interests. A certain degree of power inequality is needed for trust to be needed
[16].
Therefore, the central epistemological question about trust is, “Should I to trust or not?”.
In short, given the way things seem to the trustor, is it reasonable for him or her to trust? People
tend to ask themselves this question only in situations where they know trusting could get them into
trouble [15].
Trust can have instrumental value and may also have a great deal of intrinsic value. Instrumentally,
trust include opportunities for cooperative activity, meaningful relationships, knowledge, autonomy,
self-respect, and a certain degree of moral maturity. These advantages may benefit the trustor, the
trustee, or society in general, they are therefore social as well as individual advantages. Intrinsically,
trust can be construed as a sign of respect for others which makes it intrinsically valuable.
Trustworthiness may be considered a virtue therefore trust can be a sign of respect for others as an
attitude of optimism about the trustee’s character: it is assumed that person’s character holds that
virtue [15]. Despite its philosophical importance, trust is a key element to be approached in an
integrated manner, a topic that can be easily placed in the field of a third generation of ethics [17].

Current literature on mechanisms that instil trust

Several studies emphasize the importance of medical outcomes for trust in doctor-patient
relationship to be maintained. Perception of competence means expectations that the patients have
concerning treatment are met. This seems to inspire trust in the doctor and to maintain it [18]. In what
trust in primary care is concerned, patients seem to consider trust as reinforced if they perceive
effectiveness in the care they receive [19]. There is mention in the current literature about a longer
form of trust, constructed during stronger relationships. Constructs like long-term trust [20] or secure
trust [19] connect well with relationship’s length and the medical outcomes.
Loyalty is also mentioned in the current literature. When it comes to the doctors that patients trust
the most, regardless of the illness they suffer from, they tend to come to the same doctor, leading to
longer relationships [18]. Even in oncology, it seems that once trust built, it prevents patients from
requesting a second opinion [20].
Regarding honesty, providers want to trust that their patients disclose important information like
non-adherence to treatment, alcohol or drug-related problems. Patients hope providers believe them
when they provide information about their health and concerns [21].
Patient-centred communication is another important aspect. Listening to the patient, and paying
attention to all doubts and questions are two determinants of patients’ trust in health care providers
[18]. When patients feel cared for, they build trust based on the devotion of time and individual
attention the doctor shows [20]. On the other hand, when doctors are not taking the time to explain
diagnoses or answer questions, this leads to patient’s distrust and resentment between patient and the
healthcare team [22], [23]. In what cancer is concerned, one way in which the doctor could instil trust,
is explaining ways in which patient’s disease is not as bad as it might have been [24].
For doctors to reach the correct diagnosis, laboratory tests are perceived by patients as a competent
medical endeavour. Patients tend to perceive doing tests as a mark of competence, which, in turn,
leads to greater trust. Being subject to some tests make patients trust the physician and the facility,
even if they do not know why the tests are performed [18]. Some patients find it difficult not being
able to ask the GP for tests or procedures like they were used in the past [25]. This is particularly
important in the context of irritable bowel syndrome, where colonoscopy can be witnessed by patient,
either live, either as recording [26].
With respect to pitfalls, research with cancer patients shows that admitting one’s mistakes might
be an important feature in gaining patient’s trust. If the doctor misjudges a situation and later comes
back to it, this instils trust for patients [18]. Other results, however, suggest that inappropriate or
missed diagnoses are a distinct feature of distrust [22].

106
 Finally, in what confidentiality is concerned, results are contradictory. Patients judge in some
contexts confidentiality as unimportant for trust [20] while in other studies, pitfalls in patient privacy
and confidentiality is seen as a problematic feature [23].

Pathways of building trust for IBS patients

In a study pertaining to the pathways that lead to doctor-patient mutual trust in the context of
irritable bowel syndrome we have found several mechanisms that might be specific to this functional
disease [27].
Our study emphasized the importance of results in medical care, for both patient and doctor.
Results meant for patient proof of the effectiveness of medical care and of doctor’s competence
and for the doctor, proof of a compliant patient. It meant that patients did tell the truth about how they
managed their own treatment. These successes also lead to loyalty, to visiting the same doctor for
different health problems. It’s a result that matches other studies with respect to the importance of
patient’s treatment expectation and loyalty [18], [20].
Exchanging questions and answers in doctor-patient dyad seemed to instil trust on both sides.
Patient seemed to interpret the quantity of questions the doctors asked as a sign the doctor really
cares to find the correct diagnosis and treatment. The doctor seemed to interpret the patient’s
questions and answers as a competent involvement in the management of treatment and as validity of
information being provided. The importance of communication’s quality is also stressed in other
studies dealing with trust [18], [22].
How doctors dealt with patient’s anxiety and overreacting with respect to medical check-ups was
also important. The doctor supported the anxious patient by showing him/her that the reactions might
have been exaggerated. Subsequently, patient became aware of his/her psychological processes, more
in control with them, and this, in turn, instilled even more trust in the doctor. This result was valid
especially in a long-lasting relationship and might be interpreted as a psychotherapeutic insight.
Uncertainty and anxiety got soothed once investigations were carried out and reasons for fears
excluded. This seemed to lead to more trust. Being uncertain about having something worse, the
patient regarded investigations as having the power to exclude a possible worse diagnosis [like
cancer]. Once this happened, patient became suddenly soothed and reinforced in his/her feeling of
trust towards the physician. This result partially confirms that by explaining ways in which patient’s
disease is not as bad as it might have been, patients get a stronger feeling of trust [24].
Being a witness of the colonoscopy mattered for trust. This soothed patient’s anxiety. Patient
believed he could see with his own eyes the “proof” for the exclusion of a worse possible diagnosis.
Indeed, other studies support the idea that patients value tests as a competent medical manoeuvre
despite not knowing exactly what tests are performed and how [18], [25].
Perceived attention-related mistakes in the doctor-patient interactions was an important feature of
distrust. The pitfalls can include transcription mistakes or errors in prescribing. An anxious patient
became more uncertain about the course of treatment by noticing the mistakes which, in turn, made
the patient question if the doctor is reliable. It is likely that the same mechanism is responsible for
previous results mentioned in literature related to inappropriate or missed diagnoses [22].
One of our most interesting findings have been related with the use of labels like scared or panicky.
Patients felt the “panicky” label as stigma and questioned if he/she is taken seriously.
Consequently, the patient loses trust because he/she doubts the procedure meant to arrive at a
correct diagnosis. It is an example of interaction where both actors seem to lose trust simultaneously.
It also matches the previous results regarding not taking the time to explain or answer questions
[22].

Conclusion

Trust is important because it allows people to depend on other people with respect to important
interest the former have. Irritable bowel syndrome is a good example of need for mutual trust in the
107
context of chronic diseases thanks to the particulars of uncertainty and anxiety feelings these patients
have. Moreover, trust is important in chronic diseases in general and in IBS in particular, because it
is the way evidence based medicine is implemented. Without it, patients tend not to comply with
therapeutic recommendations and to fail in seeking care. Literature is not abundant in data with
respect to how trust is built and maintained, especial for functional disorders. In this paper, we
reviewed some of the previous findings, and we presented the results of a qualitative study dealing
with trust of IBS patients. All the information presented is interconnected, in order to show how
different philosophical and practical aspects of trust do apply to the particulars of IBS patients.

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27. Rotaru T-S, Drug V, Oprea. How Doctor-Patient Mutual Trust Is Built in the Context of Irritable Bowel
Syndrome: A Qualitative Study. Rev Cercet si Interv Soc [Internet]. 2016; 55: 185–203. Available from:
http://www.rcis.ro/en/current-isue/2324-how-doctor-patient-mutual-trust-is-built-in-the-context-of-irritable-
bowel-syndrome-a-qualitative-study.html.

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Do TLRs Play a Role in IBS?

RUSU Flaviu1, DUMITRASCU Dan L.1

1Emergency County Hospital Cluj, 2nd Medical Department, University of Medicine and Pharmacy “Iuliu Hatieganu”,
Cluj-Napoca (ROMANIA)
Emails: flaviurusu@yahoo.com, dan_dumitrascu@yahoo.de

Abstract

Introduction
The irritable bowel syndrome (IBS) is a functional gastrointestinal disorder whose pathogenesis is
not completely understood. Recent studies suggest that low grade mucosal immune activation
contribute to the pathopsysiology of IBS. Toll-like receptors (TLRs) are a family of pathogen-
recognition receptors in the innate immune system.

Materials and methods

We performed a systematic review study using data from PubMed. We decided to look only for
papers indexed in Pubmed, thus having at least English abstract. We searched on PubMed following
keywords: irritable bowel syndrome, TLRs, inflammation. Only relevant studies were selected for
analysis.

Results
We identified a few papers appropriate to this survey. Were measured expression of TLRs (TLR1-
TLR10) in the colonic mucosa and in the blood of IBS patients. Was found an increased expression
of TLR2, whereas the expression of TLR4 was fluctuating in the blood. It seems that an exaggerated
response to the TLR8 agonist for all cytokines investigated was seen in IBS patients. In human colonic
mucosa was determinated increased expression of TLR2, 4, 5, 9 and decreased levels of TLR7, 8.
Significant upregulation of TLR4 expression relative to controls were found in colonic mucosa of
IBS-D, increased expression of TLR9 was found in PI-IBS and upregulation of TLR2 expression was
found in IBS-M patients. TLR2 and TLR4 mRNA expression correlates significantly with duration
of symptoms.

Conclusions
The TLRs and their subsequent cellular activation and production of messenger molecules can
play a role in pathogenesis of IBS, but future research is required.
Keywords: IBS, TLRs, inflammation

Introduction

Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders, a
chronic debilitating condition with a reported prevalence of approximately 10% to 20% worldwide
(1, 2). IBS is primarily characterized by symptoms like abdominal pain associated with an altered
bowel function in the absence of any organic cause. Patients commonly report abnormal defecation
ranging from diarrhoea to constipation, including a combination of the two, the degree of which can
vary in both duration and severity (3, 4). The symptoms are troublesome and affects the quality of

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life and work capacity of patients which can increase the risk of occurrence of depression and social
isolation (5, 6).
The pathogenesis of IBS is unclear but a role for lowgrade mucosal inflammation and
immunological alterations in the development of IBS has become evident through a number of
previous studies (7, 8). Intestinal epithelial surfaces are constantly exposed to antigens from the
normal microbiota, food antigens, and pathogenic microorganisms. Bacterial wallproducts play an
important role in activation of immune and nonimmune cells of the intestinal mucosa. The intestine
needs to be able to respond to pathogenic organisms while at the same time maintain tolerance to the
commensal flora. The abilities of epithelial cells to detect bacterial cellular components require the
expression of pattern recognition receptors (PRRs) that recognize repetitive patterns present on Gram-
positive and Gram-negative bacteria, fungi, viruses, and parasites (9).
Toll-like receptors (TLRs) are members of the pattern recognition receptor family and they play a
central role in the initiation of innate cellular responses and the subsequent adaptive immune response
to a variety of pathogens. There are ten TLRs in humans and they recognise different microbial
ligands during infection (10). Toll like receptors (TLRs) belong to the family of PRRs and are present
in macrophages of the lamina propria, dendritic cells, Paneth cells, and intestinal epithelial cells (11).
After recognition of their ligands TLRs activate intracellular signalling pathways leading to
production of proinflammatory cytokines and chemokines (12). There are a few data about the role
of TLRs in IBS. The presence of low-grade inflammation and immunological alterations in IBS
patients suggests a possible involvement of TLRs in the pathopsysiology of IBS. The aim of this
study was to investigate the role of TLRs in IBS.

Materials and methods

We performed a systematic review study using data from PubMed till 2017. We selected only
PubMed indexed papers, papers which had at least the abstract in English. All others papers were
excluded. We searched on the PubMed these keywords: irritable bowel syndrome, toll-like receptors,
inflammation. Only relevant studies were selected for analysis. We started from a total of 18 PubMed
indexed papers on TLRs published between 2008-2017. All studies used Rome criteria for diagnosis
of IBS. Statistical methods: we used SPSS version 22.0 for Windows

Results

We analyzed 18 PubMed indexed papers. Number of papers containing the materials and methods
are represented in Table 1. In terms of which TLRs were investigated, compared to the number of
trials, the results are represented in Table 2. Regarding the methods of the trials, most of the trials (9)
used colonic biopsy samples and 5 trials used venous blood.

Table 1. Sudies distribution

Total numbers of the Experimental models IBS patients Review
analyzed papers
18 2 12 4

Table 2. Distribution of classes of TLRs compared to the number of trials

Classes TLR1 TLR2 TLR3 TLR4 TLR5 TLR6 TLR7 TLR8 TLR9 TLR10
of TLRs
No of 4 8 5 13 4 4 4 4 5 1
trials

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 Distribution of the trials by countries is represented in Fig. 1.

No. of trials

Countries

Fig.1. TLRs were most investigated in Irland

In 2008, Wang XM used immunohistochemistry to detect the expression of TLR4, in the colon
mucosa specimens of 30 patients with IBS-D and 12 healthy volunteers obtained by colonoscopy.
The results show that the expression of TLR4 in the IBS specimens was significantly higher than
that of the specimens from the controls (0.3971±0.0996 vs 0.3044±0.0481) (13).
McKernan DP evaluate in 2009 the TLR expression in the colonic mucosa of two rat strains that
display colonic visceral hypersensitivity and the results show a significant increase in the mRNA
levels of TLR3, 4 & 5 in colonic mucosa of MS rats compared with controls and no significant
differences were noted for TLR 2, 7, 9 & 10 while TLR 6 could not be detected in any samples in
both rat strains (14).
In 2010, Brint EK invetigated the expression of TLRs in colonic biopsy samples obtained from 26
IBS patients and compared with 19 healthy controls. Quantitative reverse transcriptase-PCR showed
increased levels of TLR4 and TLR5 and decreased levels of TLR7 and TLR8 in IBS patients (15).
In 2010, Rodriguez-Fandino O writed a review about cytokines and toll-like receptors. Brint et al,
reported a 5-fold up-regulation of TLR4 in women with IBS compared to healthy controls, while
reporting a reduced expression of TLR7 and TLR8 in the same patients and Villani found the presence
of genetic variants involved with TLR9 to be independent risk factors for developing IBS following
an episode of acute gastroenteritis (16).
McKernan DP investigated 30 IBS patients and 30 healthy controls. The results show that an
exaggerated response to the TLR8 agonist for all cytokines investigated was seen in IBS patients. In
addition, enhanced TLR2-induced TNFα release, TLR3-induced IL-8 release, TLR4-induced IL1β
and TNFα release, TLR5-induced IL1β and TNFα release and TLR7-induced IL-8 release was also
observed in IBS patients. No differences in TLR1, TLR6 or TLR9 activity were detected (17).
In 2012 Belmonte L, evaluate the TLR2 and TLR4 expression, in the colonic mucosa of IBS
patients classified into the three main subtypes (with constipation, with diarrhea or mixed). The IBS-
Mixed subgroup displayed a significant up-regulation of TLR2 (p=0.02) and TLR4 (p=0.04) in the
colonic mucosa (18).
Ohman L, hypothesized in 2012 that monocytes are more activated in patients with IBS than in
the healthy population. Blood samples from 74 patients with IBS and 30 controls were obtained.
The resusults show that monocytes from patients demonstrated an increased expression of TLR2,
whereas the expression on monocytes of TLR4 was comparable in patients and controls (19).
In 2012 Clarke G, investigated whether activation of specific TLRs elicits exaggerated kynurenine
production in IBS patients compared to controls. IBS subjects had an elevated plasma kynurenine:
tryptophan ratio compared to healthy controls. This profile included alterations at TLR1, TLR2,
TLR3, TLR5, TLR7, and TLR8 (20).

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 At UEG Week Berlin 2013, Rusu F presents the preliminary results of a study about the mucosal
expression of TLRs on 34 patients with IBS and 17 healthy controls. The results show that the
expression of TLR 9 tended to be lower in patients relative to controls, whereas the expression of
TLR2 and TLR6 was similar in patients and controls (21).
In 2014 Yuan B, investigated if the TLR4 activation may play a vital role in functional visceral
pain in IBS. The finding that NCI significantly enhanced TLR4 expression without altering the
expression of TLR3 and TLR7 in rat DRGs further suggests a receptor-subtype specific upregulation
of the TLR family in functional visceral pain. These studies add TLR4 to the list of key nociceptive
molecules that are involved in functional visceral hypersensitivity (21).
Kristen L Reti investigated in 2015 the relation between TLR and E. coli. The results indicate that
while untreated E. coli failed to change TLR4 expression, TLR4 gene expression is decreased when
colonic epithelial cells are infected with E. coli that had been exposed to C. jejuni in comparison to
controls. Reduced epithelial TLR4 expression in enterocytes exposed to C. jejuni-modified E. coli
may disrupt host homeostasis, thereby promoting a proinflammatory response (22).
In 2016, Kocac E investigate the TLR2 and TLR4 levels in 51 IBS patients and 15 healthy controls.
Colonic tissue levels of TLR2, TLR4 were detected (23). The colonic tissue levels of TLR4 were
significantly higher in IBS patients than in healthy controls. TLR2 levels were significantly higher
among individuals with diarrhea-predominant IBS than among constipation-predominant IBS
patients and healthy controls. The TLR4 levels were significantly higher in the diarrhea-predominant
IBS patients and constipation-predominant IBS patients than in comparison healthy controls.
In summary, the expression of TLRs in IBS patients is represented in Table 3.

Table 3. Expression of TLRs in IBS patients

Normal expression of Increased expression of Decreased expression Fluctuating expression
TLRs TLRs of TLRs of TLRs
TLR 6 TLR 2 TLR 7 TLR1
TLR10 TLR 4 TLR8 TLR 3
TLR 5
TLR 7
TLR 9

Conclusions

• up-regulation of TLR4 in IBS patients may contribute to occurrence of IBS;

• there is an activation of the signal transduction pathway of TLR4 in the colonic mucosa of
patients with IBS-D;
• patients with IBS have increased expression of TLR2 on monocytes and the activation level
on monocytes correlates with less severe psychological symptoms and better quality of life;
• the results support the presence of an immune engagement between the microbiota and the
host in IBS;
• elevated cytokine levels and toll-like receptor activity in the periphery of patients with the
irritable bowel syndrome, indicate some immune dysregulation in IBS patients;
• differential expression of TLR in IBS patients according to the disease can plays a central role
in the complex pathophysiology of IBS.

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Predictive Factors of Depression in Irritable Bowel Syndrome Patients
FADGYAS STANCULETE Mihaela1, POJOGA Cristina2,3,
DUMITRASCU Dan Lucian4
1 UMF Iuliu Hatieganu Cluj Napoca, Department of Neurosciences, Psychiatry (ROMANIA)
2 Babes-Bolyai University, Department of Clinical Psychology and Psychotherapy, International Institute for Advanced Study of
Psychotherapy and Applied Mental Health (ROMANIA)
3 Regional Institute of Gastroenterology and Hepatology O Fodor, Cluj-Napoca (ROMANIA)
4 UMF Iuliu Hatieganu Cluj-Napoca, Department of Internal Medicine (ROMANIA)

Emails: mihaelastanculete@yahoo.com, cristinapojoga@yahoo.com, dan_dumitrascu@yahoo.de

Abstract

Patients with irritable bowel syndrome (IBS) often have comorbid psychiatric disorders,
particularly depression. The presence of depressive symptoms is associated with more severe
gastrointestinal symptoms and less favourable clinical course compared to patients without this type
of comorbidities. The aim of this study was the identification of psychosocial factors that can give a
prediction of the emergence of depressive symptoms in patients with irritable bowel syndrome (IBS).
Keywords: depression, irritable bowel syndrome, psychosocial factors

Introduction

Patients with IBS often report both somatic extra-intestinal symptoms and psychiatric symptoms.
The most commonly psychiatric symptoms reported are depressive. The reported prevalence of
depression in patients with IBS ranges from 6 to 70% [1-5]. The Fond’s meta-analysis in 2014 has
confirmed increased levels of anxiety and depression in IBS patients compared to healthy individuals
[6].
On the other hand, various researchers reported a prevalence of irritable bowel syndrome in
patients with depressive disorders ranging from 17% to 37% [7].
The presence of depressive symptoms in patients with IBS is associated with a more severe
gastrointestinal symptomatology and leads to a more unfavourable clinical progression compared to
patients without this type of comorbidity [8, 9].
Many of the studies reported in the literature used Hospital Anxiety and Depression Scale (HADS)
to evaluate anxiety and depressive symptoms. Norton’s team, following the meta-analysis of 21
studies, recommended that this scale should be avoided when the aim of the research is to provide an
accurate analysis of anxiety and depressive symptomatology [10].
Identifying the underlying factors in the development of depression in IBS is necessary for
enhancing understanding and developing more effective interventions for patients whose comorbid
mood disorder increases the likelihood of an unsatisfactory response to specific medication and a
disappointing progression.
Starting from the data identified in the literature, the objective of this research was to identify those
specific factors that can ultimately provide us with a prediction of the occurrence of depressive
symptomatology in patients with IBS.
The purpose of the current study was to explore the psychological and demographic factors that
can be associated with the presence of depression and to obtain information about psychological
symptoms and cognitive attitudes that may eventually be used in the development of specific
treatment strategies. More specifically, we evaluated the relationships between anger as a state and
trait, the coping mechanisms used to adapt to chronic stress represented by IBS symptoms, and
depressive symptoms. We also introduced in the analysis the socio-demographic variables.
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 Based on data from the literature, this research aims to test the following assumptions:
1. Demographic factors are predictive factors for depression in patients with IBS.
2. Factors related to the disease (the level of pain perceived in the last month, duration of illness)
are predictive factors of depression.
3. Psychological factors (irrational beliefs, coping mechanisms, anger as state and trait) are
predictive factors of depression.

Methodology
We conducted a cross-sectional study on a sample of seventy patients recruited consecutively from
two tertiary gastroenterology centres in Cluj-Napoca. The diagnosis of IBS has been confirmed by
gastroenterologists using Rome III criteria.
The criteria for inclusion in the study were: a) at least 18 years, b) did not suffer from a chronic
concomitant disease, c) the ability to read and write in Romanian. Participants were excluded if they
did not meet the criteria mentioned above. This study was approved by the Ethics Committee of the
University of Medicine and Pharmacy Cluj-Napoca, all participants signing an informed consent to
participate in the study.
We used Beck Depression Inventory (BDI), State-Trait Anger Expression Inventory (STAXI-2),
Brief COPE Inventory (B-COPE), Dysfunctional Attitude Scale (DAS), and Visual Analog Scale
(VAS). We followed a protocol that complies with ethical rules on the confidentiality of data
processing. After obtaining the participants’ agreement, the scales were administered without the
need for a time limit.
To test the study hypotheses, we used correlation analysis and regression analysis.
Intercorrelations were calculated using the Pearson correlation coefficient, and the predictors of
depression were determined using stepwise multiple regression analysis.

Results

The average BDI score was 14.3 with a standard deviation of 9.54. The correlation matrix between
the variables listed above is shown in Table 1. As can be seen from this matrix, the BDI score
statistically correlated statistically with state anger (r = .489, p <0.05), with anger as a trait (R = .487,
p <0.05), avoidance-oriented coping (r = .507; p <0.05), and increased level of irrational cognition (r
= 0.474, p <0.05).
We did not observe statistically significant correlations between BDI scores and disease duration
(r = -0.097), as well as between BDI scores and pain intensity (r = .117).

Table 1. Pearson correlation coefficients for depression score, demographic factors, anger as trait-state, coping
mechanisms, irrational cognition, duration of illness, pain intensity

BDI Age Gender S- T- PFC AEC AOC DAS Disease VAS

total Ang Ang total duration
score score score

BDI total Pearson 1 -.135 .169 .489** .487** .044 -.178 .507** .474** -.097 .116
score Correlation

Age Pearson -.135 1 .277* -.027 .031 .050 -.100 .104 .175 .397** .169
Correlation

Gender Pearson .169 .277* 1 .178 .330** .148 -.046 -.004 .132 .095 .119
Correlation

S-Ang Pearson .489** -.027 .178 1 .453** -.118 -.221 .131 .375** -.010 .012
Correlation

T-Ang Pearson .487** .031 .330** .453** 1 -.073 -.389** .254* .563** .130 .007
Correlation

116
 PFC Pearson .044 .050 .148 -.118 -.073 1 .485** .125 -.272* -.054 -.091
Correlation

EOC Pearson -.178 -.100 -.046 -.221 - .485** 1 .205 - -.033 -.143
Correlation .389** .499**

AOC Pearson .507** .104 -.004 .131 .254* .125 .205 1 .341** .117 .086
Correlation

DAS total Pearson .474** .175 .132 .375** .563** -.272* -.499** .341** 1 -.005 .152
score Correlation

Disease Pearson -.097 .397** .095 -.010 .130 -.054 -.033 .117 -.005 1 -.063
duration Correlation

VAS Pearson .116 .169 .119 .012 .007 -.091 -.143 .086 .152 -.063 1
score Correlation

* significant correlation at p < 0.05, ** significant correlation at p< 0.01

S-Ang=state anger; T-Ang= trait anger; PFC=problem-focused coping; EOC=emotion-oriented coping; AOC-avoidance
oriented coping

The model 1, in which we introduced demographic factors, did not explain a significant percentage
of the variance of depressive symptoms, R square =, 049, F (2, 63) = 1,617, sig F change = 0,207 (see
Table 2).
Table 2. Model 1 Summary
Model Unstandardised Standardised T Sig
coefficients coefficients
B Standard Beta
error
Age -0.129 0.093 -0.179 -1.394 0.168
Gender 4.073 2.725 0.192 1.495 0.140

We obtained the same results for the model two, where we included the IBS variables (disease
duration, pain level experienced in the last month): R square =, 067, F (2,61) =, 582, sig F Change =,
562 (see Table 3).
Table 3. Model 2 Summary
Model Unstandardised Standardised T Sig
coefficients coefficients
B Standard Beta
error
Age -0.131 0.103 -0.182 -1.279 0.206
Gender 3.956 2.746 0.187 1.441 0.155
Disease
-0.079 0.309 -0.035 -0.256 0.799
duration
Pain
0.475 0.473 0.127 1.004 0.319
intensity

Model 3 included the psychological factors. The results indicated that psychological factors had a
significant increase in the explained variance: R square =, 597, F (6,55) = 12,056 (see Table 4).
Table 4. Model 3 Summary
Model Unstandardised Standardised T Sig
coefficients coefficients
B Standard Beta
error
Age -0.150 0.075 -0.209 -2.018 0.049
Gender 1.448 2.065 0.068 0.701 0.486

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 Disease
-0.178 0.224 -0.078 -0.796 0.430
duration
Pain
0.219 0.337 0.058 0.651 0.518
intensity
S-Ang 0.366 0.133 0.274 2.757 0.008
T-Ang 0.126 0.167 0.095 0.757 0.453
PFC 0.254 0.192 0.130 1.325 0.191
EOC -0.354 0.194 -0.213 -1.831 0.073
AOC 0.793 0.194 0.444 4.080 0.000
DAS total
0.045 0.039 0.148 1.168 0.248
score

Looking at the individual coefficients, we can see that variables that have made a significant
contribution to explaining depressive symptoms were: state-anger (Beta = .274, t (df = 59) = 2.757,
sig = .008) and avoidance-oriented coping (Beta = .444, t (df = 59) = 4.08, sig <0.001). We also
noticed that age has become a significant predictor in the model three, when we considered all the
variables (Beta = - .209, t (df = 59) = - 2.018, sig = 0.49) (see Table 5).
Table 5. Individual coefficientsa
Model R R Square Change Statistics
R Square Change F Change df1 df2 Sig. F Change
1 .221a .049 .049 1.617 2 63 .207
2 .258b .067 .018 .582 2 61 .562
3 .773c .597 .530 12.056 6 55 .000
a. Predictors:gender, age
b. Predictors: gender, age, pain intensity, disease duration
c. Predictors: gender, age, pain intensity, disease duration, emotion-oriented coping, avoidance-oriented coping,
problem-focused coping, state-anger, trait- anger, DAS total score
a
dependent variable= BDI total score

Discussions

The results of the regression analysis have highlighted that psychological factors (more precisely
the dimensions of anger as state and trait, as well as the use of avoidance-oriented coping
mechanisms) and, to a lesser extent, demographic factors (age) can be predictors of depressive
symptomatology in patients with IBS. These results partly confirm the study assumptions.
Specifically, the results of this study highlight the importance of the types of coping mechanisms
used as a resource that contributes to patients’ ability to adapt to a fluctuating chronic disease.
IBS patients who have used dysfunctional coping mechanisms have been more prone to develop
depressive symptoms. Thus, if a patient with IBS uses dysfunctional coping mechanisms, then there
is a high probability that the patient will work inappropriately in stressful situations, developing
consecutive depressive symptomatology.
The results of our research are in line with literature data showing that people who use avoidance-
oriented coping mechanisms predominantly are more vulnerable to stressful life events and are prone
to developing depression [11, 12].
Among the emotional triggers of the characteristic symptoms of IBS, anger, fear, and anxiety are
listed in the literature. Under the influence of these factors, an increase in intestinal motility was
observed in both IBS patients and healthy subjects. However, it has been observed that patients with
IBS have a higher and more sustained motor response to these factors [13].
The results of our study show that anger is involved in the psychological profile of the patient with
IBS. The data obtained are consistent with other studies that evaluated the anger expression, and
control of anger in patients with IBS and the link between these aspects and gastrointestinal
symptoms. Anger has been shown to associate with the decrease of antral motor activity in patients
with IBS, while in healthy individuals the antral activity increased in anger-generating situations [14].

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 There are studies in the literature that reported that the pattern of intestinal motility might be
modified under the influence of emotional stimuli. Thus, under the effect of stressful events, there
was an exaggeration of the gastrocolic reflex, an alteration of the stomach emptying, as well as an
increase in the transit of the small intestine [15, 16].
The data obtained in our study pave the way for other research needed to clarify the relationship
between gastrointestinal symptoms of IBS patients and anger as a state or a trait, which is important
in establishing therapeutic strategies.
One of the explanatory theories for justifying this depression vulnerability in IBS patients is that
they have lower coping skills to deal with stressful events and negative emotions [17]. We can assume
that the results of our study provide additional support for these hypotheses.
We have not obtained data to support a link between the factors related to the symptoms of IBS
and depression. These data are consistent with the results of other studies that have shown that the
severity of IBS symptoms does not necessarily correspond to the severity of depressive symptoms.
In one of the trials that explored the link between the symptoms of depression and depression,
Drossman and colleagues found that, although high scores obtained in depression scales characterized
patients with severe symptoms, depression was not a predictive factor for the severity of
gastrointestinal symptoms [18].
Patients with functional gastrointestinal disorders like IBS have been reported to have an increased
utilisation rate of healthcare services because they become alarmed by their symptoms as a result of
personal psychological traits or psychiatric symptoms.
It has not yet been possible to demonstrate whether psychological factors or comorbid psychiatric
disorders have a causal role in the development of IBS symptoms; so far there is no clear and
conclusive evidence to support this causal link [19, 20]. However, our study highlighted interesting
relationships between different psychopathological aspects in IBS patients.
The limits of the study
Our results are obtained from a group of patients recruited from tertiary gastroenterological centres
who were ready to undergo a psychiatric evaluation. Therefore, our results can not necessarily be
generalized to all the patients with IBS.

Conclusions

Depression in patients with IBS was found to be associated with psychological factors rather than
factors related to disease (disease duration and level of perceived pain).

REFERENCES

1. Lydiard RB, Falsetti SA. (1999). Experience with anxiety and depression treatment studies: implications for
designing irritable bowel syndrome clinical trials. Am. J. Med; 107, pp. 65S- 73S.
2. Alonso J, Angermeyer MC, Bernert S, Bruffaerts R, Brugha TS, Bryson H, Vollebergh W AM. (2004). Use of
mental health services in Europe: results from the European Study of the Epidemiology of Mental Disorders
(ESEMeD) project. Acta Psychiatrica Scand.;109(s420): pp. 47-54.
3. Guthrie E, Creed F, Dawson D, Tomenson B. (1993). A randomised controlled trial of psychotherapy in patients
with refractory irritable bowel syndrome. Br J Psychiatry.;163, pp. 315-21.
4. Whitehead WE, Palsson O, Jones KR. (2002). Systematic review of the comorbidity of irritable bowel syndrome
with other disorders: what are the causes and implications? Gastroenterology;122(4), pp. 1140-56.
5. Walker EA, Katon WJ, Jemelka RP, Roy-Bryne PP. (1992). Comorbidity of gastrointestinal complaints,
depression, and anxiety in the Epidemiologic Catchment Area (ECA) Study. Am J Med;92(1A), PP. 26S-30S.
6. Fond G, Loundou A, Hamdani N, Boukouaci W, Dargel A, et al. (2014). Anxiety and depression comorbidities
in irritable bowel syndrome (IBS): a systematic review and meta-analysis. Eur Arch Psychiatry Clin Neurosci.
264(8), pp. 651-60.
7. Garakani A, Win T, Virk S, Gupta S, Kaplan D, Masand PS. (2003). Comorbidity of irritable bowel syndrome
in psychiatric patients: a review. Am J Ther. 10, pp. 61–7.
8. Creed F, Ratcliffe J, Fernandes L, Palmer S, Rigby C, Tomenson B, et al. (2005). Outcome in severe irritable
bowel syndrome with and without accompanying depressive, panic and neurasthenic disorders. Br J Psychiatry.
186, pp. 507–15.

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9. Mayer EA, Tillisch K. (2011). The brain-gut axis in abdominal pain syndromes. Annu Rev Med. 62, pp. 381-
96.
10. Norton S, Cosco T, Doyle F, Done J, Sacker A. (2013). The Hospital Anxiety and Depression Scale: a meta
confirmatory factor analysis. J Psychosom Research. 74(1), pp. 74-81.
11. Jones MP, Wessinger S, Crowell MD. (2006). Coping strategies and interpersonal support in patients with
irritable bowel syndrome and inflammatory bowel disease. Clin Gastroenterol Hepatol. 4(4), pp. 474-81.
12. Sirois FM, Molnar DS. (2014). Perfectionism and maladaptive coping styles in patients with chronic fatigue
syndrome, irritable bowel syndrome and fibromyalgia/arthritis and in healthy controls. Psychother Psychosom.
83(6), pp. 384-5.
13. Qin HY, Cheng CW, Tang XD, Bian ZX. (2014). Impact of psychological stress on irritable bowel syndrome.
World J Gastroenterol. 20(39), pp. 14126-31.
14. Welgan P, Meshkinpour H, Ma L. (2000). Role of anger in antral motor activity in irritable bowel syndrome.
Dig Dis Sci.45(2), pp. 248-51.
15. Mönnikes H. (2011). Quality of life in patients with irritable bowel syndrome. J Clin Gastroenterol. 45,pp S98-
S101.
16. Bach DR, Erdmann G, Schmidtmann M, Mönnikes H. (2006). Emotional stress reactivity in irritable bowel
syndrome. Eur J Gastroenterol Hepatol. 18(6), pp. 629-36.
17. De Gucht, V. (2015). Illness perceptions mediate the relationship between bowel symptom severity and health-
related quality of life in IBS patients. Quality of Life Research, 24(8), pp. 1845-56.
18. Drossman DA, Leserman J, Zhiming L. (2000). Effects of coping on health outcome among women with
gastrointestinal disorders. Psychosom Med. 62, pp 309–17.
19. Lee SK, Yoon DW, Lee S, Kim J, Choi KM, Shin C. (2017). The association between irritable bowel syndrome
and the coexistence of depression and insomnia. J Psychosom Res. 2 28(93), pp.1-5.
20. Van Oudenhove, L., Törnblom, H., Störsrud, S., Tack, J. and Simrén, M. (2016). Depression and somatization
are associated with increased postprandial symptoms in patients with irritable bowel syndrome.
Gastroenterology, 150(4), pp. 866-74.

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Irritable Bowel Syndrome and the Off – Label Therapy: Ethical
Perspectives
TOADER Elena1,2, HORDILA Alexandra2
1University of Medicine and Pharmacy “Gr. T. Popa” Iasi, Department of Bioethics and Medical Deontology (ROMANIA)
2“St. Spiridon” Emergency Hospital, Institute of Gastroenterology and Hepatology, Iasi (ROMANIA)
Emails: toader.elena@yahoo.com, alexandra.hordila@gmail.com

Abstract

Off-label use can provide the best therapeutic interventions available to a patient, as well as a
standard of care for a particular health problem. Several fields of medical practice frequently reported
situations in which patient care could not have continued without prescribing an off-label drug.
Irritable bowel syndrome (IBS), a functional gastrointestinal disorder, is sometimes treated with
antibiotics or drugs used for depression, such as tricyclic antidepressants and selective serotonin
reuptake inhibitors (SSRIs). Prescription and off-label use in current clinical practice can become an
important ethical issue when there is a lack of solid evidence base or there are significant
uncertainties. In order to reduce off-label risks and inefficiency and to improve off-label prescribing
quality, medical community has to intervene with ethical justifications, to identify proper prescription
and off-label use. Legal authorities (e.g. FDA) have to use their legal expertise to detect off-label use
issues, with public information commitment and additional measures to discourage inadequate off-
label prescription.
Keywords: irritable bowel syndrome, off-label, antidepressants, rifaximin, ethical perspective

Introduction

According to the National Agency for Medicines and Medical Devices, Art. 46 - the words “safe”
or “risk-free” should never be attributed to a drug without appropriate scientific arguments.
Also, “new” should not be used to describe a pharmacological product or a presentation form, that
has generally been available for more than 1 year on the romanian drug market (1). This explanatory
note adds extra significance when referring to off-label therapy, a topic of interest for contemporary
medicine, from statistical aspects to responsibilities and regulatory status on off-label prescribing, in
accordance with ethical standards. As a general consideration, off-label use can provide the best
therapeutic interventions available at that time to a patient, as well as a standard of care for a particular
health problem. Several fields of medical practice such as oncology, pediatrics, geriatrics, obstetrics,
frequently reported situations in which patient care could not have continued without prescribing an
off-label drug (2). Consequently, when scientific and medical evidence justifies the use of off-label,
doctors promote the interests of patients by prescribing off-label drugs, considering that benefits
exceed the risks and the adverse events that can emerge in patients.

Off label use in irritable bowel syndrome

In gastroenterology, off-label use of drugs comes into question in irritable bowel syndrome (IBS),
defined by The World Gastroenterology Organisation (WGO) guidelines as a relapsing functional
bowel disorder, characterised by abdominal pain or discomfort, associated with defecation and/or a
change in bowel habit (3). Diagnostic strategies are in constant update, the newest being Roma IV
diagnostic criteria, unveiled in May 2016. As for the treatment, similar to diagnostic strategies, the
goal is to improve the therapeutic options, considering the fact that, in IBS, the current approach is

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clinically oriented because there is no general agreement on the cause of IBS. Thereby, there is no
treatment currently regarded throughout the world as being universally applicable to the management
of all IBS patients. Thus, in order to ease the therapeutic decision, the experts divided patients with
IBS into three categories: patients with constipation-predominant symptoms (IBS-C), those with
diarrhea-predominant symptoms (IBS-D) and IBS with mixed bowel habits (IBS-M) (4). The failure
of some therapeutic classes to control clinical symptoms of irritable bowel syndrome induced the
need for off-label use of different drugs, that were initially indicated for other conditions. Regarding
the relief of abdominal pain, smooth muscle relaxants (also called antispasmodic) are used as the first
line of treatment. There is data in the published literature according to which these drugs are having
excellent safety profiles and are able to regulate motility and defecation disturbances (3, 5).
Despite promising results on the efficacy of this drug category, not all the patients with IBS
respond to their administration. The efficacy of other drugs in reducing painful symptoms has been
studied for several years. The off-label use of antidepressants in IBS is a subject of ongoing research.
They act by reducing pain perception via a central modulation of visceral afferents and they also
minimize psychological factor that may play a role in the persistence of abdominal symptoms,
impairment of quality of life and determine excessive use of health-care services (3, 6). The concept
of a dysregulated gut-brain axis has been adopted as a model for this condition, considering that
changes in the composition of the gut microbioma, via pathways of the brain-gut axis, may arise as a
result of changes in central function, a level at which antidepressants might act. This observation
creates the possibility of using these drugs as a therapeutic option for IBS patients who associate
psychiatric comorbidities (7). Selective serotonin reuptake inhibitors (SSRIs) and tryciclic
antidepressants (TCAs) are the main two classes of antidepressants off-label prescribed in patients
with IBS, their safety and afficacy being analyzed in multiple studies. Drossman (2003) deepened the
subject in his article, a randomized controlled trial, concluding that Desipramine, a TCA, is effective
in patients with IBS, with significant benefits compared with placebo (8). There is limited data on the
off-label use of SSRIs in the treatment of IBS. Duloxetine (Cymbalta), FDA approved for the
treatment of major depressive disorder and diabetic neuropathy, has been off-label prescribed for IBS,
given its clinical support in the therapy of this conditions (9). The choice of antidepressants in IBS
patients still remains controversial, as long as there is no conclusive data in the literature regarding
comparisons of different classes of antidepressants. The available data suggest a beneficial
therapeutic effect of Doxepine and Desipramine on elderly patients or those with constipation-
predominant IBS, considering their least anticholinergic effects. For diarrhea-predominant IBS and
patients with insomnia imipramine or amitriptyline use is suggested (6) Even if these drugs are
recommended as the second-line therapy in current guidelines, it is mentioned that their use is limited
to patients experiencing psychiatric comorbidities, given the lack of conclusive data on efficacy and
overall outcomes. The high risk of developing side effects, the greater costs of some medications
(especially SSRIs) and potential patient reluctance to take antidepressants are also considered (3).
Among off-label prescribed drugs for the treatment of IBS, the anticonvulsants Gabapentin and its
successor Pregabalin (Lyrica), approved by the FDA for epilepsy therapy, diabetic neuropathy and
postherpetic neuralgia, are included (10). In some studies, a reduction in rectal sensitivity and bloating
after administration of these anticonvulsants has been observed, but the lack of conclusive data on
the use of these agents in IBS limits their use (11, 12). The prescription of antibiotics for the treatment
of IBS is explained by the identification of a different enteric flora in these patients compared to
healthy people. Even if the contribution of bacterial overgrowth to IBS pathogenesis is carefully
studied, it has not been fully clarified. A mildly increased small‐bowel bacteria has been seen in IBS,
but it’s role in this condition remains unclear, the authors of the study considering this an
epiphenomenon due to altered motility (10, 13). Several randomized, placebo-controlled trials
demonstrated improvement of IBS symptoms (e.g. bloating) after antibiotic therapy, with the greatest
efficacy seen with the antibiotic rifaximin. It is a rifamycin derivative with minimal absorption, FDA
approved for the treatment of traveler’s diarrhea and reduction in risk of hepatic encephalopathy
recurrence. It is off label prescribed for the treatment of IBS, some experts considering this drug as

122
being more effective than placebo in reliefing symptoms, especially bloating (10). In 2014, Generali
concluded that Rifaximin has modest effect on global IBS symptoms and benefit in bloating in IBS
patients without constipation (14). Other studies regarding this subject have continued, the most
recent data from a prospective, randomized, placebo-controlled trial demonstrating clinical
improvement after repeated treatment (up to 3 courses) with rifaximin 550 mg TID for 2 weeks in
patients with recurrent IBS-D (15). The American Gastroenterology Association suggests the use of
rifaximin in patients with IBS–D (moderate-quality evidence). At present, this drug is not approved
by the FDA for the treatment of IBS-D, but, in clinical practice, it is off-label prescribed by clinicians
(4).
There are situations in which prescription and off-label use in current clinical practice can become
an important ethical issue. It seems that the potential for harm is greater when off-label use does not
have a solid evidence base or there are significant uncertainties. These issues were also highlighted
by the experts of the scientific forums from US, involved in off-label use in pediatric hospitals, who
believe that “there is still incomplete evidence about the safety and efficacy of many drugs commonly
used in the treatment of children” (16). In this context, taking into account the experts’ opinion, the
following questions can be asked: Are there risks for patients receiving off-label treatments? Do
patients following an off-label treatment have minimum standards of care provided for disease
control?

Off label use in medical practice – scientific evidence

The use of off-label is relatively common in medical practice, although it is often not supported
by solid scientific evidence. There are numerous statistical data attesting the fact that off-label
prescribing practices reach high levels. For example, studies in the US have shown that about 20%
of prescriptions are off-label (17). Moreover, the use of off-label as a prescription and the utilisation
outside the therapeutic indications approved by the marketing authorization, is a controversial issue
due to concerns about the safety of medicines because they have not been evaluated by a regulatory
authority for that indication. A study from 2006, evaluating 169 drugs among the most commonly
prescribed, concludes that off-label use is high and most cases have insufficient data as a probative
scientific support or there is a lack of evidence (18). This information, obtained from opinion polls
which were conducted in medical university centers by medical staff, reveals that there is concern
and preoccupation in their institutions for the lack of data (as scientific support), but also for possible
associated costs that can occur when off-label therapeutic indications are inappropriate. As a result,
it appears that 50% of the respondents agree to prescribe medical products only in accordance to label
indications and 50% agree with off-label prescription (19). Summarizing this information, it can be
said, at least at first site, that the regulatory status of off-label prescription and use is controversial.
Further clarifications on the off-label prescribing regime are mentioned in the “Temporary Use
Recommendations (TUR)” issued in France, May 2012 (20). The normative act offers clear
indications on the prescription of medicines for yet unapproved indications, for a maximum of 3
years, within a regulated framework and with well defined limits, closely monitored by the Medicines
Agency, only for rare diseases or specific subgroups of patients, for whom no other approved
medicines yet exist. These provisions are also associated with the recommendations of the Experts
Committee of the Regulatory Authority on the quality of scientific evidence and drug safety.
It is preferable to TURs for a well-known drug than for a new or short-lived drug or TUR for rare
and/or severe diseases (21). These considerations are also agreed by the superior forums and they are
found in the FDA-approved Regulatory Framework, which not only does not disapprove off-label
use, but believes that physicians can prescribe for different patient groups, using indications and drug
doses which are not included on the label. In the FDA’s view, off-label use is a therapeutic option,
responsibly assumed by the prescribing physician based on professional experience, considering
medical techniques and professional conduct (22).

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Off label use – ethical standars

From an ethical perspective, off-label comes with the justification that it can provide the best
treatment available to a particular patient, along with the presumption of a guarantee for the protection
and assurance of the right to health. As an ethical requirement for off-label prescription, it is
imperative to assess existing evidence and, when missing or insufficient, information will be collected
and research carried out. Also, from the perspective of ethical considerations regarding off-label use,
it is necessary to analyze the patient’s situation (if there is a state of urgency and the degree of
urgency), availability of alternative treatment (is it the only treatment or are there other solutions) and
what is the best off-label use (as a new therapy or another indication of an old drug) (23).
These considerations take into account the fact that off-lable also implies possible risks, as it results
from the series of common examples identified in current practice on off-label use of newly
authorized products (drugs, devices) or approval based on relatively small group studies or treatment
followed a relatively short time, as well as previously undiscovered side effects. Thus, appears the
necessity of ethical standards to be applied to at least three levels (24):
• at the level of clinical trials, where off-label use displays ethical justification for compliance
with the proposed goal, when developing new therapies or clarifying the optimal use of
existing treatments is required.
• in research, where off-label promotion and use is interested in “field discovery”, in identifying
new areas of therapeutic applications, in safe conditions for the patient and respecting ethical
principles.
• medical practice aims, in prescribing off-label procedures, to achieve the therapeutic goal to
which the individual interests of the patient should be oriented.
Regardless of the level of ethical standards approach and application, medical practice is
increasingly supported by the fact that, in the management of off-label procedures, a strong
relationship between physician and patient is needed. What and how much doctors should tell patients
about off-label interventions (?), a rhetoric of accurate (quantitative and qualitative) information with
responses that polarize respondents’ views (22). Patients should receive information about what off-
label is, that is, that they benefit from an approved drug for a particular condition, a disease that has
genetic, physiological similarities, etc. with their affection, for which there are no available
therapeutic resources at that particular moment. Do we have the evidence for off-label use?
As a general consideration, it is accepted that the evaluation of off-label evidence from randomized
controlled trials (RCS), cohort studies, case-control studies, poorly controlled or uncontrolled studies,
case reports or expert opinions, is a logical extension of the authorization method of off-label use and
prescription (25). The prescribing physicianhas the resposibility to go through an assessment stage,
to prove that there is sufficient evidence to justify off-label use. Also, when adequate evidence is
lacking, he has to conduct research, providing full patient information with data on uncertainties and
potential costs associated with off-label. Off-label is a common and necessary prescription, especially
in critical patients, ethically justified as the only treatment option. An indication to be retained refers
to the non-reproducibility of the beneficial effects of the drug in another medical context.
For milder cases, ethics comes with the justification of the need for an evidence base, centered on
product safety and patient’s quality of life. The aim is to avoid incidents, as shown by the off-label
use of dexfenfluramine, an approved drug for obesity, pulmonary hypertension and heart disease
patients. A therapeutic target for off-label use are the patients affected by rare diseases, considered
therapeutically “orphaned”. This context faces a lack of motivation for product development for small
populations, as well as a number of issues involved in developing the evaluation criteria of the product
(26).
An ethical justification is to ensure the safety and efficacy at the same parameters as in previous
situations. In addition, with regard to the approval of products aimed at treating rare diseases, FDA
supports systematic studies and flexible data collection, to demonstrate, with appropriate evidence,
the safety and effectiveness of study results, even when they involve less than eight cases. In clinical

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practice, off-label use is still dealing with reticence for studies and application of off-label, in fields
such as pediatrics, obstetrics, geriatrics, minors, pregnant women, the elderly, drug studies (17).
This approach is contrary to actions and policies to promote and support research in under-
represented populations. This is the reason why we need interventions and strategies to reduce off-
label risks and inefficiency, improve off-label prescribing quality, regulatory proposals for certain
off-label policies and systematically monitor off-label patient responses.

Conclusions

Until a regulatory framework for off-label prescribing and use is established as clear conclusions,
we can say that patients need access to the benefits of off-label treatments, as well as protection for
risky and ineffective interventions. Consequently, the medical community has to intervene with
ethical justifications in actively promoting actions to identify proper prescription and off-label use,
but also to limit prescription and off-label use in ethically unjustified situations. Also, legal authorities
(e.g. FDA) have to use their legal expertise to detect off-label use issues, with public information
commitment and additional measures to discourage inadequate off-label prescription.

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3. World Gastroenterology Organisation. Irritable Bowel Syndrome: A Global Perspective. (Updated September
2015).
4. Chang, L., Lembo, A., Sultan, S. American Gastroenterological Association technical review on the
pharmacological management of irritable bowel syndrome (2014).
5. Annaházi A, Róka R, Rósztoczy A, Wittmann T. Role of antispasmodisc in the treatment of irritable bowel
syndrome. World J Gastroenterol. 2014 May 28; 20(20): 6031-6043.
6. Rahimi R, Nikfar S, Rezaie A. Efficacy of tryciclic antidepressants in irritable bowel syndrome: a meta-analysis.
World J Gastronterol. 2009 Apr 17; 15(13): 1548-1553.
7. Kennedy PJ, Cryan JF, Dinan TG, Clarke G. Irritable bowel syndrome: a microbiome-gut-brain axis disorder?
World J Gastroenterol. 2014 Oct 21; 20(39): 14105-14125.
8. Drossman D.A., Toner B.B., Whitehead W.E., Diamant N.E., Dalton C.B., Duncan S. et al. (2003) Cognitive-
behavioral therapy versus education and desipramine versus placebo for moderate to severe functional bowel
disorders. Gastroenterology 125:19–3.
9. Brennan BP, Fogarty KV, Roberts JL et al. Duloxetine in the Treatment of Irritable Bowel Syndrome: an open-
label pilot study. Hum Psychopharmacol. 2009 Jul;24(5):423-8.
10. Lacy B, Weiser K, De Lee R. The Treatment of Irritable Bowel Syndrome. Therap Adv Gastroenterol. 2009 Jul;
2(4): 221–238.
11. Hughton LA, Fell C, Whorwell PJ, Jones I, Sudworth DP, Gale JD. Effect of a second generation alpha2delta
ligand (Pregabalin) on visceral sensation in hypersensitive patients with irritable bowel syndrome. Gut.2007 sept;
56(9):1218-25.
12. Gale JD, Hughton LA. Alpha 2 delta (α2δ) ligands, gabapentin and pregabalin: what is the evidence for potential
use of these ligands in irritable bowel syndrome. Front pharmacol. 2011; 2: 28.
13. Posserud I, Stotzer P, Björnsson ES, et al. Small intestinal baterial overgrowth in patients with irritable bowel
syndrome. Gut. 2007 Jun; 56(6): 802-808.
14. Generali JA, Cada DJ. Rifaximin: Irritable Bowel Syndrome. Hosp Pharm. 2014; 49(11): 1014–1016.
15. Lembo A, Pimentel M, Rao SS, Schoenfeld P, et al. Repeat treatment with rifaximin is safe and effective in
patients with diarrhea-predominant irritable bowel syndrome. Gastroenterology.2016 dec; 151(6):1113-1121.
16. Kumar P, et al. Medicinal Use in the Neonatal Intensive Care Unit: Current Patterns and Off-Label Use of
Parenteral Medications. Journal of Pediatrics. 2008; 152 (3): 412-415.
17. Dresser R1, Frader J. Off-label prescribing: a call for heightened professional and government oversight. J Law
Med Ethics. 2009 Fall; 37 (3): 476-86, 396.
18. Radley DC, Finkelstein SN, Stafford RS. Off-Label Prescribing among Office-Based Physicians. Archives of
Internal Medicine. 2006; 166 (9): 1021-1026.
19. Evola, EG., Off-label Prescribing: Pediatrician Beliefs and Experience. Seton Hall University Dissertations and
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20. Emmerich J, Dumarcet N, Lorence A. France's New Framework for Regulating Off-Label Drug Use. N Engl J
Med 2012; 367: 1279-1281.
21. Crupariu A, Vîlceanu N, The Use of Off-label Medicines in the View of the National Agency for Medicines and
Medical Devices. Pharmaceutical Practice, 2013, 6 (4): 197.
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Regional Offices J4259 2,2007.
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Pharmacy and Therapeutics, 2009; 34 (8): 428-440.
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Neurogastroenterology topics in children

127
Celiac Disease in the Pediatric Patient: Serological and
Histopathological Correlations

BACIU Ginel1, FOTEA Silvia2

1“Lower Danube” University, Faculty of Medicine and Pharmacy, Galati, (ROMANIA)
2“Sf. Ioan Clinical Emergency Hospital for Children”, Galati, (ROMANIA)
Emails: ginelbaciu@yahoo.com, silvia_ghimpu@yahoo.com

Abstract

Introduction
Celiac disease represents an exaggerated immunological reaction of the intestinal mucosa, induced
by gluten, in individuals with a genetic predisposition.

Methodology
We have conducted a retrospective study on a group of 46 children diagnosed with celiac disease
and undergoing follow-up in the Pediatric Clinic no. III, Cluj-Napoca. The selected children had the
same clinical characteristics, positive serological tests (tissue transglutaminase antibodies IgA – ATg
and anti-endomisium antibodies IgA-AAE), had undergone digestive endoscopy, followed by
intestinal biopsy and anatomopathological analysis.

Results
Out of the 64 children studied, 11 were classified Marsh IIIb (17.18%). Two of them exhibited
positive antibodies (18.18%), 2 positive AAE (18.18%) and 5 were ATg positive (45.45%).

Conclusion
All patients with celiac disease classified Marsh IIIC with morphopatologic modifications had also
exhibited the presence of high values of at least one specific antibody.
Keywords: gluten, anti-endomisium, antibodies

Introduction

Celiac disease represents an amplified immunological reaction of the intestinal mucosa, induced
by gluten, in individuals with a genetic predisposition. The most difficult problem with establishing
the diagnosis of celiac disease represent cases with atypical forms. This is why a serological marker
based screening is very important in discovering new cases of celiac disease. Also, for a certified
diagnosis an endoscopic examination, followed by a histological examination is necessary.

Methodology
We have conducted a retrospective study on a group of 46 children diagnosed with celiac disease
and undergoing follow-up in the Pediatric Clinic no. III, Cluj-Napoca, between 2005-2007. Children
were selected based on the clinical characteristics, positive serological tests (tissue transglutaminase
antibodies IgA – ATg and anti-endomisium antibodies IgA-AAE), upper digestive endoscopy,
followed by intestinal biopsy and anatomopathological analysis. The chemiluminescence method was
used for quantitative determination of the IgA antitransglutaminase antibodies. A value of 8AU/ml
was considered positive. The indirect imunofluorescence method was used to detect IgA

128
antiendomisium antibodies. When the tissue appeared in fluorescent green, it was considered a
positive reaction. The biopsy samples were colored with eosin hematoxylin.

Results

Out of all the patients with no histological characteristics of early celiac disease (9 patients -
14.06% out of the patients with celiac disease) only one (11.11%) had positive AAE and ATg, 2
patients (22.22%) had positive AAE, 4 patients (44.44%) had positive ATg and 2 patients (22.22%)
had no positive antibodies at the moment of diagnosis. Later in their evolution, positive serology was
detected in the last 2 patients (Fig. 1). Out of the 7 patients classified Marsh I, 3 were positive for
AAE (42.86%) and 4 presented positive ATg (57.14%) (Fig.1). The 10 patients classified Marsh II
had the following serological findings: 2 patients with positive AAE (20%), 2 patients with positive
ATg 20%) and 6 with negative serology (Fig.1). Out of the patients classified Marsh IIIa, 1 patient
was positive for both antibodies (6.66%), 4 for AAE (26.66%), 6 for ATg (40%) and 4 had negative
serology (26.66%) (Fig. 1). Patients classified Marsh IIIb had an even distribution based on their
serology: 2 patients were positive for both antibodies (18.18%), 2 patients’ positive for AAE and 2
with negative serology; 5 out of these patients (45.45%) were positive for ATg (Fig. 1).
All patients classified Marsh IIIc had positive serology: 4 (33.33%) with both antibodies positive,
2 (16.66%) with positive AAE and 6 (50%) with positive ATg (Fig. 1).

Fig. 1. Correlation between histological classification of the intestinal biopsy and serology findings in patients with
celiac disease
Non- Marsh Marsh Marsh Marsh Marsh IIIc Total
characteristic I II IIIa IIIb
aspect
AAE+ 1 0 0 1 2 4 8
ATg+
AAE+ 2 3 2 4 2 2 15
ATg+ 4 4 2 6 5 6 27
AAE- 2 0 6 4 2 0 14
ATg-
Total 9 7 10 15 11 12 64

If we are to compare patients with non-characteristic histological modifications and those that can
be classified Marsh I and Marsh II, separately from those classified as Marsh III, we can see that 8
patients had negative serology out of 38 (15.79%) and positive serology for at least 1 antibody is
found in 18 patients (69.23%) for the first group, compared to 32 patients (84.21%) in the second
group (p=0.1868). (Fig.2)
Fig. 2. Patients serology classified Marsh III (IIIa, IIIb, IIIc)

AAE &
Negative; 6 Atg; 7
16% 18%

AAE; 8
Atg; 17 21%
45%

129
 Among the patients with celiac disease, 14 had negative serology initially. If we analyze based on
the histological findings, patients can be grouped in:
• uncharacteristic histologic aspect for celiac disease 2 patients (14.29%),
• Marsh I 0 patients (0%),
• Marsh II 6 patients (42.86%),
• Marsh III 6 patients (42.86%):
➢ Marsh IIIa 4 patients (28.57%),
➢ Marsh IIIb 2 patients (14.29%) (Fig. 2).

Fig. 3. Distribution of histological findings in patients with negative serology with celiac disease

6
5
4
3
2
1
0

No statistical correlation can be made between the lack of positive serology in celiac disease and
a less severe histological result. But the majority of patients (8/14 patients, 57.14%) with positive
serology did not have villous atrophy or any other significant histological modification. These
patients had non-characteristic histological modifications or modification, classified as Marsh II or
III.
ATg determination is a precise method for diagnosis, and follow-up, in children with celiac
disease. Studies have shown a great sensibility (96-100%) and a specificity of (96-100%) in children,
while in mixed groups, sensibility varies between 91.5-98% with a specificity a 98-99% [1, 2, 3, 4].
In adult studies, sensibility is the same but, with a specificity of 82-97%. AAE levels are correlated
with the degree of mucosal injury, but sensibility decreases with the increase of the number of patients
with less severe mucosal alterations that are included in the study [5, 6, 7, 8]. For this reason,
serological determination must be accompanied by histological analysis to increase the diagnosis
percentage by 20%. [9]
Donaldhson conducted a study on 117 children with celiac disease who were diagnosed through
serological determination and intestinal biopsy with the purpose of determining the correlation
between serological and histological findings and the results showed a positive statistical correlation
between ATg IgA levels (r=0.704, P<0.001) and AAE (r=0.740, P<0.001) and villous atrophy. [10]
Tursi, based upon many other studies which supported the fact that anti-gliadin antibodies and
ATg are not useful in diagnosing the celiac disease with minor modifications, he underwent his own
study to ascertain the prevalence and seric levels of ATg depending on the severity of the histological
modifications. Likewise, Tursi concludes that ATg prevalence and medium seric levels are greater in
patients with severe celiac disease (Marsh IIIb, c) than in those with less important modifications
(Marsh I-IIIa). Using serological testing without histological evaluation can underestimate the real
prevalence of the disease, posing a risk for delayed diagnosis, complications and malignancy. [11].
As a result of his studies, Barker recommends limiting intestinal biopsies for patients with high
levels of ATg, and advises the method to be used in cases of weak response to a gluten free diet. [12].
These recommendations are challenged taking into account the small number of patients on which
the study was performed. But, we have not yet reached the point where we can eliminate intestinal
130
biopsy. No child should begin a gluten free diet without a confirmation of celiac disease through
intestinal biopsy. [13]

Conclusions

The majority of patients with celiac disease (62.5%) had at least one positive antibody (AAE, ATg)
at the moment of diagnosis. All patients with histological abnormalities classified Marsh IIIc had
positive serology for at least one antibody. Positive serology correlates with the severity of
histological modifications, and this correlation is greater if both antibodies are used. At least one
positive serological marker was detected in 69.23% of the patients with less severe histological
modifications, compared to 84.21% of those with complete or incomplete villous atrophy (Marsh III).
Negative serology was present in 21.88% of the patients with celiac disease included in our study.
The small number of cases makes a statistical analysis inconclusive, and for this reason our study
remains open and continuing.

REFERENCES

1. Baudon JJ, Johanet C, Absalon YB, Morgant G, Cabrol S, Mougenot JF.

Diagnosing Celiac Disease: A Comparison of Human Tissue Transglutaminase AntibodiesWith Antigliadin and
Antiendomysium Antibodies, Arch Pediatr Adolesc Med 2004;158:584-8.
2. Sblattero D, Berti I, Trevisiol C, et al. Human recombinant tissue transglutaminase ELISA: an innovative
diagnosis assay for celiac disease. Am J Gastroenterol. 200; 95: 1253-7.
3. Hansson T, Dahlbom I, Rogberg S, et al. Recombinant human tissue transglutaminase for diagnosis and follow-
up of childhood celiac disease Pediatr Res.2002;51:700-5.
4. Wolters V, Vooijs-Moulaert AF, Burger H, et al. Human tissue transglutaminase enzyme linked immunosorbent
assay outperform both the guinea pig based tissue transglutaminase assay and anti-endomysium antibodies when
screening for celiac disease. Eur J Pediatr.2002;161:284-7.
5. Tursi A, Brandimarte G, Giorgetti G, Giglioblanco A, Lombardi D, Gasbarrini G. Low prevalence of antigliadin
and anti-endomysium antibodies in suclinical/silent celiac disease. Am J Gastroenterol 2001; 96: 1507-10.
6. Sategna- Guidetti C, Pulitano R, Grosso S & Ferfoglia G. Serum IgA antiendomysium antibody titers as a marker
of intestinal involvement and diet compliance in adult cealc sprue. J Clin Gastroenterol 1993;17 (2):123-7.
7. DickeyW, Hughes DF & McMillan SA. Reliance on serum endomysial antibody testing underestimates the true
prevalence of celiac disease by one fifth. Scand J Gastroenterol 2000; 35(2):181-3.
8. Abrams J, Diamond B, Rotterdam H & Green PHR. Seronegative celiac disease: increased prevalence with lesser
degrees of vilous atrophy. Dig Dis Sci 2004; 49:546-50.
9. Dahele A, Kingstone K, Bode J et al. Anti-endomysial antibody negative celiac disease: does additional
serological testing help? Dig Dis Sci 2001; 46(1):214-21.
10. Donaldson MR, Fifth SD, Wimpee H, Leiferman KM, Zone JJ, Horsley W, et al. Correlation of duodenal
histology with tissue transglutaminase and endomysial antibody levels in pediatric celiac disease. Clin
Gastroenterol Hepatol. 2007; 5(5):567-73.
11. Tursi A. Brandimarte G, Giorgetti GM. Prevalence of antitissue transglutaminase antibodies in different degrees
of intestinal damage in celiac disease. J Clin Gastroenterol. 2003; 36(3):219-21.
12. Barker CC, Mitton C, Jevon G, Mock T. Can Tissue Transglutaminase Antibody Titers Replace Small-Bowel
Biopsy to Diagnose Celiac Disease in Select Pediatric Populations, Pediatrics 2005; 115 (5):1341-6.

131
Clinico-Therapeutic Particularities of Anorexia Nervosa in Children
and Adolescents
BOLOS Alexandra1, UNTU Ilinca1, SAVLOVSCHI Dumitrita2,
SZALONTAY Andreea Silvana1
1Gr.T. Popa University of Medicine and Pharmacy Iasi, Romania, Socola Institute of Psychiatry Iasi, (ROMANIA)
2Institute of Gastroenterology Iasi, (ROMANIA)
Emails: alex_andra_bolos@yahoo.com, ilinca_tzutzu@yahoo.com, savlovschi_dumitrita21@yahoo.com, andrszal@yahoo.com

Abstract

Anorexia nervosa has recorded a dramatic reduction of age at onset, thus frequently affecting the
paediatric population. Despite the life-threatening character of anorexia nervosa, researches are scarce
regarding the particularities of this nosological category among children and adolescents, compared
to other mental disorders targeting the same age group. The present study is a review performed in
order to highlight the particularities of anorexia nervosa in children, adolescents and young adults, in
terms of clinic-therapeutic approach. A number of 20 articles related to this subject, published
between 2012 and 2016 had been studied. The prepubertal incidence of anorexia nervosa is
approximately 3% of all children and adolescents diagnosed with this disorder. On the other hand,
the therapeutic approach to anorexia nervosa has been predominantly neglected: only 12 of the 100
most cited papers on anorexia nervosa focus on a treatment for it. At the same time, a series of
scientific evidence plead for the association between anorexia nervosa among the paediatric
population with autism spectrum disorder or with mental disorders. The studies conducted thus far
begin to depict particularities related to both the clinical presentation of anorexia nervosa in children
and adolescents, as well as a series of particularities related to the therapeutic approach, especially
the one concerning psycho-emotional disturbances and social skills, which contribute fundamentally
to avoiding relapses. This paper is meant to be a premise for future researches because it synthesizes
the latest literature on this topic.
Keywords: anorexia nervosa, children and adolescents, family-centred therapies, cognitive-behavioural therapies, autistic elements

Introduction

Eating is a basic need, taken for granted by most individuals. Eating disorders are severe
psychopathological conditions, listed among the most common pathologies with chronicity potential
in children, adolescents and young adults. They often involve high personal, familial and social costs.
In case of anorexia nervosa, mortality risk is higher than for asthma, diabetes mellitus type 1 or
any other psychiatric pathology encountered among the paediatric population [1], [2].
Anorexia nervosa is a potentially life-threatening medical-psychiatric condition, which refers to
the failure of maintaining a minimum normal weight for one’s age, an extreme fear manifested for
weight gain, unhealthy eating habits meant to avoid weight gain, as well as a pathological alteration
of perceived body image [1], [3].

Methods

The present study is a review performed with the aim of highlighting the particularities of anorexia
nervosa in children, adolescents and young adults, in terms of clinic-therapeutic approach. A group
of 20 articles related to this subject, published between 2009 and 2016 had been studied. The research

132
has been performed on Pub Med database, by key words and combinations of key words: anorexia
nervosa, anorexia nervosa in children and adolescents, family-centred therapies in anorexia,
cognitive-behavioural therapies in anorexia, autistic elements in children and adolescents with
anorexia. The purpose of this paper is to present a succinct, synthetic view of the most recent scientific
outcomes obtained on international level regarding the particularities of the clinico-therapeutic
approach to anorexia nervosa in children and adolescents.

Results

Anorexia nervosa has recorded a significant decrease of age at onset, thus frequently affecting the
paediatric population. Despite the life-threatening character of anorexia nervosa, there are only a
scarce number of researches regarding the particularities of this nosological category among children
and adolescents, compared to other mental disorders targeting the same age group. The therapeutic
approach to anorexia nervosa has been predominantly neglected: only 12 of the 100 most cited papers
on anorexia nervosa focus on a treatment for it. At the same time, a series of scientific evidence plead
for the association between anorexia nervosa among the paediatric population with autism spectrum
disorder or with mental disorders. Recent studies report that, in children aged between 9 and 29
months, a developmental disorder was pinpointed, described in terms of both separation anxiety and
infantile anorexia. These children associate low growth rate and food refusal. Determining these
children to eat becomes a genuine fight for autonomy. The child’s unconscious fight for independence
manifests itself through anorexia, countered by the marasmic pattern [2], [4], [5].

Positive Diagnosis Elements

Statistics have shown that anorexia nervosa has been reported from the age of 4. The cases of
anorexia nervosa among the paediatric population must meet the general criteria of anorexia. Among
children, however, due to the low amount of body fat, one must take into amount a 25% loss of the
total body mass. In female paediatric patients, primary amenorrhea is frequent. The prepubertal
incidence of anorexia nervosa is approximately 3% of all children and adolescents diagnosed with
this disorder. On the other hand, 73% of all children diagnosed with anorexia nervosa are female [1],
[2], [5], [6].
A major modification of DSM-5 criteria compared to DSM-IV is represented by the elimination
of the criterion concerning amenorrhea, which is inadequate for the female patients who had not had
their period yet, for those on birth control pills or for male patients. This change was also argued by
the similarity of disease severity in patients with amenorrhea and in those with normal menstruation.
It is also fundamental to relate undernourishment to age, sex, development trajectory and physical
health. Whereas DSM-5 may not regulate the severity of weight loss in children and adolescents, on
European level it is related to the Body Mass Index [1], [3], [6], [7].
General, organic symptoms – which may emerge in the context of anorexia nervosa in children –
include hypotension, bradycardia, hypothermia, as well as tegument dehydration, hirsutism,
acrocyanosis, breast atrophy, peripheral oedema, decreased hair quality and dental erosions. At the
same time, it must be stated that the characteristic signs of insufficient caloric intake, encountered
among patients with anorexia nervosa, include hypothermia, acrocyanosis, bradycardia (40-49 beats
per minute), orthostatic hypotension, lean mass loss, hypoglycaemia with decreased insulin clearance,
low parathyroid hormone levels and decreased number of leukocytes [1], [3], [4], [7], [8].
Following a long-term evolution, children with anorexia nervosa may manifest psychomotor
retardation, as well a level of affective flattening. Recent studies support the association of anorexia
nervosa with mental disorders, mostly in case of females [2], [9].

133
Psycho-Emotional Causes of Anorexia Nervosa in Children and Adolescents

Three different categories of prepubertal patients diagnosed with anorexia nervosa were identified,
depending on clinical manifestations and the psycho-emotional developmental profile. Hence, the
first category refers to food refusal as consequence of the fear of becoming obese, materialised in
slow growth rate and in delayed emotional development [2], [3], [9]. On the other hand, the second
category refers to girls before their prepubertal period, aged between 10 and 12, who exhibit a
psychological pseudo-precocity and an anorexic behaviour similar to pubertal or adolescent girls.
Often, their parents actually discourage age-specific behaviours and they support their pseudo-
adolescent behaviours [1], [2], [4], [7], [10]. The third category concerns an equal distribution by
gender: it has been reported among children with a labile psychological background, with disorders
related to perceived self-image and with significantly low self-esteem (they may even exhibit
psychotic symptoms that precipitate or coexist with food deprivation symptoms). A series of studies
even identify the possibility of associating premorbid features such as timidity, schizoid elements,
depressive elements, or even pre-psychotic or psychotic symptoms [2], [4], [10], [11].
At the same time, clinical evidence attests an association between anxiety disorders among this
population and higher prevalence of anorexia nervosa. Early detection of symptoms and the
determination of therapeutic measures are essential for preventing the disorder from becoming
chronic and for avoiding mental and somatic complications [3], [4], [11], [12].
Polymorphism of Clinical Context in Anorexia Nervosa

The emergence of anorexia nervosa symptoms in adolescence can be associated, under certain
circumstances, with an under-diagnosis of autistic symptoms manifested since early childhood,
which, through social interactions and inadequate social behaviours, makes mostly females more
prone to developing eating disorders. A meta-analysis conducted in 2013 (Huke et al.) reported a
22.9% prevalence of autistic symptoms in the cases of anorexia nervosa, but most studied included
refer to adults [5], [6], [7].
Studies regarding the potential correlation between autism spectrum disorder and anorexia nervosa
have intensified remarkably: outcomes indicate both common characteristics of the two nosological
entities, and high prevalence of autistic features in paediatric patients with anorexia nervosa. Whereas
anorexia nervosa and pervasive developmental disorders seem two fundamentally different
nosological entities, several autistic features emerge in the clinical picture of anorexia nervosa.
We refer here to low adaptability to various social situations, to difficulties in solving current
problems, to low coherence, to failure to understand the mental state of others and, of course, to
difficulties in processing one’s own emotions [6], [7], [13]. Whereas males seem more frequently
affected by autism spectrum disorders, new scientific evidence suggests that – in the context of
symptomatic heterogeneity and gender-specific clinical particularities – females are often under-
diagnosed when it comes to pervasive developmental disorders or even misdiagnosed. Thus, girls
may exhibit milder or more subtler stereotypical behaviours, harder to discover [3], [7], [8], [9].
Prognosis and Therapeutic Approach to Prevent Chronicity and Relapses

Hospitalisation is imperious for the patients who require intensive nutrition and hydroelectrolytic
and acid-base rebalancing or for those who failed to respond to home treatments. Among the
paediatric patients admitted to hospital, almost 50% need more than one hospital stay, while 40% of
them need more than three hospital stays for specific therapeutic conduct. Therefore, the fundamental
criteria requiring the hospitalisation of children and adolescents with anorexia nervosa include
suicidal and self-aggressive behaviour, insufficient response to home treatment, severe social
maladjustment and, of course, altered somatic state [2], [9], [10], [11].
A series of studies conducted on numerous samples of patients indicate an 85% rate of relapses at
the follow-up conducted 2 and 7 years after the inpatient treatment. This is meant to highlight the
harmful effect of hospitalisation upon the long-term evolution of paediatric patients with anorexia
134
nervosa. Unlike researches on anorexia nervosa in adults, studies focusing on paediatric population
use mostly observational data [12], [14], [15].
However, several studies concern the efficiency of family-centred therapies, which reportedly
provide better protection against long-term relapses. They have been recommended strongly by a
series of therapeutic guidelines regarding anorexia in children and adolescents. In the past few years,
the trend is to try new therapeutic approaches, with the purpose of avoiding or at least reducing the
rate of anorexia nervosa relapses among the paediatric population. Fundamentally, they represent
interventions initially assessed for adults and subsequently adapted to the specific needs of children
and adolescents. Such an example is the one of cognitive-behavioural therapies, adapted as CBT-E
(cognitive-behavioural therapy for eating disorders). Alongside CBT-E, other interventional
techniques have been adapted to the paediatric population, mostly to teenagers, such as cognitive
remediation therapy, used mainly in cases exhibiting premorbid cognitive inflexibility [14], [15],
[16], [17].
Of course, other studies concern several parent-focused therapeutic strategies and therapeutic
interventions conducted at home; the two have proven better because they shorten the period
necessary for readjustment, present in case of patients who had been initially hospitalised. Concerning
therapeutic success predictors in anorexia nervosa among the paediatric population, studies are scarce
and most of them are not very relevant. However, it has been reported that family therapy is better
than individual therapy for children and adolescents with many obsessive elements related to eating
habits or with eating disorders psychopathology [2], [18], [19], [20].

Conclusions

The long-term prognosis of eating disorders under treatment is better among the paediatric
population compared to adults. This means it is important to optimize the therapeutic approach in
these cases, to exploit the entire recovering potential of paediatric patients with anorexia nervosa.
Thus, various therapeutic means have been promoted during the past decades, including home care
or inpatient treatment. Nonetheless, the rate of therapeutic success is still low, as shown by statistical
data: despite the 50-73% of the patients who recorded a relapse, 20-30% of them evolve toward
chronicity and 9-14 % of the cases toward exitus [10], [11], [20].
Anorexia nervosa has recorded a dramatic reduction of age at onset, thus frequently affecting the
paediatric population. Despite the life-threatening character of anorexia nervosa, researches are scarce
regarding the particularities of this nosological category among children and adolescents, compared
to other mental disorders targeting the same age group. The studies conducted thus far begin to depict
particularities related to both the clinical presentation of anorexia nervosa in children and adolescents,
as well as a series of particularities related to the therapeutic approach, especially the one concerning
psycho-emotional disturbances and social skills, which contribute fundamentally to avoiding
relapses.
Anorexia, and the malnutrition that results, can adversely affect nearly every organ system in the
body, increasing the importance of early diagnosis and treatment; anorexia can be fatal. This paper is
meant to be a premise for future researches because it synthesizes the latest literature on this topic.

REFERENCES

1. Smink, F.R., van Hoeken, D., Hoek, H.W. (2012). Epidemiology of eating disorders: incidence, prevalence and
mortality rates. Curr Psychiatry Rep14:406–414.
2. Lock, J., La Via, M.C. (2015). Practice parameter for the assessment and treatment of children and adolescents
with eating disorders. J Am Acad Child Adolesc Psychiatry.54(5):412–25.
3. Campbell, K., Peebles, R. (2014). Eating disorders in children and adolescents: state of the art review. Pediatrics
134(3):582–92.
4. Lipsman, N., Woodside, D.B., Lozano, A.M. (2014). Trends in anorexia nervosa research: an analysis of the top
100 most cited works. Eur Eat Disord Rev 22:9–14.

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5. American Psychiatric Association (2013). Diagnostic and statistical manual of mental disorders (DSM-5). APA,
Washington, DC.
6. Dutch Knowledge Centre for Child and Adolescent Psychiatry (2013). http://www.kenniscentrum-
kjp.nl/en/professionals/Disorders/Eating-disorders-in adolescents.
7. Huke, V., Turk, J., Saeidi, S., Kent, A., & Morgan, J. F. (2013). Autism spectrum disorders in eating disorder
populations: A systematic review. European Eating Disorders Review, 21(5), 345–351.
8. Huke, V., Turk, J., Saeidi, S., Kent, A., & Morgan, J. F. (2014). The clinical implications of high levels of autism
spectrum disorder features in anorexia nervosa: A pilot study. European Eating Disorders Review, 22(2), 116–
121.
9. Wouters, S. G. M., & Spek, A. A. (2011). The use of the Autism Spectrum Quotient in differentiating high-
functioning adults with autism, adults with schizophrenia and a neurotypical adult control group. Research in
Autism Spectrum Disorders, 5(3), 1169–1175.
10. Zucker, N., Wagner, H. R., Merwin, R., Bulik, C. M., Moskovich, A., Keeling, L., & Hoyle, R. (2015). Self-
focused attention in anorexia nervosa. International Journal of Eating Disorders, 48, 9–14.
11. Micali, N., Hagberg, K. W., Petersen, I., & Treasure, J. L. (2013). The incidence of eating disorders in the UK
in 2000–2009: Findings from the general practice research database. BMJ Open.
12. Catalan Agency for Health Technology Assessment and Research (2009) Clinical practice guideline for eating
disorders. Quality Plan for the National Health System of the Ministry of Health and Consumer Affairs.
13. Watson, H.J., Bulik, C.M. (2013). Update on the treatment of anorexia nervosa: review of clinical trials, practice
guidelines and emerging interventions. Psychol Med 43:2477–2500.
14. Kass, A.E., Kolko, R.P., Wilfley, D.E. (2013) Psychological treatments for eating disorders. Curr Opin
Psychiatry 26:549–555.
15. Madden, S., Miskovic-Wheatley, J., Wallis, A., Kohn, M., Lock, J., Le Grange, D., Clarke, S., Rhodes, P., Hay,
P., Touyz, S. (2014). A randomized controlled trial of in-patient treatment for anorexia nervosa in medically
unstable adolescents. Psychol Med 14:1–13.
16. Bourion-Bedes, S., Baumann, C., Kermarrec, S., Lignier, F., Feillet, F., Bonnemains, C., Guillemin, F., Kabuth,
B. (2013). Prognostic value of early therapeutic alliance in weight recovery: A prospective cohort of 108
adolescents with anorexia nervosa. Journal of Adolescent Health.52(3):344–350.
17. Franko, D.L., Keshaviah, A., Eddy, K.T., Krishna, M., Davis, M.C., Keel, P.K., Herzog, D.B. (2013). A
longitudinal investigation of mortality in anorexia nervosa and bulimia nervosa. American Journal of
Psychiatry.170(8):917–925.
18. Gulliksen, K.S., Espeset, E.M.S., Nordbö, R.H.S., Skårderud, F., Geller, J., Holte, A. (2012). Preferred therapist
characteristics in treatment of anorexia nervosa: The patient’s perspective. International Journal of Eating
Disorders. 45(8):932–941.
19. Lock, J., Le Grange, D. (2015). Treatment manual for anorexia nervosa: A family-based approach. New York:
Guilford Publications.
20. Toulany, A., Wong, M., Katzman, D.K., Akseer, N., Steinegger, C., Hancock-Howard, R.L., et al. (2015). Cost
analysis of inpatient treatment of anorexia nervosa in adolescents: hospital and caregiver perspectives. CMAJ
Open.3(2): E192–7. doi: 10.9778/cmajo.20140086.

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Clinical and Histopathological Aspects of Idiopathic Eosinophilic
Duodenitis in Children

FOTEA Silvia1, DOINA Mihaila2, TRANDAFIR Laura3, ANTON Dana Teodora4,

BACIU Ginel5
1 “Sf. Ioan Clinical Emergency Hospital for Children”, Galati, (ROMANIA)
2 Anatomopathology Laboratory of “Sf. Maria” Clinical Emergency Hospital for Children, Iasi (ROMANIA)
3 Pediatric Clinic no. III of “Sf. Maria” Clinical Emergency Hospital for Children, Iasi (ROMANIA)
4 Pediatric Clinic no. III of “Sf. Maria” Clinical Emergency Hospital for Children, Iasi (ROMANIA)
5 “Lower Danube” University, Faculty of Medicine and Pharmacy, Galati, (ROMANIA)

Emails: silvia_ghimpu@yahoo.com, doinami@yahoo.com, trandafirlaura@yahoo.com, antondana66@yahoo.com,

ginelbaciu@yahoo.com

Abstract

Introduction
Eosinophilic gastroenteritis represents a recurrent, chronic, idiopathic entity characterized by an
eosinophilic, inflammatory tissue infiltration of the gastrointestinal tract.

Method and material

We have studied 45 children diagnosed with idiopathic eosinophilic duodenitis between years
2002-2008 in the Pediatric Clinic no. III of “Sf. Maria” Clinical Emergency Hospital for Children,
Iasi. Patients were included based on anamnestic data, clinical manifestations, laboratory
investigations, upper digestive endoscopy followed by biopsy and histopathological exam.
The histopathological exam remains gold standard for establishing a diagnosis of eosinophilic
gastroenteropathy. To confirm such a diagnosis, the exam must determine more than 20
eosinophils/field.

Results
The most common symptoms were: abdominal pain 77.78%, lack of appetite 71.1%, chronic
diarrhea 42.22%, failure to thrive 24.44%. Anatomopathological exam showed that 55.55% cases
were of mild chronic eosinophilic duodenitis and 28.88% were moderate chronic eosinophilic
duodenitis.

Conclusion
Idiopathic eosinophilic duodenitis is an underdiagnosed illness in which abdominal pain is the
most common clinical manifestation.
Keywords: eosinophils, eosinophilic duodenitis

Introduction

Eosinophilic gastroenteritis represents a recurrent, chronic, idiopathic entity characterized by an

eosinophilic, inflammatory tissue infiltration of the gastrointestinal tract, which may appear at any
age. The gastrointestinal tract is the primary nonhematopoetic organ in which eosinophils exist in
healthy individuals, in the lamina propria. Eosinophils are multifunctional leukocytes involved in
many inflamatory processes. [1, 2, 3]

137
Methodology

We have studied 45 children diagnosed with idiopathic eosinophilic duodenitis between years
2002-2008 in the 3rd Pediatric Clinic of “Sf. Maria” Clinical Emergency Hospital for Children, Iasi.
Patients were included based on anamnestic data, clinical manifestations, laboratory
investigations, upper digestive endoscopy followed by biopsies and histopathological examinations
which confirmed the diagnosis. Clinical manifestations were characterized by abdominal pain, loss
of appetite, chronic diarrhea, failure to thrive, vomiting, malaise, intestinal bleeding, encopresis,
constipation, heartburn and eructation. For the children included in this study, an allergic component
was taken in consideration, which was not confirmed through laboratory investigations, but was
confirmed through therapeutic trials. To confirm such a diagnosis, the histopathological examination
must determine more than 20 eosinophils/field.

Results

There have been established 3 groups of patients based on symptomatology:

- One with a high frequency of hospital admittance for: abdominal pain (77.78% - 35 cases),
loss of appetite (71.11% - 32 cases) (Fig. 1);
- One with a medium frequency of hospital admittance for: chronic diarrhea (42.22% - 19
cases), failure to thrive (24.44%-11 cases), vomiting (20%-9 cases), malaise (8.89%- 4 cases)
(Fig. 1);
- One with a very low frequency of hospital admittance for: intestinal bleeding (4.44% - 2
cases), encopresis (2.22% - 1 case), constipation (2.22% - 1 case), heartburn (2.22% - 1 case)
and eructation (2.22% - 1 case). (Fig. 1)
Fig. 1. Group distribution based on symptomatology

These symptoms were found in similar studies in the literature [1, 2]. According to a study by
Khan et al, most children had malnutrition and failure to thrive [4], but in our group, failure to thrive
was present in 24.44% compared to abdominal pain 77.78%.
Anemia was found in a small number of cases (15.55% - 7 patients), which was considered to be
present at a value of less than 11 g/dl hemoglobin. The rest of the patients (84.45%) had a normal
value of hemoglobin of over 11 g/dl. Normal iron levels were considered at a value of 50 γ-150 γ%
(93.33%), with low iron levels (<50 γ%) detected in only 3 cases (6.67%). Hipoproteinemia was
present in a small number of cases at a value of <60 g/dl (13.33% - 6 patients) hiperproteinemia whith
values of >80 g/dl in 4.44% - 2 patients.(Fig. 2). Again, most cases (82.22%) had normal protein
values between 60g/dl-80 g/dl. The mean value of total proteins in our group was 70.24 g/l, with a
138
median of 72 g/l, a minumum of 54 g/l and a maximum of 82.8%. The dispersion value was 29.97
and standard deviation 5.47, which implies small variation and homogenous collectivity. Peripheral
eosynophilia was present in 21 patients (46.67%). A value >350/mm3 in peripheral blood was
considered pathological (Fig. 3). Peripheral eosynophilia can be present in 50-100% of cases, but it
is not an obligatory condition for a diagnosis [5, 6, 7]. In our group peripheral eosynophilia was
present in 46.67% of the cases.
In another study conducted by Friesen et al., in 2004, involving 40 children, abdominal pain was
present in all cases, malaise in 89% of cases, vomitting in 54% of cases , an existing attopical terrain
was found and peripheral eosinophilia was absent [8].
Fig. 2. Group structure based of protein values

Fig. 3. Group distribution based of eosinophil values

Eosynophils No. cases Percentage(%)
< 350/mm3 24 53,33
>350mm3 21 46,67
Total 45 100,0

Upper digestive endoscopy identified 3 main stomach aspects:

1. a high frequency of congestive antrum 68.89%;
2. a medium frequency of normal appearance (31.11%), forming nodule (26.67%) and
congestive cardia (2.22%);
3. a low frequency of congestive folds (6.67%), linear erosions (4.44%) and body-antrum
polyps (2.22%).
Endoscopic investigations found 10 cases (22.22%) of mild chronic gastritis, 9 cases (20%) of
medium chronic antrum gastritis, 5 cases of antrum gastritis with forming nodule (11.11%), 2 cases
(4.44%) of pangastritis with antrum gastritis and forming nodule, 1 case (2.22%) of solitary gastric
polyp, 18 cases (40%) within normal.
The upper endoscopy at the duodenum level revealed: 36 cases of (80%) within normal, nodular
bulbus in 5 cases (11.11%), congestive duodenum with white deposits in 2 cases (4.44%), congestive
bulbus in 1 case (2.22%), nodular bulbus in 1 case (2.22%). (Fig. 4)

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 Fig. 4. Duodenal endoscopy diagnosis

The most common endoscopic aspects at the duodenum level were normal or of chronic
nonspecific inflammation. [9]
The anatomopathological exam conducted on our group showed the following: in 100% of the
cases idiopathic eosinophilic duodenitis, idiopathic eosinophilic gastritis in 17.77% of the cases,
chronic gastritis without H. pylori in 46.66% of the cases, chronic gastritis with H. pylori in 6.66%
of the cases. Also, 25 patients (55.55%) had mild idiopathic eosinophilic duodenitis (Fig. 5), 13 cases
(28.88%) moderate idiopathic eosinophilic duodenitis and 7 cases (15.15%) (Fig. 5, 6) had severe
idiopathic eosinophilic duodenitis (Fig. 5). With help from the Pathological Anatomy Laboratory of
“Sf. Maria” Emergency Clinical Hospital for Children – Iasi, we could establish aspects of
eosinophilic duodenitis.

Fig. 5. Group distribution based on the classification of disease

Classification No. cases Percentage(%)

Mild 25 55,55

Moderate 13 28,88

Severe 7 15,15

Fig. 6. Moderate chronic eosinophilic duodenitis, Hex 200 coloration

For this study, we took in consideration a value of >20 eosinophils/field [9, 10]. Studies have
shown that the stomach is affected in 26-82% of cases and the small bowel in 28-100% of cases [4].
In our group stomach injury occurred in 71.11% of cases and intestinal and duodenal injury
occurred in 100% of cases based on the histopathological examination.

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Conclusions

Clinical manifestation in our study was nonspecific and mostly comprised of abdominal pain
(77.78%) followed by loss of appetite (71.11%).
Upper digestive endoscopy showed in most cases, a normal aspect of the duodenum in 36 cases
(80%) and nodular bulbus in 5 cases (11.11%).
Peripheral eosinophilia was present in 21 cases (46.67%).
The anatomopathological exam remains gold standard in diagnosing of idiopathic eosinophilic
duodenitis.
Mild idiopathic eosinophilic duodenitis was present in 25 cases, and moderate idiopathic
eosinophilic duodenitis in 13 cases (28.88%).
In the future, many studies are necessary to establish criteria of diagnosis and to evaluate the
treatment effects in idiopathic eosinophilic duodenitis.

REFERENCES

1. Rothenberg, M.E. and Hogan, S.P. The eosinophil. Annu Rev Immunol. 2006; 24: 147–174.
2. Rothenberg ME, Eosinophils in the new millennium, J Allergy Clin Immunol, 2007;119:1321-1322.
3. Simon p. et al., Eosinophils: biological properties and role in health and disease, Clinical and Experimental
Allergy,2008,38,709-750.
4. Khan, S and Orenstein, SR. Eosinophilic gastroenteritis: epidemiology, diagnosis and management. Paediatr
Drugs. 2002; 4: 563–570.
5. Marc E. Rothenberg, Eosinophilic gastrointestinal disorders( EGID), J Allergy Clin Immunol 2004;113:11-28.
6. Talley, NJ, Shorter, RG, Phillips, SF, and Zinsmeister, AR. Eosinophilic gastroenteritis: a clinicopathological
study of patients with disease of the mucosa, muscle layer, and subserosal tissues. Gut. 1990; 31: 5.
7. Simon HU, Rothenberg ME, Bochner BS, et al. Refining the definition of hypereosinophilic syndrome. The
Journal of allergy and clinical immunology. 2010; 126(1):45–49.
8. Friesen A.C, Mucosal eosinophilia and response to H1/H2 antagonist and cromolyn therapy in pediatric
dyspepsia, Clin Pediatr (Phila) 2006; 45:143.
9. Uppal V, Kreiger P, Kutsch E. Eosinophilic gastroenteritis: a comprehensive review. Clin Rev Allergy Immunol.
2016; 50: 175–88.
10. Chen MJ, Chu CH, Lin SC, et al. Eosinophilic gastroenteritis: clinical experience with 15 patients. World J
Gastroenterol. 2003;9:2813–6.

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Gastrointestinal Disorders in Childhood Obesity
TRANDAFIR Laura Mihaela, FRĂSINARIU Otilia Elena, SUBOTNICU Mirabela,
MIRON Ingrith Crenguța
Universitatea de Medicină și Farmacie “Grigore T. Popa” Iași, (ROMANIA)
Email: otiliafrasinariu@gmail.com

Abstract

Introduction
Childhood obesity has reached epidemic proportion in the last decades. Classically, obesity is
associated with several comorbidities linked to metabolic syndrome. In addition, recent data have
reported, both in adults and children, an association between obesity and a wide range of
gastrointestinal disorders (GID), such as celiac disease, inflammatory bowel disease, functional
constipation, functional abdominal pain.

Methods
The authors present three cases that underline the GID in obese children.

Results
The first case was a teenager aged 13 years, with a weight of 60 kg and a BMI of 26.2, admitted
for heartburn and epigastric pain. He was diagnosed with gastro-esophageal reflux and investigations
revealed Helicobacter pylori infection. Under diet of 1200 calories, liver protective drugs and triple
therapy (pump inhibitors and two antibiotics), the outcome was favorable. The second case was an 8
years old boy, 42kg and BMI 24.10, hospitalized for chronic constipation. Following a fiber-rich diet,
exercise program, administration of prokinetic drug and symbiotics, evolution has been favorable.
The third case was a ten years old boy, 48 kg and BMI 23.1, diagnosed with celiac disease at the
age of five (weight=16kg). Under gluten-free diet, he presented a weight gain of 32kg in five years.
The weight curve was descendant after restrictive diet with 1200 calories and gluten free was
recommended, associated with physical exercises.

Conclusions
There is an association between obesity and GID in children. Obesity can adversely affect the
outcome of GID. The mechanism of this association is still unclear and need further studies.
Keywords: obesity, children, gastrointestinal disorders

Introduction

Obesity in childhood is a major health problem, which has reached epidemic proportion in the last
decades. Classically, obesity is associated with several comorbidities linked to metabolic syndrome,
including hypertension, dyslipidemia, diabetes, hepatic steatosis. In addition, recent data have
reported, both in adults and children, an association between obesity and a wide range of
gastrointestinal disorders (GID), such as celiac diseases (CD), inflammatory bowel disease (IBD),
functional constipation, functional abdominal pain, gastroesophageal reflux (GER) (1). In this article,
the authors present three cases of obese children with gastrointestinal disorders.

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Cases reports

Clinical case I
The first case was a teenager aged 13 years, with a weight of 60kg and a BMI of 26.2, admitted in
our clinic for heartburn and epigastric pain. At the physical examination, we observed: Weight = 60kg
BMI = 26.2kg/m2, discrete pharyngeal congestion mucosa, overly adipose tissue on the abdomen,
thorax and limbs, waist circumference = 94cm, excessive appetite, globular abdomen, normal
intestinal transit.
The laboratory investigations reveled no inflammatory syndrome, lower hepatocytolysis syndrome
(ALT= 43 U/L, AST= 52 U/L). Other tests were required to screening of dyslipidemia, type 2 diabetes
mellitus and thyroid function and were normal. The Helicobacter Pylori antibodies were present.
Abdominal ultrasound showed normal echo-structure of the liver, kidneys, spleen and pancreas.
Because we suspected the gastroesophageal reflux disease, we performed contrast radiography of
the upper gastrointestinal tract which confirmed the diagnosis.
The patient had been diagnosed with with gastro-esophageal reflux and Helicobacter Pylori
infection on the basis of a clinical condition characterized by heartburn and epigastric pain, the aspect
of the contrast radiography of the upper gastrointestinal tract and present of Helicobacter Pylori
antibodies. Under diet of 1200 calories, physical activity, liver protective drugs and triple therapy
(pump inhibitors and two antibiotics), the outcome was favorable.

Clinical case II
The second case was an 8 years old boy who presented for recurent abdominal pain and chronic
constipation. The medical history of the patient revealed gradual slowing of intestinal transit along
with weight gain over the past year. Family history showed the presence of obesity in parents.
Physical examination at admission showed obesity (weight = 42kg, BMI = 24.10), overly adipose
tissue on the abdomen, thorax and limbs. The respiratory and cardiac systems were normal.
The examination of the digestive system showed abdominal distension, abdominal pain at
palpation, slowed intestinal transit. The appetite was significantly increased. The laboratory
investigations reveled no inflammatory syndrome, normal liver function, and thyroid function was
normal, too. Abdominal ultrasound showed normal echo-structure of the liver, kidneys, spleen and
pancreas. Following a fiber-rich diet, exercise program, administration of prokinetic drug and
symbiotics, evolution has been favorable.

Clinical case III

The third case was a ten years old boy, weight = 48 kg and BMI 23.1, diagnosed with celiac disease
at the age of five and 2 months. At five years old, he was diagnosed with celiac disease because he
presented loss of appetite, recurrent abdominal pain, weight gain decrement. Anamnesis revealed that
the child had normal height and weight gain during the first two years of his life. Physical
examination at diagnosis showed a relatively good general state, weight = 16kg, height = 119cm,
BMI =9.2, normal stethacoustic pulmonary and heart functioning, loss of appetite, soft depressible
abdomen, periumbilical spontaneous and palpation pain and physiological intestinal transit.
In the order to diagnose the etiology of malabsorption syndrome, we performed the anti-tissue
transglutaminase antibodies (ATTGA) IgA and IgG which revealed the pathological titers: 53.5UI/l
and 13.4UI/l, respectively. The presence of HLA DQ2 supported the diagnosis of celiac disease. After
restricted diet, the patient regained his appetite, the abdominal pain disappeared, the weight gaining
curve was slightly ascending. The clinical-biological evolution was favorable under a gluten-free diet.
The ATTG antibodies were negative after 6 months of gluten-free diet (1.5 UI/l). After 8 months
of gluten-free diet, the patient weighed 18kg, he was 121cm tall and his BMI = 12.3.
Under gluten-free diet, the patient presented a weight gain of 32kg (weight=48kg and BMI 23.1)
after five years. In order to determine the cause of weight gain, we evaluated the thyroid function
(TSH, freeT4 – normal values, normal thyroid gland ultrasound scan), the IgA and IgG ATTG
antibodies were assessed (normal values) and the compliance to the gluten-free diet which was good.
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 Alimentary habits and daily dietary composition showed an excess.
The weight curve was descendant after 1200 calories-gluten free-restrictive diet was
recommended, associated with physical exercises.

Discussions

In the last years, studies had shown that the prevalence of gastrointestinal disorders (GIDs) has
increased in obese patients (1).
Many evidences had shown that obesity is a risk factor for gastroesophageal reflux (GER).
There is a higher prevalence of GER symptoms in overweight and obese children (2,3). Lang et
al. reported that obese children had seven times higher odds of reporting multiple GER symptoms
(4).
Mechanisms involved in GER in obese patients include hiatal hernia, increased intra-abdominal
pressure, vagal abnormalities associated with obesity that cause a higher output of bile and pancreatic
enzymes, higher sensitivity to the presence of acid in the oesophagus (5). Furthermore, the association
between obesity and infection of H. pylori is unclear, as various studies have reported conflicting
findings. Highest prevalence of Helicobacter pylori infection was showed in overweight and obese
CD children (46%) in comparison to normal weight (27%) and underweight CD children (13%) (6).
In contrast, Choi et al. showed that obesity was not associated with H. pylori infection, although
triple eradication therapy led to an increase in body weight (7). The long-term outcome of obese
children with GER is likely that they will grow into obese adults with gastric acid reflux, susceptible
to reflux related complications like esophagitis, Barrett’s esophagus, malignancy (1).
The prevalence of functional GIDs, such has as functional abdominal pain (FAP), functional
constipation (FC) and irritable bowel syndrome (IBS), is higher in healthy obese/overweight children
and normal-weight children (1). A recent study on 450 children, reported at least one functional
gastrointestinal disorder in 47% of the obese/overweight group compared with 27% of the normal-
weight children (8). From children referred to a paediatric gastroenterology, in obese patients were
more frequent IBS, FC, encopresis (9) and they complain more pain intensity, higher pain frequency,
more school absenteeism (10). The prevalence of FC was reported 21% in morbid obese children
(11).
The mechanisms of developing FGIDs in obese children more than controls are not entirely
explained (12). Some studies showed that children with morbid obesity have significantly delayed
colonic transit (11) and poor gastric accommodation to satiety drink test that may explain possible
pathophysiological mechanism to develop pain (13). Moreover, FGIDs in obese children has long
term repercussions, being associated with poor health related quality of life and poor school
performances (12).
Literature reported also increasing prevalence of overweight and obesity in organic gastrointestinal
disease, such as celiac disease and inflammatory bowel disease. The surge in the diagnosis of celiac
disease in children may be due to the increased awareness for this disease and the prompt work-up
which helped diagnosing these children early before growth failure is set in (1).
Pediatric celiac disease was classically defined thought symptoms like failure to thrive and weight
loss (14). But there are increasing evidences that more children with celiac disease are likely to be
overweight and obese than being underweight (15, 16). Franceze et al. reported a case of a patient
with obesity resistant to low-calorie diet and steatohepatatis, in which CD was diagnosed on the basis
of the gastrointestinal symptoms (17). The characteristics of celiac disease among overweight/obese
children and the growth outcomes after long term gluten free diet of children with a normal or an
elevated body mass index (BMI) are still unclear. A study on North-American children reported a
prevalence of 19% of overweight and obesity at the time of diagnosis children with celiac disease
(18).
Similarly, Livshits et al., 2017, reported 17,4% overweight or obese patients at diagnosis in a
group of children with CD (6). Furthermore, Reilly et al., evaluated the BMI outcomes in children

144
with CD after 35.6 months mean duration of follow-up under a long-term treatment with gluten free
diet.
The prevalence of overweight increased after treatment because of development of overweight in
several children with previously normal BMI. From the patients initially overweight, the ones with
dietary compliance had significant decreases in BMI, whereas noncompliant overweight children
increased their BMI significantly during the follow-up period (18). Others studies emphases that
overweight patients lose their weight after strict GFD (1).
A special attention should be paid to the development of obesity in children with celiac disease,
malabsorption and low or normal-presenting BMI (19). There are multiple case reports of the
development of obesity after GFD in children who initially had malabsorbtion (20, 21). Oso et al.,
reported on a 14-year old boy with CD who gained excessive weight after starting on a GFD (21).
Similarly, our patient had malabsorption and low weight followed by obesity after GFD.
Often the adoption of RFG leads to weight gain and disruption of long-term lipid metabolism in
the child and adolescent. It is unclear whether the GF diet is responsible for unwanted increases of
weight in children with CD (18). The risk of overweight or obesity increases in patients with CD after
GFD because of improved intestinal absorption and nutritional imbalance and hypercaloric content
of commercial or natural gluten-free food (21). In GFD gluten-derived carbohydrates are replaced
with an increased consumption of fats, proteins and hypercaloric beverages and to decrease fiber
intake (22). Behavioral characteristics can also lead to weight gain on GFD. The authors suggest the
need for a careful follow-up of nutritional status after the diagnosis of CD, as new morbidities could
also emerge in children strictly compliant with GFD.

Conclusions

There is an association between obesity and GID in children. The mechanism of this association
is still unclear and further studies are needed. Obesity can adversely affect the outcome of GID. By
implementing appropriate measures, health care professionals need to minimize the dual burden of
both obesity and GIDs.

REFERENCES

1. Phatak UP, Pashankar DS. Obesity and gastrointestinal disease in children. JPGN 2015;60: 441–445.
2. Stordal K, Johannesdottir G, Bentsen B, et al. Asthma and overweight are associated with symptoms of gastro-
oesophageal reflux. Acta Paediatr 2006; 95: 1197–1201.
3. Pashankar DS, Corbin Z, Shah SK, Caprio S. Increased prevalence of gastroesophageal reflux symptoms in
obese children evaluated in an academic medical center. J Clin Gastroenterol. 2009 May-Jun; 43(5):410-413.
4. Lang JE, Hossain J, Holbrook JT, Teague WG, Gold BD, Wise RA, Lima JJ. Gastro-oesophageal reflux and
worse asthma control in obese children: a case of symptom misattribution? Thorax. 2016;71(3):238-246.
5. Barak N, Ehrenpreis ED, Harrison JR, Sitrin MD. Gastro-oesophageal reflux disease in obesity:
pathophysiological and therapeutic considerations. Obes Rev. 2002; 3(1):9-15.
6. Livshits, O.E., Shauol, R., Reifen R., Matthias T., Lerner A. Can Celiac Disease Present Along With Childhood
Obesity? International Journal of Celiac Disease, 2017, 5(1).
7. Choi, J. S., Ko, K. O., Lim, J. W., Cheon, E. J., Lee, G. M., & Yoon, J. M. The Association between Helicobacter
Pylori Infection and Body Weight among Children. Pediatric Gastroenterology, Hepatology & Nutrition,
2016.19(2), 110–115.
8. Phatak UP, Pashankar DS. Prevalence of functional gastrointestinal disorders in obese and overweight children.
Int J Obes (Lond). 2014; 38(10):1324-1327.
9. Teitelbaum JE, Sinha P, Micale M, Yeung S, Jaeger J. Obesity is related to multiple functional abdominal
disease. J Pediatr 2009; 154: 444-446.
10. Bonilla S, Wang D, Saps M. Obesity predicts persistence of pain in children with functional gastrointestinal
disorders. Int J Obes (Lond) 2011; 35: 517-521.
11. vdBaan-Slootweg OH, Liem O, Bekkali N, et al. Constipation and colonic transit times in children with morbid
obesity. J Pediatr Gastroenterol Nutr 2011; 52: 442-445.
12. Rajindrajith, S., Devanarayana, N. Benninga, M.A. Obesity and Functional Gastrointestinal Diseases in
Children. J Neurogastroenterol Motil 2014; 20(3): 414-416.

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13. Hoffman, I, Tack J. Assessment of gastric motor function in childhood functional dyspepsia and obesity.
Neurogastroenterol Motil 2012; 24:108-112, e81.
14. Aurangzeb B, Leach ST, Lemberg D a, Day a S. Nutritional status of children with celiac disease. Acta Paediatr.
2010; 99:1020-1025.
15. Venkatasubramani N, Telega G, Werlin SL. Obesity in pediatric celiac disease. J Pediatr Gastroenterol Nutr.
2010; 51:295-297.
16. Kelly CP. Celiac sprue - current concepts. N Engl J Med. 2002; 346:180-188.
17. Franzese A, Iannucci MP, Valerio G, Ciccimarra E, Spaziano M, Mandato C, Vajro P. Atypical celiac disease
presenting as obesity-related liver dysfunction. J Pediatr Gastroenterol Nutr. 2001; 33(3):329-332.
18. Reilly NR, Aguilar K, Hassid BG, Cheng J, DeFelice AR, Kazlow P, et al. Celiac disease in children with normal
weight and overweight: clinical features and growth outcomes following a gluten-free diet. J Pediatr
Gastroenterol Nutr. 2011; 53(5):528-531.
19. Valletta E, Fornaro M, Cipolli M, Conte S, Bissolo F, Danchielli C. Celiac disease and obesity: need for
nutritional follow-up after diagnosis. Eur J Clin Nutr. 2010; 64: 1371-1372.
20. Czaja-Bulsa G, Garanty-Bogacka B, Syrenicz M, Gebala A. Obesity in an 18-year-old boy with untreated celiac
disease. J Pediatr Gastroenterol Nutr. 2001; 32(2):226.
21. Oso O, Fraser NC. A boy with coeliac disease and obesity. Acta Paediatr 2006; 95:618–619.
22. Ferrara P, Cicala M, Tiberi E, Spadaccio C, Marcella L, Gatto A et al. (2009). High fat consumption in children
with celiac disease. Acta Gastroenterol Belg 72, 296–300.

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Gastrointestinal Manifestations in Children with Cystic Fibrosis

TRANDADFIR Laura Mihaela1,2, TESLARIU Oana1,2,

ANTON-PADURARU Dana Teodora1,2
1University of Pharmacy and Medicine “Grigore. T. Popa” Iasi (ROMANIA)
2Children’s Hospital “Sf. Maria” Iasi (ROMANIA)
Emails: trandafirlaura@yahoo.com, oana.teslariu@gmail.com, antondana66@yahoo.com

Abstract

Cystic fibrosis (CF) is an autosomal recessive genetic disease characterized by an abnormality of

chloride ion transport, resulting in an increased viscosity of the secretions in the lungs, the
gastrointestinal tract, the biliary tract and the pancreas. In addition to respiratory symptoms,
gastrointestinal manifestations play an important role in the prognosis and quality of life of CF
patients. It was studied a group of 40 pediatric patients diagnosed with cystic fibrosis, hospitalized in
IIIrd Pediatric Clinic, Children’s Hospital St. Mary Iasi, between 2011-2015. There were followed
anthropometric parameters, age at time of diagnosis, age at onset of symptoms, digestive
manifestations initially present. From the examined group, 17 patients had gastro-intestinal disorders,
such as chronic diarrhea (7 cases), failure to thrive associated with food refusal (4 cases), ileus
meconium (3 cases), intestinal obstruction (1 case), peritonitis through perforation of transverse colon
(1 case), ano-rectal prolapse (1 case). Age at onset of symptoms ranged from 2 days to 9 months.
Age at diagnosis ranged between 4 days and 3 years and 6 months. Analysis of weight evolution
showed a statistically significant increase between the time of diagnosis and at 6 months after
initiating specific therapy. Considering that in CF gastrointestinal manifestations often develop before
the onset of respiratory symptoms, a good knowledge and correct and early diagnosis contribute to
better management and improvement in prognosis, as well as increasing the quality of life of patients
with CF.
Keywords: cystic fibrosis, gastrointestinal manifestations, children

Introduction

Cystic fibrosis (CF) is an autosomal recessive genetic disease characterized by an abnormality of

chloride ion transport, resulting in an increased viscosity of the secretions in the lungs, the
gastrointestinal tract, the biliary tract and the pancreas. One of the most common pathology in CF is
the lung disease and pulmonary complications represent one of the main cause of mortality.
But considering that life expectancy in CF patients has improved, and the nutritional status is
strongly linked to the pulmonary function, the gastrointestinal manifestations also need to be
considered with a great importance in the management and treatment of CF [1].
In the digestive tract the hyperviscosity of the secretions, characteristic of the disease, can cause
the following complications: chronic diarrhea, constipation, failure to thrive, meconium ileus,
intestinal obstruction, peritonitis, ano-rectal prolapse, intussusception [2].
Meconium ileus often represents the first manifestation of cystic fibrosis. Affecting 10-15% of
patients presenting the disease, meconium ileus is a manifestation of intestinal and pancreatic
dysfunction which causes the accumulation of an adhering intraluminal meconium with a much
higher consistency [3], [4].
Pancreatic insufficiency is the main reason for malnutrition and failure to thrive, especially before
diagnosing the disease, when more than 80% of lipids are found in the stool because of lipase
deficiency [3], [5].

147
 Constipation is commonly found in patients with FC due to diminished intestinal motility and
decreased water secretion. Constipation is an obstructive process that starts from sigmoid and extends
proximally. Distal intestinal obstruction syndrome is an obstructive process that begins at the terminal
ileum and extends distally. These often can occur together but can also be manifested individually
[6].

Material and Methods

We conducted a retrospective study of a group of 40 pediatric patients diagnosed with cystic

fibrosis, hospitalized in IIIrd Pediatric Clinic, Children's Hospital “Sf, Maria” Iasi, between 2011-
2015.
Cystic fibrosis was diagnoses using 2 positive values of sweat test (chloride level >60 mmol/ml).
For each patient, we investigated the following anthropometric parameters: weight, height, body
mass index, at the time of diagnose and 6 months after the start of nutritional therapy. We evaluated
the presence of respiratory and digestive symptoms, age at onset of symptoms, age at time of
diagnosis, digestive manifestations initially present, consequences of clinical manifestations on
physical development, evolution of nutritional status after 6 months of specific therapy.
The nutritional therapy consisted of pancreatic enzymes, fat-soluble vitamins, hypercaloric food
supplements.

Results and discussions

From the examined group, 13 patients were diagnosed with respiratory form of cystic fibrosis.
The rest of 17 patients had gastro-intestinal disorders, such as chronic diarrhea (7 cases), failure
to thrive associated with food refusal (4 cases), meconium ileus (3 cases), intestinal obstruction (1
case), peritonitis through perforation of transverse colon (1 case), ano-rectal prolapse (1 case) (Fig.
1).
17 cases with gastro-intestinal manifestations

6%
6%
6% chronic diarrhea
food refusal
41% ileus meconium
18% intestinal obstruction
peritonitis
23% ano-rectal prolaps

Fig. 1. Distribution of gastrointestinal symptoms of the selected patients from the study group

Age at onset of symptoms ranged from 2 days to 9 months. Most patients (59%) developed the
first digestive symptoms during infancy and young childhood. Also, an important number (35%) had
the onset of gastrointestinal manifestations in the neonatal period, while in only one case the disease
started later than 3 years old (Table 1).
Table 1. Time of disease onset in selected patients from the study group
No. cases Age of onset of digestive symptoms
6 (35%) Neonatal period
10 (59%) Toddler and infant (< 3 years)
1 (6%) Child (> 3 years)

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 The earliest digestive manifestation of CF which appears in the first days of the neonatal period is
meconium ileus [4]. Our results are consistent with the literature data, 5 of the patients having
meconium ileus, 2 of which with complications such as intestinal obstruction and intestinal
perforation with peritonitis. In these cases, the onset of the symptomatology coincided with the
moment of diagnosis.
CF is characterized by pancreatic insufficiency. One of the most common effect on the digestive
system of this condition is chronic diarrhea, due to decreased pancreatic enzymes activity and
malabsorption [7]. Chronic diarrhea was also the most frequent digestive manifestation in our study
group, being present in 41% of the patients, 6 cases during infancy and young childhood and 1 case
later than the age of 3 years (Table 2). The diagnose was established later than the beginning of the
modified stools, with a delay that ranged from 2 months to 28 months.
Table 2. Distribution of digestive symptoms according to age of onset
Age of onset of digestive Types of symptoms
symptoms
Intestinal obstruction
Meconium ileus x 2
Neonatal period Chronic diarrhea x 2
Perforation of transverse colon with peritonitis
Meconium ileus
Failure to thrive x 4
Toddler and young infant (<3 Chronic diarrhea x 4
years) Ano-rectal prolapse
Child (>3 years) Chronic diarrhea

Rectal prolapse occurs in a percentage of 20% of CF patients and usually before the age of 3 years,
and should be considered a suggesting sign for establishing the diagnose [8]. In our study group, ano-
rectal prolapse was diagnosed in one patient at the age of 2 years.
Our data showed that the age at diagnosis ranged between 4 days and 3 years and 6 months, taking
in consideration the fact that in our country there is no neonatal screening for CF. Recent literature
data showed that the average age of diagnosis in an area without newborn screening was 5 months.
Patients diagnosed later than the age of 2 years had a higher rate of morbidity than those diagnosed
between 2 months and 1 year [9]. The delay of diagnose after 2 months of age is associated with
worse progression of the clinical manifestations and more therapy requirements [10].
A regular monitoring of nutritional status is important in CF [1]. Early detection of failure to thrive
is essential for a successful nutritional therapy. The present study detected 4 cases of failure to thrive
associated with food refusal, which represented the first symptoms of the disease and led to an early
diagnosis and an immediate initiation of nutritional therapy.
A consensus report of the North American Cystic Fibrosis Foundation recommends a diet that
contains 35-40% calories from fat, in order to ensure the energy needs of normal weight development
of CF patients [11]. The daily caloric requirement should represent 100-150% from a normal diet of
a healthy child [12]. Analysis of weight evolution showed in our group a statistically significant
increase between the time of diagnosis and at 6 months after initiating specific therapy.

Conclusions

Digestive manifestations can affect the nutritional status of the CF patient and can contribute to
worsening the evolution of other symptoms of the disease and as well of life expectancy. Considering
that in CF gastrointestinal manifestations often develop before the onset of respiratory symptoms, a
good knowledge and correct and early diagnosis contribute to better management and improvement
in prognosis, as well as increasing the quality of life of patients with CF.

149
REFERENCES

1. Sabharwal, S. (2016). Gastrointestinal Manifestations of Cystic Fibrosis. Gastroenterol Hepatol 12(1), pp. 43-47.
2. Sathe, M.N., Freeman, A.J. (2016). Gastrointestinal, Pancreatic and Hepatobiliary Manifestations of Cystic
Fibrosis. Pediatr Clin North Am 63(4), pp. 679-698.
3. Chaudry, G., Navarro, O.M., Levine, D.S., Oudjhane, K. (2006). Abdominal Manifestations of Cystic Fibrosis in
Children. Pediatric Radiology 36 (3), pp. 233 – 240.
4. Agrons, G.A., Corse, W.R., Markowitz, R.I., Suarez, E.S., Perry, D.R. (1996). Gastrointestinal Manifestations of
Cystic Fibrosis: Radiologic-pathologic Correlation. Radiographics 16(4), pp. 871-893.
5. Sinaasappel, M., Stern, M., Littlewood, J. et al. (2002). Nutrition in Patients with Cystic Fibrosis: a European
Consensus. J Cyst Fibros 1, pp. 51 – 57.
6. Gelfond, D., Borowitz, D. (2013). Gastrointestinal Complications of Cystic Fibrosis. Clin Gastroenterol Hepatol
11(4), pp. 333-342.
7. Haak, A., Aragao, G.G., Carvahlo Garbi Novaes, M.R. (2013). Pathophysiology of Cystic Fibrosis and Drugs
Used in Associated Digestive Tract Disease. Wold J Gastroenterol 19(46), pp. 8552-8561.
8. Hubbard, V.S. (1985). Gastrointestinal Complications in Cystic Fibrosis. Semin Respir Med 6, pp. 299-307.
9. De Monestrol, I., Klint, A., Sparen, P., Hjelte, L. (2011). Age at Diagnosis and Disease Progression of Cystic
Fibrosis in an Area without Newborn Screening. Paediatr Perinat Epidemiol 25(3), pp. 298-305.
10. Sims, E.J., Clark, A., Mehta, G. et al. (2007). Cystic Fibrosis Diagnosed after 2 Months of Age Leads to Worse
Outcomes and Requires More Therapy. Pediatrics 119(1), pp. 19-28.
11. Kalnins, D., Wilschanski, M. (2012). Maintenance of Nutritional Status in Patients with Cystic Fibrosis: New and
Emerging Therapies. Drug Des Devel Ther 6, pp. 151-161.
12. Hortencio, T.D.R., Nogueira, R.J.N., de Lima Marson, F.A. et al. (2015). Factors Impacting the Growth and
Nutritional Status of Cystic Fibrosis Patients Younger than 10 Years of Age Who Did Not Undergo Neonatal
Screening. Rev Paul Pediatr 33(1), pp. 3-11.

150
Varia

151
The Management of Gastrointestinal Motility Disorders in Pregnancy
ANTON Carmen1,2, DIMACHE Mihaela1,2, HARTIE Codrina2,
BISTRICEANU Sandina2, ANTON Emil1,3
1 University of Medicine and Pharmacy, “Gr.T. Popa”, Iasi, (ROMANIA)
2 Institute of Gastroenterology and Hepatology, “St. Spiridon” Hospital, Iasi, (ROMANIA)
3 II Clinic, “Cuza-voda” Hospital, Iasi, (ROMANIA)

Emails: carmen_ro2008@yahoo.com, mimidimache@yahoo.com, hartiecodrina@gmail.com, sandinabistriceanu@gmail.com,

emil.anton@yahoo.com

Abstract

The management and treatment of gastrointestinal disorders in pregnant women requires special
care and expertise, since the safety of the mother, fetus and neonate remains the primary focus.
Nausea and vomiting during pregnancy are common, as is symptomatic gastroesophageal reflux
disease. Peptic ulcer disease occurs less frequently and with fewer complications. Constipation can
develop during pregnancy and if it is chronic can increase in severity. Management of acute diarrhea
should focus on supportive therapy, maintenance of hydration, dietary changes, and treatment of
chronic diarrhea should be considered in the context of therapy for the underlying disorder. Irritable
bowel syndrome and inflammatory bowel disease present a therapeutic challenge in disease control,
while minimizing toxicity to the fetus and mother. Gastroenterologists and obstetricians should be
familiar with safe treatment options for these conditions, because they can profoundly impair the
quality of life of pregnant women.
Keywords: gastrointestinal disorders, pregnancy, management

Introduction

During pregnancy, gastrointestinal (GI) ailments, that might be pre-existent to pregnancy or

develop de novo, represent special challenges to the clinician. Drug therapy requires careful
assessment before conception, during pregnancy and in the postpartum period. The focus of therapy
has to be guided by the dictum “first, do no harm”, but this must be achieved by overcoming the delay
or withhold treatment that could potentially produce an adverse outcome for the mother or the fetus.
The current FDA five categories for drug use during pregnancy are defined from A to X, depending
on their safety, effectiveness and risk of the fetal abnormalities in any trimester of pregnancy. [1, 2]
The most commonly encountered GI motility disorders in pregnancy include nausea and vomiting
(NVP), hyperemesis gravidarum (HG), gastroesophageal reflux disease (GERD), peptic ulcer disease
(PUD), irritable bowel syndrome (IBS).

Nausea and vomiting in pregnancy

NVP is common in early pregnancy, usually self-limiting and occurs in 50-90% of pregnancies,
whereas vomiting, as an associated complaint, appears in 25-55% of pregnancies. Risk factors for
nausea in pregnancy include first pregnancy, youth, obesity, and smoking. Nausea tends to recur in
subsequent pregnancies, though it may be shorter in duration. [3, 4]
Nausea in pregnancy occurs in 91% of women in the first trimester and is more frequently in
women who have multiple gestations compared with women who have a single gestation. In its mild
form, is known as morning sickness. Persistence of NVP into the second or third semester of
pregnancy requires a prompt search for other causes that can include gastroenteritis, PUD, biliary
tract disease, pancreatitis, hepatitis, appendicitis, adrenal insufficiency, urinary tract infections and

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increased intracranial pressure. In later pregnancy, considerations also include preeclampsia,
hydramnios and onset of labor.
The pathophysiology of this condition has been attributed to hormonal fluctuations, GI motility
disorders, and psychosocial factors.
Management of symptoms

The severity of symptoms settles the therapy approach in pregnant woman with nausea.
Mild symptoms can be managed by avoidance of precipitating factors, reassurance, and changes
in diet (smaller, frequent meals, low fat intake, increased carbohydrate intake).
A number of therapies have been investigated in the treatment of severe NVP.

Antiemetics
For severe and intractable symptoms, pharmacotherapy with antiemetics is indicated and offers
symptomatic relief in patients with NVP.[5] The safety of the phenothiazines, promethazine and
prochlorperazine (both category C) have not yet been proven; however, they are widely used in
pregnancy.[6] Metoclopramide (category B) is frequently used for the treatment of NVP and seems
to be safe in pregnancy because it has not been shown to induce teratogenic effects.[7] Although there
is limited experience using ondansetron for NVP, available studies do not indicate any increased risk
of fetal malformations during pregnancy.[8]

Vitamin B6
Pyridoxine (vitamin B6) is atherapeutic alternative in patients with severe NVP. [9]
Vitamin B6 (category A) administered at a dose of 10-25 mg three times daily, was shown to
improve NVP in two studies. [10, 11]

Doxylamine
Doxylamine (category B), an antihistamine that has been used to treat severe NVP, is available in
two preparations: as doxylamine succinate alone, or in combination with pyridoxine hydrochloride
(Diclectin®).4 Bendectin® (Debendox) was withdrawn from the USmarket because a possible
teratogenicity, although a subsequent meta-analysis revealed no association between Bendectin® and
birth defects.[12] A study of 225 patients treated with high-dose Diclectin® (5-12 tablets per day)
and two meta-analyses of doxylamine revealed no increase in fetal congenital malformations. [12,
13]

Prognosis
The prognosis for the mother and child is generally good, and women with mild NVP have better
pregnancy outcomes compared with women without these symptoms.

Hyperemesis gravidarum

HG occurs in 3 to 10 cases per 1000 pregnancies and is characterized by intractable NVP that
occurs in early pregnancy, leading to fluid and electrolyte imbalances. [14, 15, 16] This condition
may be considered to be at the severe end of the spectrum of NVP and hormonal with psychologic
factors may play a role. Risk factors associated with this condition include obesity, nulliparity,
multiple gestations, and trophoblastic disease.
HG occurs early in the first trimester, usually within weeks 4 through 10. Symptoms usually
resolve by weeks 18 to 20. The symptoms of HG include, except intractable vomiting, also ptyalism,
weight loss over 5% of body weight, possible malnutrition, abdominal pain, ketosis, hypokalemia,
metabolic alkalosis, alteration of kidney and liver function tests and mild hyperthyroidism.

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 In contrast to NVP, HG is a serious condition that can result in dehydration and weight loss,
necessitating parenteral or enteral nutrition. [6, 17]
Management of symptoms
The only FDA-approved drug for treating NVP is doxylamine-pyridoxine (Diclegis). [18] Initial
management should be conservative and may include reassurance, dietary recommendations and
support. Management also involves symptomatic treatments for severe NVP, as well as correction of
dehydration and electrolyte abnormalities. Alternative therapies may include acupressure and
hypnosis. [6] A randomized trial showed that acupuncture was as effective as metoclopramide plus
vitamin B12 therapy for symptomatic relief in pregnant women with HG, and was significantly more
effective than this drug regimen in improving functional status. [19] Ondansetron 4-8 mg three times
daily seems safe but based on limited data.
Corticosteroids (category B) have been used to treat women with severe HG. [6] Although
corticosteroid therapy is generally considered safe during pregnancy, a meta-analysis demonstrated
an increased risk of congenital malformation and a 3.4-fold increased risk of oral cleft in infants who
had been exposed to corticosteroids in the first trimester. [5]
Prognosis
The prognosis of HG is good and no differences in birth weight or birth defects have been observed
in pregnancies affected by this condition.

Gastroeophageal reflux disease and peptic ulcer disease

Symptomatic GERD is commonly reported in pregnancy, with 45-80% of women experiencing

reflux. The condition usually begins in the first or second trimester and generally persists throughout
pregnancy, with significant improvement after delivery. [20] Symptoms of GERD (heartburn and
regurgitation) are similar in pregnant and nonpregnant women, but complications are uncommon in
pregnancy. Both mechanical and hormonal factors are involved in GERD. Abnormal esophageal
motility, decreased lower esophageal sphincter (LES) pressure and increased gastric pressure
contribute to GERD in pregnancy. [21, 22]
On the other hand, PUD occurs less frequently, with fewer complications and with less-severe
symptoms in pregnant women. [23]
Management of symptoms
In particular, the patient should be advised to avoid fatty foods, caffeine, citrus juices, mint
chocolate, alcohol, smoking, and nonsteroidal anti-inflammatory drugs (NSAIDs). Nocturnal reflux
symptoms can be alleviated by elevating the head of the bed at 15cm, and by decreasing food intake
within 4h of bedtime. If symptoms are refractory to these measures, then a medical therapy is
appropriate. Antacids containing magnesium, calcium or aluminum, in normal therapeutic doses, are
considered acceptable during pregnancy. Land and Dougall demonstrated the efficacity by reliefing
the reflux symptoms within 2 weeks of using magnesium or aluminum-containing antacids, in 50%
of pregnant women, without any increase in congenital abnormalities in newborn babies. [20]
Histamine-2 receptor antagonists (H2 blokers) are preferred over proton pump inhibitors (PPIs)
and are used in more severe symptoms who have not responded to antacid therapy. Ranitidine and
Famotidine (class B drugs) are used, but they can cross the placental barrier. [24] However, a recent
large cohort study found that exposure to PPIs in the first trimester of pregnancy was not associated
with increased risk of birth defects. Registry studies and case reports have demonstrated that
lansoprazole, rabeprazole, pantoprazole and esomeprazole are safe in pregnancy, and are
characterized as category B drugs during pregnancy.[20, 25] Studies of omeprazole (category C) in
laboratory animals have demonstrated its lethality for embryos.[25] Large registry studies, however,
such as the Swedish Medical Birth Registry, did not demonstrate any increase in congenital
defects.[26] Since the dyspeptic symptoms of GERD and PUD tend to overlap, it is reasonable to
apply a similar, stepwise approach for treatment of PUD during pregnancy.
154
 Endoscopy is recommended during pregnancy for the diagnosis of suspected PUD only when
symptoms are severe and refractory to medical therapy, or in the setting of PUD complications, such
as hemorrhage or gastric-outlet obstruction. 24-hour ambulatory pH studies can be useful in patients
with atypical presentations (cough, wheezing, sore throat) and refractory symptoms.

Helicobacter pylori eradication therapy

Treatment of Helicobacter pylori infection with antibiotics and PPI regimens should be avoided
during pregnancy, because the risk of complications from untreated H. pylori infection is low in the
short term, and because of the potential teratogenicity of certain antibiotics used in these regimens.
While PUD treatment with H2 blockers and PPI relieves symptoms and induces ulcer healing,
multidrug therapy for H. pylori infection is best deferred until the postpartum period. [26]

Irritable bowel syndrome

IBS is common in childbearing age women and the effect of the pregnancy on IBS, also the safety
of drugs is important. There are no large studies with followed IBS during pregnancy, and it is not
known whether women require a modified, or the same therapeutic regimen. It is also important to
consider the risks and benefits when treating a pregnant woman with IBS, or who is trying to
conceive. [25, 27]

Treatments for constipation

Constipation in a pregnant woman with IBS can occur de novo and chronic constipation increases
in severity during pregnancy. Although many women attribute their constipation to use of prenatal
vitamins that contain iron, these vital substances should be continued if it is possible. Dietary changes,
increasing physical activity, Kegel exercises and bulk-forming laxatives (psyllium, methylcellulose,
pectin) or flax seed to 25-40g/day of fiber are safe and effective. [28] Hyperosmolar laxatives
(lactulose, glycerin) are safe, but induce bloating/cramping. Lubricant and stimulant laxatives should
be avoided, or limited to short periods. Tegaserod (category B) is approved for treatment of
constipation-predominant IBS in women for up to 12 weeks. Although the drug has not produced any
side effects on pregnant animals, experience is very limited in pregnant and nursing women. [29]
It should, therefore, be used only when other measures fail to control severe symptoms of
constipation in pregnant IBS patients. If rectal bleeding is present, anoscopy or rectosigmoidoscopy
can be performed to exclude anorectal lesions.

Treatments for diarrhea

During pregnancy women often increase lactose ingestion, and those who are lactose intolerant
consequently develop diarrhea, bloating, and abdominal pain. In these cases, limitation of lactose
intake and calcium supplementation might be necessary.
Loperamide (category B) in dose of 2-4mg daily or after each unformed stool is used in pregnancy.
Colestyramine (category C), a bile-acid sequestrant, can also be used as an antidiarrheal drug, but
it produces malabsorption of fat-soluble vitamins if used for a long time, in large doses. [30]

Antispasmotic medications
Antispasmodic agents should be reserved for pregnant women with IBS whose symptoms are
refractory to more conservative treatments. [27]
Dicycloverine (dicyclomine-category B) does not seem to pose a problem to the mother or fetus,
as shown by the Michigan Medicaid recipient surveillance study, which did not indicate an increased
occurrence of birth defects, except for polydactyly in babies born to women who had taken

155
dicycloverine. In addition, hyoscyamine (category C), has not been shown to have adverse effects in
pregnant women. [25]

Tricyclic antidepressants
The use of the tricyclic antidepressants in pregnancy should be limited to the severely symptomatic
patient. [27]
Amitriptyline and nortriptyline are both category D drugs in pregnancy and can due to limb
abnormalities in animals and humans. [25] However, subsequent investigation of infants born to
mothers exposed to tricyclic antidepressants before and during pregnancy did not confirm an increase
in congenital malformations. [31] Urinary retention in neonates has been associated with nortriptyline
use in pregnancy. [25]

Selective serotonin reuptake inhibitors

The selective serotonin reuptake inhibitors (SSRIs-category C) have been used in women with IBS
and depression. These drugs should only be considered for the severely symptomatic pregnant IBS
patient, keeping in mind the potential neonatal complications associated with fluoxetine and
paroxetinelate pregnancy exposure. [32]

Conclusions

Pregnancy represents a unique state with physiologic changes that can have profound effects on
pre-existent GI diseases, as well as predisposing women to other specific GI disorders. The
management and treatment of GI ailments in pregnant women requires special attention, since the
safety, benefits and risks for the mother, fetus and neonate remain the primary focus. Initiation of
medical therapy during pregnancy must be undertaken after discussion with the patient’s obstetrician.

REFERENCES
1. Reproductive Toxicology Center online information system [www.reprotox.org].
2. Motherrisk Online [www.motherisk.org].
3. Koch KL. Gastrointestinal factors in nausea and vomiting of pregnancy. Am J Obstet Gynecol. 2002 May. 186(5
Suppl Understanding): S198-203.
4. Koch KL, Frissora CL. Nausea and vomiting during pregnancy. Gastroenterol Clin North Am. 2003 Mar.
32(1):201-34.
5. Quinlan JD and Hill DA (2003) Nausea and vomiting of pregnancy. Am Fam Physician 68: 121–128.
6. Koch KL and Frissora CL (2003) Nausea and vomiting during pregnancy. Gastroenterol Clin North Am 32:201–
234.
7. Berkovitch M et al. (2000) Fetal effects of metoclopramide therapy for nausea and vomiting of pregnancy. N
Engl J Med 343:445–446.
8. Einarsen A et al. (2004) The safety of ondansetron for nausea and vomiting of pregnancy: a prospective
comparative study. BJOG 111:940–943.
9. Flake ZA, Scalley RD, Bailey AG. Practical selection of antiemetics. Am Fam Physician. 2004 Mar 1. 69(5):1169-
74.
10. Shahakian V et al. (1991) Vitamin B6 is effective therapy for nausea and vomiting of pregnancy: a randomized,
double blind, placebo-controlled study. Obstet Gynecol 78:33–36.
11. Niebyl JR and Goodwin TM (2002) Overview of nausea and vomiting in pregnancy with an emphasis on vitamins
and ginger. Am J Obstet Gynecol 186 (Suppl): S253–S255.
12. Atanackrovic G et al. (2001) The safety of higher than standard dose of doxylamine–pyridoxine (Diclectin) for
nausea and vomiting of pregnancy. J Clin Pharmacol 41:842–845.
13. McKeigue PM et al. (1994) Bendectin and birth defects: a meta-analysis of the epidemiologic studies. Teratology
20:27–37
14. Abell TL, Riely CA. Hyperemesis gravidarum. Gastroenterol Clin North Am. 1992 Dec. 21(4):835-49.
15. Eliakim R, Abulafia O, Sherer DM. Hyperemesis gravidarum: a current review. Am J Perinatol. 2000. 17(4):207-
18.
16. Kuscu NK, Koyuncu F. Hyperemesis gravidarum: current concepts and management. Postgrad Med J. 2002 Feb.
78(916):76-9.

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17. Goodwin TM (2002) Nausea and vomiting of pregnancy: an obstetric syndrome. Am J Obstet Gynecol 186
(Suppl): S184–S189.
18. Nina Nuangchamnong and Jennifer Niebyl. Doxylamine succinate–pyridoxine hydrochloride (Diclegis) for the
management of nausea and vomiting in pregnancy: an overview. Int J Womens Health. 2014; 6: 401-409.
19. Neri I et al. (2005) Acupuncture versus pharmacological approach to reduce hyperemesis gravidarum discomfort.
Minerva Ginecol 57:471–475.
20. Richter JE (2003) Gastroesophageal reflux disease during pregnancy. Gastroenterol Clin North Am 32:235–261
21. Fisher RS, Roberts GS, Grabowski CJ, Cohen S. Inhibition of lower esophageal sphincter circular muscle by
female sex hormones. Am J Physiol. 1978 Mar. 234(3): E243-7.
22. Brock-Utne JG, Downing JW, Dimopoulos GE, Rubin J, Moshal MG. Effect of domperidone on lower esophageal
sphincter tone in late pregnancy. Anesthesiology. 1980 Apr. 52(4):321-3.
23. Borum ML (1998) Gastrointestinal diseases in women. Med Clin North Am 82:21–50.
24. Pasternak B, Hviid A. Use of proton-pump inhibitors in early pregnancy and the risk of birth defects. N Engl J
Med. 2010 Nov 25. 363(22):2114-23.
25. Briggs GG et al. (1998) Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk edn
5. Baltimore: Williams & Wilkins.
26. Cappell MS (2003) Gastric and duodenal ulcers during pregnancy. Gastroenterol Clin North Am 23:263–308.
27. Hasler WL (2003) The irritable bowel syndrome during pregnancy. Gastroenterol Clin North Am 32:385–390.
28. Wald A (2003) Constipation, diarrhea and symptomatic hemorrhoids during pregnancy. Gastroenterol Clin North
Am 32:309–322.
29. DeYoung GR (2004) Tegaserod (Zelnorm) for irritable bowel syndrome. Am Fam Physician 69: 363–364.
30. Latikainen T (1978) Effect of cholestyramine and phenobarbitol on pruritus and serum bile acid levels in
cholestasis of pregnancy. Am J Obstet Gynecol 132:2020–2025.
31. Misri S and Sivertz K (1991) Tricyclic drugs in pregnancy and lactation: a preliminary report. Int J Psych Med
21:157–171.
32. Eydie L et al. (2005) Neonatal signs after late in utero exposure to serotonin reuptake inhibitors. JAMA 293:2372–
2383.

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The Role of Stress Hormones and Gastrin in Gastroduodenal
Dysfunction in Patients with Chronic Viral Hepatitis
LUPASCO Iulianna1, DUMBRAVA Vlada-Tatiana1, DUMITRAȘCU Dan-Lucian3,
VENGHER Inna1, BEREZOVSCAIA Elena2
1 Scientific Laboratory of Gastroenterology, State University of Medicine and Pharmacy “Nicolae Testemitanu” Chișinau,
(REPUBLIC OF MOLDOVA)
2 Laboratory of Neurosanocreatology, Institute of Physiology and Sanocreatology, ASM Chișinau, (REPUBLIC OF MOLDOVA)
3 Medical Clinics II, University of Medicine and Pharmacy “Iuliu Hatieganu” Cluj Napoca, (ROMANIA)

Email: flowercat_2004@yahoo.com

Abstract

Chronic diffuse liver diseases (CDLD) are known as stressful diseases in which is disturbed the
balance between the emotional and mental state of the body, the interaction of hormone and metabolic
systems and affected liver. Chronic viral hepatitis causes prolonged stress affecting neuro-endocrine
system, including the function of the gastrointestinal tract. In our study have been investigated the
levels of well-known stress hormones as adrenocorticotropic hormone (ACTH) and cortisol on one
hand and gastrin on the other in patients with chronic viral hepatitis (CVH) in order to reveal the
relations between gastric functional state and prolonged stressful condition as chronic viral hepatitis.
Patients with CVH were divided into 2 groups: without gastroduodenal zone (GDZ) pathology and
gr.B with GDZ hypofunction. In gr.A patients, basal ACTH, cortisol and gastrin levels were higher
than the values of healthy individuals. In patients with chronic hepatitis gr.B and functional duodenal
stasis were found a significant diminishing of gastrin level and lowering cortisol indices compared to
healthy individuals. ACTH concentration in gr.B patients was increased, though not as significant as
in gr.A with CH. The majority of patients in the group had reduced not only the motor activity of the
stomach and duodenum but also the secretory as well. In chronic viral hepatitis stress hormones
ACTH and cortisol varies synchronously with gastrin. Gastrin level and pituitary-adrenal hormones
in chronic hepatitis change in dependence on the state of the motor-evacuation activities of
gastroduodenal zone.
Keywords: stress hormones, ACTH, cortisol, gastrin, chronic viral hepatitis

Introduction

Chronic diffuse liver diseases (CDLD) present the group of liver diseases that are characterized
by diffuse inflammatory process in liver parenchyma, clinical symptoms and abnormal laboratory
data, ongoing 6 and more months that are caused by different etiology factors such as:
- Viruses HBV, HCV, HDV, HEV, HFV as well as their possible combinations, causing
viral hepatitis;
- Other hepatotropic viruses - Cytomegalovirus, Epstein-Barr;
- Abnormal lipid metabolism, lipid droplets accumulation with development of liver
steatosis and/or liver steatohepatitis;
- Alcohol intake, followed by development of alcoholic liver disease;
- Incorrect medication and/or drugs usage with appearance of toxic and/or drug induced liver
disease;
All these different agents and circumstances cause different uninflammotory or necro-
inflammatory changes of hepatocytes as well as structural and metabolic disturbances of liver.

158
 Liver plays a vital role in human organism, being responsible for literally hundreds of functions
affecting the entire body, including hormonal balance, taking part in their production on one hand
and in the body’s use of hormones, produced naturally in human bodies, on the other. Liver acts as a
hormone processor, manufacturing and/or regulating some hormone levels, and directing various
hormones to perform their proper function in other parts of the body. These multiple functions are
intimately connected to each other and could be affected by different causes, as well as by the
hepatotropic viruses or whatever hepatotropic agents, including hormones per se. In case of a
hormonal disturbances (whether produced by the body or introduced by hormone therapy), the liver
may not be able to process the hormones as quickly or efficiently, causing a hormone imbalance,
which in turn can provoke a cascade of other impairments of other metabolic functions. Maintaining
a healthy liver is central to maintaining hormone balance, which in turn helps to maintain overall
health.
Hormones act through sensible cells. Various extrinsic and intrinsic excitations provoke impulses
to specified and sensible receptors. [1] Hormones influence and coordinate some specific functions
(of the respiration, digestion, agitation) and some biologic processes (growth, ageing, energy
utilization, emotion reactions) and, not to the less extend, the susceptibility to stress [2].
Over time, stress has been revised many times and received many definitions in the scientific
papers, more or less accurate or definitive. One of the most widely accepted psychological definitions
has been that stress occurs when demands from the environment challenge and individual’s adaptive
capacity, or ability to cope [3]. Several life-changing or threatening events are considered to be
“stressors”, or stressful agents – factors that are either acute or chronic, based on the duration of their
interaction. Both have been associated to immune system dysfunctions, whether or not the individual
is affected by an acute or chronic disease [4].
In the majority of studies, the viral agent is not referred to a stressful agent, as it has to be. From
the other point, in chronic viral hepatitis the major etiology factor is the virus by itself (HBV, HCV,
HDV, or another hepatotropic virus). The viral chronicity has several general concepts of
pathogenesis. Pathogenic mechanisms of viral disease include (1) implantation of virus in the
organism, (2) its local replication, in case if it is possible, or (3) spread to target organs (disease sites,
in chronic viral hepatitis, this is mainly liver), and (4) spread to sites of shedding of virus into the
environment (in chronic viral hepatitis, this is blood stream). Factors that affect pathogenic
mechanisms are (1) accessibility of virus to tissue, (2) cell susceptibility to virus multiplication, and
(3) virus susceptibility to host defenses. Natural selection favors the dominance of low-virulence virus
strains [5]. So, viral pathogenic mechanism, in general has two main issues
- the viral survival virulent mechanism
- the host defense mechanism
At the same time, it is impossible not take into account the stressful event that is happening to the
host body attacked by the virus. Humans have been designed with a complex of metabolic instruments
intended to maintain normal homeostasis. Every change that human body receives develop a cascade
of reactions that are governed by central nervous system [6]:
1. stressful event
- Virus as a threat
- The psychosocial awareness of the chronic viral disease
2. “state of threatened homeostasis or disharmony”
- Physical condition
- Psychological stare
3. counteraction by “adaptive stress response”, a complex array of physiologic and
behavioral responses intended to re-establish homeostasis with its three-stage process of:
- alarm reactions
- Adaptation stage and in many cases
- exhaustion stage

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 The brain is the key organ of stress reactivity, coping and recovery processes [7]. Within the brain,
a distributed neural circuitry determines what is threatening and thus stressful to the individual.
Instrumental brain systems of this circuitry include the hippocampus, amygdala, and areas of the
prefrontal cortex. Together, these systems regulate physiological and behavioral stress processes,
which can be adaptive in the short-term and maladaptive in the long-term. Once an individual is
subjected to such as stressor, specific pathways within the brain lead to the activation of the
hypothalamic-pituitary-adrenal axis (HPA) as well the central sympathetic outflow. This constitutes
the stress response, releasing key peripheral mediators-glucocorticoids and cateholamines (dopamine,
noradrenalin γ-aminobutyric acid) in which metabolism participate the liver [8, 9]. For a period of
time it was suggested that stress influence the hepatic circulation disturbance, inducing vasospasm
and provoking the centrilobular hypoxia, affecting the liver parenchyma [10, 11]. More recently, as
the understanding of the stress and stress mediators has improved, appeared a new vision on the onset
and development of acute and chronic liver diseases and the role of HPA axis, stress hormones and
other factors in this process [12, 13]. Importantly, such stress processes arise from bidirectional
patterns of communication between the brain and the autonomic, cardiovascular, as well as the
immune systems via neural and endocrine mechanisms in the battle with chronic stressful agent.
These bidirectional stress interrelations are designed to be protective in that they promote short-
term adaptation (allostasis). The benefit of such stress comes out of the pressure it exerts in order to
accomplish the necessary goal – to kill the stressful agent, to manage the health in the war with
disease.
However, these stress mechanisms can lead to a long-term dysregulation of allostasis promoting
maladaptive wear-and-tear on the body and brain under chronically stressful conditions (allostatic
load) [14]. In these conditions, stress riches chronic in time and harmful levels which affect the
normal physiologic reactions, compromising immune and metabolico-hormonal reactions.
Allostasis, is defined as a dynamic regulatory process wherein homeostatic control is maintained
by an active process of adaptation during exposure to physical and behavioral stressors, and
Allostatic load, defined as the consequence of allodynamic regulatory wear-and-tear on the body
and brain promoting ill health, involving not only the consequences of stressful experiences
themselves, but also the alterations in lifestyle that result from a state of chronic stress [15].
Chronic liver disease in the clinical context is a disease process of the liver that involves a process
of progressive destruction and regeneration of the liver parenchyma leading to fibrosis and cirrhosis
and finally – death in its natural course. Therefore, CDLD and chronic viral hepatitis present the
harmful condition in the human body, where the long-term condition of the disease can be determined
as an allostatic load.
Recent breakthroughs in the understanding of the neurobiology of the organism’s response to acute
and chronic stress, and the evolving understanding of elaborate brain-gut interactions and their
modulation in health and disease are beginning to require a reassessment of chronic stress in the
pathophysiology and management not only of functional but also of “organic” gastrointestinal
disorders. Certain stressful life events have been associated with the onset or symptom exacerbation
in some of the most common chronic disorders of the digestive system, including functional
gastrointestinal disorders (FGD), inflammatory bowel disease (IBD), gastro-esophageal reflux
disease (GERD), and peptic ulcer disease (PUD).
Evidence for alteration of HPA axis function with elevated cortisol and blunted
adrenocorticotropic hormone (ACTH) levels was shown by Chang L., et al., who came up with a
hypothesis of a generalized upregulation of the central stress system with enhanced negative
feedback, which is not specific to IBS, and may be related to overall state of well-being in stress-
related disorders [16]. There is a significant overlap in the epidemiology of all of these conditions
with IBS. While it is currently not known if these HPA axis changes are an epiphenomenon or play
a role in symptom generation and pathophysiology of these syndromes, it is possible to speculate on
their possible role in the observed findings in post-infectious IBS patients. The reported persistence
of chronic inflammatory mucosal changes after eradication of the infectious organism, and increased

160
intestinal permeability and hyperplasia of enterochromaffin cells are consistent with an inadequate
physiological response to acute gut inflammation, in particular an inadequate cortisol (and possibly
an altered sympathetic) response. If there is a possibility that a downregulated cortisol response to
intero- and exteroceptive stressors might also predispose IBS patients to chronic inflammatory
conditions, such as asthma, rheumatoid arthritis, or IBD? Animal studies indicate that corticotropin-
releasing hormone plays an important role in mediating effects of stress on small intestinal and
colonic motility, leading to delayed gastric emptying but accelerated small and large intestinal transit
[17].
There is need to be mentioned the importance of deep relationship between cortisol and liver
function, where the insufficient production of cortisol leads to hepatic dysfunction and vice a verso.
[18]
One of the most important hormones controlling the digestion and the proper functionality of upper
gut is gastrin. Gastrin is a hormone produced by G-cells of stomach antrum. Secretion of gastrin, as
the physiological mechanism of initiation of digestion, increases in response to the cholinergic (vagus
nerve) and, to a lesser extent, sympathetic stimulation of the stomach. In addition, the secretion of
gastrin is increased by insulin, histamine, the presence in the stomach or in the blood plasma of
oligopeptides and free amino acids, the products of protein cleavage. Secretion of gastrin also
increases with stress (due to increased sympathetic stimulation of the stomach), with a high level of
glucocorticoids. This explains the appearance of “stressful” stomach ulcers pathogenesis, where
anxiety like other forms of stress could act as an aggravating factor [19]. Gastrin, when it reaches the
parietal cells of the antrum, signals the stomach to secrete gastric acid and release histamine.
Gastrin also increases the secretion of pepsin by the main cells of the stomach, which, together
with an increase of the gastric juice acidity, providing an optimal pH for the action of pepsin,
promotes optimal digestion of food in the stomach. Simultaneously, gastrin increases the secretion of
bicarbonates and mucus in the gastric mucosa, thereby ensuring protection of the mucosa from the
effects of hydrochloric acid and pepsin. Gastrin inhibits the emptying of the stomach, which provides
a sufficient duration for the digestion of food exposure to hydrochloric acid and pepsin for food
lumps. At the same time, gastrin increases the production of prostaglandin E in the gastric mucosa,
which leads to local vasodilation, increased blood supply and physiological edema of the gastric
mucosa, and migration of leukocytes to the mucosa. Leukocytes take part in digestion processes,
secreting various enzymes and producing phagocytosis. Receptors for gastrin are also present in the
small intestine and pancreas. Gastrin increases the secretion of secretin, cholecystokinin, somatostatin
and a number of other hormonally active intestinal and pancreatic peptides, as well as the secretion
of intestinal and pancreatic enzymes. Thus, gastrin creates conditions for the implementation of the
next, intestinal, digestive phase. Taking into account all these complex and interrelated mechanisms
some questions appear:
• What happens in case of long duration stress with gastrin secretion?
• Does it change?
• If there is an interrelation between stress hormones and gastrin secretion in
patients with chronic diffuse liver pathology, mainly chronic viral hepatitis?

Aim of the study

Was to investigate the level of gastrin, ACTH and cortisol in patients with chronic viral hepatitis
(CVH) B and C.

▪ Material and methods

▪
In study participated 58 patients with chronic viral hepatitis of HBV and HCV etiology, 11 healthy
people served the control group. All patients were examined due to the special protocol, including
clinical, laboratory and instrumental investigations as well as X-ray barium radiography of gastric

161
epmtying and intestinal transit. Determination of ACTH and gastrin blood levels was carried on by
RIA methods (corticotropin - RIA immunoassay, gastrin - Gask-immunoassay Cea-Sorin). Cortisol
was investigated by the help of immunofluorescent method, using standard kits (Sweden LBH Deefa).
Patients with CH were divided into 2 groups: gr.A - 43 patients without functional dyspepsia and
delayed gastric emptying, and gr.B - 15 patients with clinical features of functional dyspepsia (ROME
IV criteria), postprandial distress syndrome and with radiographic signs of delayed gastric emptying
as well. Of all patients with CVH participated in the study, women were - 58,49%, the majority been
persons over 40 years old (84,91%).
▪
▪ Results
▪
In A group of patients basal ACTH (69,72 ± 2,52pg/ml) and cortisol levels (712,23 ± 16,24nmol/l,
p˂0,01) were higher than the values of healthy individuals (37,13 ± 3, 28pg/ml and 521,35 ±
14,0nmol/l) (Fig. 1, 2). In this group gastrin concentration (60,05 ± 8b70pg/ml, p˂0,05) was above
the control data (38,67 ± 9,26pg/ml) (Fig. 3).
nmol/l Cortisol B vs A

800 P<0,01

P<0,05
600

400

200

0
A group B groupl control

A group B groupl control

Fig. 1. The comparison of cortisol level in patients with chronic viral hepatitis

pg/ml
ACTH

70 P<0,05
60 P<0,05
50
40
30
20
10
0
A group A group Control

A group A group Control

Fig. 2. The comparison of ACTH level in patients with chronic viral hepatitis

162
 In patients with chronic hepatitis gr.B with delayed gastric emptying was found a significant
diminishing of gastrin level (19,61 ± 2,11pg/ml, p˂0,05) and lowering cortisol indices (421,06 ±
12,03nmol/l) compared to healthy individuals. ACTH concentration in gr.B patients was increased
(53,22 ± 5,41pg/ml, p˂0,05), though not as significant as in gr.A with CH. The majority of patients
in the group had reduced not only the motor activity of the stomach and duodenum but also the
secretory as well.
Gastrin B vs A

70
P<0,01
60
50
P<0,05
40
30
20
10
0
A group B group Control

A group B group Control

Fig. 3. The comparison of gastrin levels in patients with chronic viral hepatitis

▪ Conclusions
▪
In chronic viral hepatitis stress hormones ACTH and cortisol varies synchronously with gastrin. Gastrin level and
pituitary-adrenal hormones in CVH change in dependence on the state of the motor-evacuation activities of GDZ.
Chronic Fight for
tension/st viral Chronic viral
elimination Disruption/d
Virus as a ress of elay of inflammation of
long term immune, bidirectional liver
endocrine Fight for parenchyma,
persistent physiologic
stressful and survival progression of
mechanism
agent neural of HPA axis, disease with
adaption humoral and extrahepatic
systems Fight for manifestations
Ist hit cellular
reparation
immunity,
of altered
endocrine
systems
IInd and neural
and cells
hit adaption
system

Development of IIId hit

depression in order
to stop fighting
Decreasing of
Increasing of cAMP, Different data of
ACTH cortisol
cGMP, ACTH, thyroid, sexual
levels even
cortisol, levels, hormones levels
lower than
indices of immune even lower than
normal range,
system, sometimes normal range
insufficient
significant answer of
immune system

Fig. 4. Chronic viral infection in terms of stressful event

163
Discussion

It is known that gastrin stimulates gastric motility and release of pepsin and intrinsic factor.
The lowering of gastrin levels in our patients with CDLD with duodenal stasis is logic but why
this happened? Viewed together, these results demonstrate that the interface between the gut lumen
and neural, endocrine, pathways is under close control of the central nervous system as well as of
HPA axis. Alterations in the regulation of this interface, under conditions of stressful allostatic load,
when virus is presented as stressful agent, are likely to play an important role in the modulation of
secretion, motility and sensory response of the gut to luminal contents in 1/3 of patients who possible
are in a 3d stage of adaptive stress response that provoke a decrease of stress hormones and gastrin
secretion. In this hypothesis (Fig. 4) virus persistence and in some cases high viremia cause chronic
tension as allostatic load of different mechanisms defeating the body against this factor. During this
battle immune, endocrine and central nervous systems fight in different ways: for viral elimination,
for micro a macro survival, for reparation of affected cells and systems. The longer the viral persists,
the deeper the stress and more often appear delay or disruption of bidirectional mechanisms of HPA
axis, humoral and cellular immunity and endocrine adaptive systems, leading to the chronicity of
hepatitis, as well as progression of extrahepatic manifestations connected with affected liver.
The impairment of gastrin secretion could be a result of this complex cascade stressful event, or
may be altered liver function has its own part in this choir, but there is a need for further investigation
of chronic diffuse liver diseases, especially chronic viral hepatitis under the prism of chronic stress.

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165
First Line Helicobacter Pylori Eradication in Dyspeptic Patients

MIHAI Catalina1,2, MIHAI Bogdan1,3, CARDONEANU Anca1,4, GRANGA Mihaela1,2,

GAVRILESCU Otilia1,2, DRUG Vasile1,2, CIJEVSCHI PRELIPCEAN Cristina1,2
1 “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, (ROMANIA)
2 Institute of Gastroenterology and Hepatology, “Sf. Spiridon” Hospital, Iasi, (ROMANIA)
3 Center of Diabetes, Nutrition and Metabolic Diseases, “Sf. Spiridon” Hospital, Iasi, (ROMANIA)
4 Rehabilitation Hospital, Iasi, (ROMANIA)

Emails: catalinamihai@yahoo.com, bogdanmihai2003@yahoo.com, cardoneanu_anca84@yahoo.com, mihaela_dra@yahoo.com,

otilianedelciuc@yahoo.com, vasidrug@email.com, cristinacijevschi@yahoo.com

Abstract

Background
Helicobacter pylori (HP) eradication became a challenge due to increasing resistance to antibiotic
therapies that had been previously effective.

Aim
To compare the efficacy and safety of two first-line therapeutic regimens for HP eradication:
standard triple therapy (STT) and quadruple concomitant therapy (QCT) for 14 days with high dose
of proton pomp inhibitors (PPI) in dyspeptic patients. Methods. We had prospectively enrolled naive
patients diagnosed with HP associated dyspepsia. Endoscopy was performed in all patients; the HP
infection was diagnosed by rapid urease test. The patients were randomized 1: 1 in two groups: group
A received esomeprasole (20mg bid) – clarithromycin – amoxicillin STT for 10 days and group B
received QCT (esomeprasole 40mg bid, clarithromycin, amoxicillin, metronidazole) for 14 days.
All patients were re-evaluated 6 weeks after eradication by monoclonal stool antigen test. The side
effects of the therapy were noticed.

Results
The sample included 48 females and 32 male patients, with an average age of 50.34 years. In group
A the eradication rate was obtained in 27 patients (67.5%), versus 34 (85%) patients in group B
(p=0.03). The side effects (nausea, vomiting, diarrhoea) occurred in 7 patients from group A (17.5%)
and in 13 patients from group B (32.5%) (p=0.06). The Clostridium difficile infection was noticed in
two patients from group B.

Conclusions
QCT with high dose of PPI and prolonged duration is more effective than STT as first – line HP
eradication in dyspeptic patients but has more side effects (including Clostridium difficile infection).
Keywords: dyspepsia, Helicobacter pylori, eradication

Background

33 years from the discovery of its role in digestive disorders, the eradication of infections with
Helicobacter pylori (HP) remains a challenge, and the discovery of an efficient vaccine is yet to be
attained. The global prevalence of the infection with HP is estimated to 20 to 80%, higher in
developing countries, compared to developed countries [1]. Its role was proven in a number of
digestive disorders (gastritis, ulcer, MALT lymphoma) as well as in gastric carcinogenesis, so that
the eradication of the infection has become a public health concern. Despite the decrease in the
prevalence in developed countries, the increase in the resistance to antibiotics, as well as the failure
166
of classical eradication schemes have turned the treatment of the HP infection into a difficult problem
in current medical practice.
The aim of the study was to compare the efficacy and safety of two first-line therapeutic regimens
for HP eradication: standard triple therapy (STT) and quadruple concomitant therapy (QCT) for 14
days with high dose of proton pomp inhibitors (PPI) in dyspeptic patients.

Methods

We had prospectively enrolled naive patients diagnosed with HP associated dyspepsia. All the
patients signed the informed consent and the study was approved by the local ethics committee.
Endoscopy was performed on all patients; the HP infection was diagnosed by rapid urease test.
We excluded from the study the patients undergoing antibiotics treatment or patients who have
been administered bismuth mixtures over the last 4 weeks or PPI over the last 2 weeks. The patients
were randomized 1: 1 in two groups: group A received esomeprasole (20mg bid) – clarithromycin –
amoxicillin STT for 10 days and group B received QCT (esomeprasole 40mg bid, clarithromycin,
amoxicillin, metronidazole) for 14 days. All patients were re-evaluated 6 weeks after eradication by
monoclonal stool antigen test. The side effects of the therapy were noticed.
The data was uploaded and treated with the help of the statistical functions in SPSS 18.0. The
ANOVA test consisted in the analysis of the dispersion of the dependent variable: intra and
intergroup. In computing the significant difference between two or more groups depending on the
distribution of the series of values for a significance threshold of 95% for the quantitative variables
we applied: the t-Student test – parametric test which compares the average values registered in two
groups with normal distributions and the test 2 – nonparametric test which compares 2 or more
frequency repartitions coming from the same population, applied when the expected results exclude
one another. The ROC curve – draws the balance specificity/sensitiveness as a prognosis factor.

Results

The study sample included 80 patients, 40 in group A and 40 in group B. The patients’ age varied
from 45 to 58 years old (with an average age of 50.34 years), homogeneous by study group, even if
in group B the average age was slightly lower (49.75 y vs 50.93 y; p=0.129). The study involved 60%
women and 40% men. The percent distribution by gender highlighted the higher frequency of the
male patients in group A (55%) and female patients in group B (75%) (p=0.006), the ratio being
OR=3.67 (IC95%: 1.42-9.47).
Response to treatment was significantly higher in the patients from group B (85.0% vs 67.5%;
p=0.03) with a ratio of the quotas of QCT/STT=2.73 (IC95%: 1.02-8.13) (Fig. 1).

eradication rate
yes no

32,5 15

67,5 85

Group A Group B

Fig. 1. The eradication ratio of the HP infection in the study samples (STT vs QCT)

The ROC curve shows that the QCT treatment was more effective, but sensitiveness was only
59%, while specificity was 75% (Table 1).

167
 Table 1. Sensibility and specificity of two first-line therapeutic regimens for HP eradication
Asymptotic 95%
Therapeutic Std. Asymptot
Sensibility Specificity Area Confidence Interval
regimens for HP Error(a) ic Sig.(b)
(%) (%) Lower Upper
eradication
Bound Bound
STT 35.0 40.0 0.413 0.064 0.178 0.287 0.538
QCT 59.0 75.0 0.621 0.073 0.113 0.478 0.763

14/27 patients (51.9%) with positive response to STT and 8/34 (23.5%) with positive response to
QCT were males (p=0,043). The positive response in the age group above 50 years old was slightly
less frequent in the STT treatment (55.6% vs 38.2%; p=0.276).
The secondary effects were more frequently met in the patients from group B (32.5% vs 17.5%;
p=0.06), with an estimated risk 1.77 times higher (IC95%: 0.88-3.55). The most frequent side effects
were: diarrhoea, nausea, vomiting, abdominal pain and bloating. 5/7 patients (71.4%) with side effects
in group A and 10/13 (76.9%) in group B were women (p=0.787). Most patients with side effects
were under the age of 50 (71.4% in group A and 69.2% in group B, p = 0.921). 18.5% of the patients
with a positive response in group A (p=0.805) and 38.2% in group B (p=0.022) presented side effects
(Table 2).
Table 2. Side effects depending on the response to the treatment
Therapeutic regimens for HP eradication Response Total
Yes No
STT Side effects yes Count 5 2 7
% within Response 18.5% 15.4% 17.5%
no Count 22 11 33
% within Response 81.5% 84.6% 82.5%
Total Count 27 13 40
% within Response 100,0% 100.0% 100.0%
QCT Side effects yes Count 13 0 13
% within Response 38.2% 0.0% 32.5%
no Count 21 6 27
% within Response 61.8% 100.0% 67.5%
Total Count 34 6 40
% within Response 100,0% 100.0% 100.0%

The Clostridium difficile infection was noticed only in the patients from group B (0% vs 5%;
p=0.093). We should however mention that the presence of side effects did not influence the
compliance to the treatment; in 2 cases from the QCT group, the length of the treatment was 10 -
instead of 14, but in both cases successful eradication was noticed.

Discussion

According to the ROMA IV consensus, functional dyspepsia includes 2 entities: epigastric pain
syndrome (pain and/or epigastric burn) and post-prandial distress syndrome (post-prandial bloating)
[2].
Both types of symptoms showed improvement after the eradication of the HP infection [3].
Presently, according to the ROMA IV consensus, positive HP dyspepsia is considered to be a
distinct entity and it is no longer included under the “umbrella” of functional dyspepsia. In young
patients with non-investigated dyspepsia, without serious symptoms, the non-invasive testing and
eradication of the HP infection is recommended [4]. However, a Cochrane meta-analysis revealed
advantages as regards symptoms and patients’ satisfaction which favour the “endoscope-and-treat”
strategy, as opposed to the “test-and-treat” [5]. The American Gastroenterological Association
recommends biopsy testing for identifying the HP infection in all patients presenting dyspeptic
symptoms who undergo high digestive endoscopy [6]. In our sample, we chose to perform endoscopy
168
in order to confirm the dyspepsia diagnosis (excluding organic disorders). Moreover, the average age
in the studied sample was around the age of 50 – an age when endoscopy is recommended in all
dyspeptic patients.
The HP infection diagnosis was established by rapid urease test, swabbing two biopsies (one in
the antrum and one in the gastric body), according to the recommendations of the Maastricht V
consensus. It is recommended that the HP infection eradication be verified by respiratory test or by
faecal antigen 4-8 weeks after the completion of the eradication treatment [4]. For the sake of sample
homogeneity, and on availability grounds, in our sample we used the determination of the faecal
antigen.
Current literature data draws attention to the increase in the resistance to antibiotics and the lack
of effectiveness of the classical schemes used in the eradication of the HP infection throughout the
world, both in developing and developed countries. Despite the evidence that relates the eradication
ratio below 80% in most studies, the classical eradication scheme – the so called “legacy therapy”
(PPI, clarythromicin and amoxicillin or metronidasole) remains the most recommended first line
therapy [7]. Most general practitioners in our country recommend the triple standard therapy for 7 or
10 days in dyspeptic patients.
Recently published existing consensus (Maastricht V, Toronto, American College of
Gastroenterology), recommend as first line eradication in the areas with resistance to clarythromicin
>15% concomitant quadruple therapy (PPI, amoxicillin, clarythromicin, metronidasole) or quadruple
therapy with bismuth for 14 days [4, 8, 9]. Romania occupies the second place in Europe as regards
the consumption of antibiotics, and European studies have pointed to a worrying increase in resistance
to the antibiotics currently used in the eradication of HP [10, 11]. In our country, there is little data
regarding primary resistance to antibiotics used in first line eradication of the HP infection. A study
published in 2011 on a sample of 100 patients with HP dyspepsia indicated very high numbers as
regards resistance to antibiotics: 32% to clarythromicin, 92,8% to metronidazole and 50% to
amoxicillin [12]. The data from literature points to the fact that the length of the treatment (14 days)
is superior to that of 7-10 days, fact also confirmed in a study conducted recently in Romania [13].
Considering the absence of bismuth based mixtures on the Romanian market at the time the study
was conducted, we chose to compare STT with QCT. As regards PPI, the response varies depending
on the genetic polymorphism of the cytochrome CYP2C19, which may affect the eradication
effectiveness [14]. The practice in Europe and North America recommends the use of rabeprasole
and esomeprasole; high doses of esomeprasole (40 mg twice/day) increase the effectiveness of
eradication [15].
In the study conducted, the effectiveness of HP eradication was of 67.5% in the group treated with
STT. This fact is in agreement with recent data from specialised literature which points to 7 or 10
days STT eradication percentages below 80% [8, 16]. A meta-analysis which compared the
effectiveness of the triple therapy with clarythromicin showed a considerable decrease in
effectiveness, from 80% between 2000 and 2005 to 62% between 2006 and 2011 [17].
In the group treated with QCT, the success of eradication was 85% in agreement with studies
conducted in other European countries which demonstrated eradication percentages varying between
85 and 94% [18, 19]. Nevertheless, the eradication ratio, even in case of a double dose of PPI for 14
days, was rather low (<90%). This allows inferring that, most probably, in Romania there is increased
HP resistance both to clarythromicin and to metronidasole; it is known that dual resistance to
clarythromicin and metronidasole <15% affects the success of eradication in all non-bismuth
quadruple therapy [20]. Women and people below the age of 50 responded better to QCT compared
to STT, but the differences were not statistically significant.
On the short term, HP eradication affects the microbiota, which leads to a number of side effects
of the antibiotic treatment: diarrhoea, nausea, vomiting, bloating, abdominal pain, infection with
Clostridium difficile; these can determine treatment interruption, eradication failure and increase in
the resistance to antibiotics. The side effects were 1.77 times more frequent in the QCT group
compared to the STT group (32.5% vs 17.5%). Side effects were more frequent in women, subjects

169
below the age of 50 and those who responded to the QCT scheme. 2 patients in the QCT group
presented Clostridium difficile infection, fact also signalled by other studies in the literature [21].
Similar results regarding side effects were reported in Spain: QCT with a double dose of PPI for
14 days was more successful compared to the triple therapy (90.4% vs 81.3%); side effects were 8%
more frequent but did not influence compliance to the treatment [22].

Conclusions

To conclude, we can argue that the optimum first-line treatment for the HP infection in dyspeptic
patients in our country is yet to be found. The standard triple therapy has low effectiveness (most
probably due to high resistance to clarythromicin) and should not be recommended. Optimised
quadruple concomitant therapy (double doses of PPI for 14 days) is more effective (although below
90%), and the side effects - more numerous - do not influence compliance to the treatment. Further
study is necessary (bismuth quadruple therapy, levofloxacin therapy, sequential or hybrid therapy) in
order to identify the best strategy for the eradication of HP positive dyspeptic patients in Romania.

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Gastroenterology; 150 (6): 1257-1492.
3. Suzuki H, Moayyedi P (2013). Helicobacter pylori infection in functional dyspepsia. Nat Rev Gastroenterol
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dyspepsia: an individual patient data meta-analysis. Gastroenterology; 128: 1838–44.
6. Yang YX, Brill J, Krishnan P et al. (2015). American Gastroenterological Association Institute Guideline on the
role of upper gastrointestinal biopsy to evaluate dyspepsia in the adult patient in the absence of visible mucosal
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7. Lee JY, Kim N, Park KS et al. (2016). Comparison of sequential therapy and amoxicillin/tetracycline containing
bismuth quadruple therapy for the first-line eradication of Helicobacter pylori: a prospective, multi-center,
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8. Fallone CA, Chiba N, van Zanten SV (2016). The Toronto Consensus for the Treatment of Helicobacter pylori
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9. Chey WD, Leontiadis GI, Howden CW et al (2017). ACG Clinical Guideline: Treatment of Helicobacter pylori
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10. Megraud F, Coenen S, Versporten A et al. (2013). Helicobacter pylori resistance to antibiotics in Europe and its
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11. Boyanova L, Gergova G, Estatiev I et al. (2016). Helicobacter pylori resistance to six antibiotics by two
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Gluten: the Link between Dyspepsia and Celiac Disease
PLESA Alina1,2, MAXIM Roxana1, CIORTESCU Irina1,2
1“Grigore T. Popa”, University of Medicine and Pharmacy Faculty of Medicine, IasI (ROMANIA)
2Institute of Gastroenterology and Hepatology, “St. Spiridon” Hospital, Iasi (ROMANIA)
Emails: alinaplesaro@yahoo.com, maxim_roxxana@yahoo.com, irinaciortescu@yahoo.com

Abstract

Wheat is one of the principal components of the human diet among diverse populations around the
world. The introduction of wheat grains represented an evolutionary challenge and paved the way to
new diseases, the best known of which are mediated by the adaptive immune system: wheat allergy
(WA) and celiac disease (CD). Celiac disease, a chronic enteropathy of the small intestine caused by
ingestion of gluten, is one of the most prevalent food hypersensitivities worldwide with an increasing
prevalence over the last three decades estimated at about 1% in countries with a population of
predominantly European origin. Gluten, a proline and glutamine rich glycoprotein is the most critical
environmental driver of the disease, while both human leukocyte antigen (HLA) and non-HLA genes
are predisposing hereditary factors. MHC locus is the single most important genetic factor of the
disease, with the majority of patients carrying a particular variant of HLA-DQ2 (DQA1*05:01,
DQB1*02:01; also known as DQ2.5. Non-celiac gluten sensitivity (NCGS) is a new wheat-related
syndrome that is used to describe both intestinal and extraintestinal symptoms that occur upon
ingestion of wheat in patients who do not have confirmed cases of CD or wheat allergy. The only
current treatment for the gluten-related diseases is either a strict, lifelong adherence to a gluten-free
diet for celiac patients or avoidance of gluten containing foods for allergic or intolerant patients.
Unfortunately, in certain cases, patients experience persistent symptoms and enteropathy despite
their best efforts to avoid dietary gluten.
Keywords: gluten, celiac disease, clinical manifestations, dyspepsia

Gluten and the evolution of gluten-related disorders

Wheat is one of the principal components of the human diet among diverse populations around the
world. There is a widespread perception of wheat as an ancient and healthy food, associated with
positive emotions. Like all foods, however, wheat is capable of causing a wide range of adverse
reactions [1]. The introduction of wheat grains, which occurred about 10,000 years ago with the
advent of agriculture and domestication of gluten-containing cereals, represented an evolutionary
challenge and paved the way to new diseases, the best known of which are mediated by the adaptive
immune system: wheat allergy (WA) and celiac disease (CD). Besides CD and WA, there are cases
of gluten reactions in which neither allergic nor autoimmune mechanisms are involved. These are
generally defined as gluten sensitivity (GS) [2-4].
Celiac disease (CD), a chronic enteropathy of the small intestine caused by ingestion of gluten, is
one of the most prevalent food hypersensitivities worldwide with an increasing prevalence over the
last three decades estimated at about 1% in countries with a population of predominantly European
origin [5-7]. Exposure to gluten is an indispensable requirement for the development of CD. However,
while some subjects develop CD soon after the introduction of gluten into the diet, others do so in
late adulthood, after having been exposed to gluten for decades [8]. Therefore, clinical data have
established the existence of other environmental triggers such as the mode of birth, weaning way,
gluten introduction, antibiotics and viral and bacterial infections, being the alteration of the intestinal
microbiota one of the most important [9]. Despite advances in our understanding of its

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pathophysiology and improved diagnostic tools, the rise in CD has been a largely silent epidemic,
with undiagnosed patients going untreated and at increased risk of morbidity from intestinal and
extra-intestinal symptoms, as well as the risks of cancer and mortality [10].
The geoepidemiology of CD is efficiently conceptualized by the iceberg model, which is
influenced by the frequency of genotypes and the pattern of gluten consumption [11]. The high
prevalence of CD may be partially explained by globalization, which led to an increased consumption
of gluten-containing food worldwide [12]. The widespread use of refined grains and leavening by
chemical and baker's yeast agents are some of the classical examples of the most recent trend.
Celiac disease may develop at any time in life but is most prevalent at pediatric age with a high-
expected ratio between undiagnosed and diagnosed cases [13]. Recently, there has been evidence of
the changing nature of CD with a progressive decrease in the percent-age of patients presenting with
a diarrheal syndrome [14]. Celiac disease can be confusing for the generalist to diagnose when it
occurs outside of the “classic” gastrointestinal presentation.
As an autoimmune condition, CD symptoms can manifest in virtually every organ system.
Dyspepsia is one of the most common gastrointestinal disorders to be faced in clinical practice,
with prevalence up to 40% in population-based study so that the economic impact is very high [15].
Functional dyspepsia is an exclusion diagnosis and it is classified as a chronic abdominal pain-
related functional disorder, characterized by the presence of persistent or recurrent pain or discomfort
centered in the upper abdomen, neither relief by defecation, nor association with the onset of a change
in stool frequency or form [16]. Dysmotility-like dyspepsia symptoms are frequent in patients with
gluten-sensitive enteropathy (GSE). Current data suggest that patients with mild enteropathy may be
present with gluten-sensitive symptoms and complications. In a study performed by Santolaria et al
among 142 patients who presented dysmotility-like dyspepsia symptoms and normal upper
gastrointestinal endoscopy, GSE was found to be a frequent and unsuspected cause of dysmotility-
like dyspepsia [17].
The results of different studies among patients with functional dyspepsia showed contradictory
conclusions. In a study by Lima et al, the reported CD prevalence was 1.4% in a small series of young
female patients with dyspepsia [18]. In another clinical trial performed by Bardella et al, which
included a small prospectively enrolled cohort of 517 patients suffering from dyspeptic symptoms,
the estimated prevalence of CD in the study group was 1.2% [19]. Other similar papers by Ozaslan
et al which evaluated a small cohort of 196 patients, three were diagnosed to be celiac (1.5%) [20].
Giangreco et al argued the role of upper gastrointestinal endoscopy in CD diagnosis among
patients suffering from dyspepsia. The prevalence of CD was 2% higher than the general population
one, also considering that patients with an increased risk for CD (such as first-degree relatives) were
excluded from the study [21]. Heikkinen et al showed a low prevalence of CD of 0.5% among the
400 uselected dyspeptic patients enrolled in the study [22]. A recent meta-analysis by Ford et al
evaluated the yield of diagnostic testing for CD in patients affected by dyspepsia. The pooled
prevalence of positive celiac serology ranged from 6% to 8%. The author pooled the data from
literature and estimated that the prevalence of positive celiac serology ranged from 6% to 8%, the
biopsyproved CD prevalence was also higher in patients with dyspepsia, approximately 2%, than
controls, but not in a statistically significant way [23].
Contrary to CD, WA is an immune IgE- mediated reaction to the proteins found in food products.
Wheat allergy is an IgE-mediated reaction to the water and salt-insoluble gliadins, particularly
omega 5 gliadin [1]. These proteins also have been reported to increase in response to water stress in
durum wheat [24]. It is notable that the omega-5 gliadins are the major sensitizing allergens in a
serious food allergy called wheat-dependent exercise-induced anaphylaxis (WDEIA) that occurs in
certain individuals when the ingestion of wheat is followed by physical exercise [25]. While
symptoms of WA can affect the gastrointestinal tract, they are more frequent in the respiratory tract
and skin.
Patients may complain of discomfort and claim swelling, an itching sensation, and irritation in and
around the lips, tongue, mouth, eyes, and throat. Wheat allergy is hard to diagnose when affecting the

173
gastrointestinal tract because the symptoms are very non-specific and include generalized abdominal
pain, dyspepsia and diarrhea [26]. Studies have investigated family history, genetic predisposition,
skin barrier function, and the season of birth as risk factors for food allergy onset. Especially, the
presence of atopic dermatitis is an important risk factor. Recently, Tsakok et al reported in a
systematic review that children with atopic dermatitis were 6.18 times more easily sensitized against
food than healthy children [27].
Non-celiac gluten sensitivity (NCGS) is a new wheat-related syndrome that is used to describe
both intestinal and extraintestinal symptoms that occur upon ingestion of wheat in patients who do
not have confirmed cases of CD or WA [28]. While symptoms may be similar to CD, NCGS does
not result in intestinal damage and does not involve the adaptive immune system. Symptoms generally
disappear after withdrawal of wheat from the diet and recur when wheat is reintroduced [28-30].
To date, a complete definitive diagnostic flowchart for gluten-related disorders has yet to be
established.

Gluten toxicity in related disorders

According to the Codex Alimentarius (Codex Standard 118-1979, 2015), gluten is defined as a
“protein fraction from wheat, rye, barley, oats or their crossbred varieties and derivatives thereof, to
which some persons are intolerant and that is insoluble in water and 0.5 mol/L NaCl” [31].
The patogenesis of CD involves an interplay between environmental, genetic and immunologic
factors.
Wheat gluten and other related peptides elicit innate and adaptative immune responses in the small
intestine that lead to mucosal damage.
The principal environmental driver, dietary gluten, contains a number of distinct disease-specific
T-cell epitopes. A common feature of these epitopes is the presence of multiple proline and glutamine
residues, with the high proline content rendering these peptides resistant to proteolytic breakdown by
gastric, pancreatic, and intestinal digestive proteases [32]. This particular charge makes them resistant
to human gastrointestinal enzymes such as pepsin, trypsin and chymotrypsin that are unable to cleave
these tight bonds. These immunogenic peptides residues reach the small intestine, pass through the
epithelial barrier by the paracellular routes and initiate the immunogenic cascade in the lamina propria
in conjunction with the endogenous enzyme tissue transglutaminase (tTG2) [33]. The deamidation of
gluten peptides by tTG2 enzyme results in increased CD-immunoreactivity compared to unmodified
gluten peptides. Deamidation generates gluten peptides with negatively charged amino acid residues
that have a higher affinity to bind to HLA-DQ2/8 heterodimers on antigen-presenting cells, which
leads to increased CD4+ T-cell proliferation [34]. T lymphocytes interact with B lymphocytes that
differentiate into plasma cells and produce antibodies against gluten, deamidated gluten peptides and
autoantibodies against tTG2 and endomysium (adaptive immune response) [35, 36]. Over 1000 CD-
active (CD-toxic and CD-immunogenic) derived peptides from gluten proteins of wheat, rye, barley,
and oats have been identified so far [33]. Gluten peptides need to survive human gastrointestinal
digestion and reach the lamina propria with a length of ≥9 amino acid residues to fit into the binding
pocket of HLA-DQ2/8. Consequently, any enzyme capable of degrading gluten proteins into smaller
peptides of 9 amino acid residues would effectively abolish CD-immunoreactivity [36]. The endpoint,
the celiac lesion is characterized by villous atrophy, crypt hyperplasia, and infiltration of
inflammatory cells, both in the small intestinal epithelium and in the lamina propria.

Management tools

The essential treatment for gluten related disorders, specifically CD, is a strict lifelong gluten-free
diet based on the avoidance of gluten-containing products from wheat, rye, barley and, in rare cases,
oats. The exclusion of these products from diet of patients has some consequences. Products made
from naturally gluten-free raw materials often have inferior nutritional, textural and sensory

174
properties compared to the corresponding gluten-containing products. Therefore, the incorporation of
wheat, rye and barley flours after efficient removal of the harmful component gluten into gluten-free
products would be beneficial [37]. A gluten-free diet is an indicated for people suffering from
dermatitis herpetiformis, gluten ataxia and NCGS, although a gluten-reduced diet may be sufficient
in case of NCGS. Wheat allergic patients have to avoid wheat, but not necessarily the other gluten-
containing cereals such as rye or barley. Prior published studies have concluded that maintenance of
gluten free diet results of improvement of the majority of nutritional deficiencies [38]. Monitoring of
the nutritional status using blood tests and the use of appropriate gluten-free supplementation are the
integral components in the management of gluten related disorders. The ideal gluten free diet should
be nutrient-dense, with naturally gluten-free foods, balanced with micro and macronutrients
reasonably priced and easily accessible. Rotation of the pseudo-cereals provides a good source of
complex carbohydrates, protein, fiber, fatty acids vitamins and minerals. Dietitians specializing in
gluten related disorders play a key a critical role in the management, education and maintenance of
gluten-free diet of patients [37]. The design of novel non-dietary therapies to treat CD, WA and NCGS
is currently emerging and drug-discovery efforts are continuously made and show promising results
in clinical trials.
Celiac disease diagnosis is often delayed in asymptomatic patients or in individuals with mild
gastrointestinal symptoms, such as abdominal pain, nausea or dyspepsia. Screening for CD in patients
suffering from dyspeptic symptoms, as defined by Rome Ⅲ criteria, and routinely performing of
biopsies during upper GI endoscopy, may be useful as part of the diagnostic flow-chart of these
patients, considering the benefits of a promptly beginning of a gluten-free diet, even though further,
well-defined and case-control studies on a larger population could definitively assess if CD
prevalence is higher in dyspeptic patients [39].

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18. Lima, V.M., Gandolfi, L., Pires, J.A., Pratesi, R. (2005). Prevalence of celiac disease in dyspeptic patients. Arq
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19. Bardella, M.T., Minoli, G., Ravizza, D., Radaelli, F., Velio, P., Quatrini, M., Bianchi, P.A., Conte, D. (2000).
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Anorexia Nervosa at a Young Male Patient-Clinical and Therapeutic
Approaches. Clinical Case Presentation

BOLOȘ Alexandra1, ȘTEFĂNESCU Gabriela2, BARZU Adela³,

SZALONTAY Andreea Silvana1
1 Gr. T .Popa University of Medicine and Pharmacy Iasi, Romania, Socola Institute of Psychiatry Iasi, (ROMANIA)
2 Gr. T. Popa University of Medicine and Pharmacy Iasi, Romania, Institute of Gastroenterology Iasi, (ROMANIA)
3 Socola Institute of Psychiatry Iasi, (ROMANIA)

Emails: alex_andra_bolos@yahoo.com, correspondence author gabriela.stefanescu@gmail.com, barzu.adela@yahoo.com,

andrszal@yahoo.com

Abstract

Eating disorders are not, as can be think at first glance, a different way of life or just a diet food
that has gone too far, but it is a serious psychiatric disorder that threating patients’ lives. They have
important behavioural and emotional consequences and caused severe distortion of thoughts. Their
impact is not only physical, but also on mental health, and is associated with other medical conditions
or psychiatric disorders such as depression, anxiety, substance abuse and personality disorders.
In this paper, we present a patient, male, aged 34 years old, who came to hospitalization in
February 2016, at the Institute of Psychiatry Socola Iasi, accompanied by his mother, for symptoms
that had the onset about five years ago, with a fluctuated evolution and that was initially assisted at
the Clinic of Diabetes and Metabolic Diseases. The patient was diagnosed with a severe denutrition
and D hypovitaminosis. At the first psychiatric evaluation of the patient, the body mass index was
13,32kg/m², consequence of long periods of dietary restriction, refusal of some food categories.
It was established the diagnosis of “Anorexia nervosa”, with depressive symptoms, moderate
severity. We initiated an antidepressant treatment with Mirtazapine and after about a month of
hospitalization, the weight gain was around one kilogram. The assessment and the therapeutic
management of the patient was complex, requiring a multidisciplinary team involving neurologist,
gastroenterologist, internist, along with the psychiatrist and psychologist.
Keywords: anorexia, multidisciplinary, treatment

Introduction

In a society prone to weight gain, education regarding correct nutrition is absolutely necessary.
The way media and society in general transmit such information on normal nutrition is highly
important because persons who fail to meet the beauty standards are those at highest risk of
developing eating disorders.
Taking into account the complexity of these disorders, the implication of a multidisciplinary team,
which has to comprise psychiatrists, gastroenterologists, as well as psychologists and nutritionists, is
a veritable need. The multidisciplinary approach becomes a solution if we consider the socio-cultural,
medical, psychiatric, and psychological implications. Hence, it is obvious that these specialists within
various fields must work together to help patients obtain a favourable evolution. It is important to
highlight that the mere treating of the eating disorder does not suffice, because among these patients’
comorbidities are frequent and severe.
The Diagnostic and Statistical Manual of Mental Disorders (DSM-V) defines clear criteria for
anorexia nervosa, bulimia nervosa, and compulsive eating disorder. Additionally, compared to DSM
IV, the new edition also includes in the classification clinical criteria for pica, rumination,

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avoidant/restrictive food intake disorder, as well as preliminary diagnostic criteria for other eating
disorder, under the generic title of “Other Specified Feeding or Eating Disorders”. [1]
According to DSM-V, the diagnostic of anorexia nervosa is determined when three cardinal
criteria are met:
- Criterion A - Restriction of energy intake relative to requirements, leading to a significantly
low body weight in the context of age, sex, developmental trajectory, and physical health of
the person. Significantly low weight is defined as a weight that is less than minimally normal
or, for children and adolescents, less than that minimally expected. Comparatively, DSM IV
defines food restriction as a refusal to maintain a minimally normal body weight or over a
minimally normal level for age and height (e.g. weight loss leading to weighing less than
85% of normal weight; or failure to make expected weight gain during the period of growth,
which leads to weighing less than 85% of normal weight).
- Criterion B - Intense fear of gaining weight or of becoming fat or persistent behaviour that
interferes with weight gain.
- Criterion C - Disturbance in the way in which one’s body weight or shape is experienced.
- Additionally, DSM IV adds a criterion D of diagnostic – amenorrhea. [1], [2]
Eating disorders are associated with a great number of comorbidities. In case of anorexia nervosa,
medical complications are caused by starvation.[3] It is important to highlight that eating disorders
may affect any organ and system, and they may include gastrointestinal problems (abdominal pain,
constipation/diarrhoea, gastroparesis, gastric dilatation/perforation, gastro-oesophageal reflux
disease, pyrosis, oesophageal perforations, Mallory-Weiss syndrome), conditions of the endocrine
system (abnormal thyroid function, amenorrhea), musculoskeletal problems (osteopenia,
osteoporosis), dermatological alterations (hair loss, dry skin, lanugo hair), dental issues (tooth enamel
erosion), haematological problems (leukopenia), and even cardiovascular problems, because
restrictive food intake is often associated with bradycardia, hypotension, while electrolytic
imbalances may cause cardiac arrhythmias [4].
Concerning psychiatric comorbidities, over half of the individuals suffering from anorexia nervosa
meet the criteria for one or several more mental disorders [5]. Anxiety disorders count among the
most frequent ones, such as obsessive–compulsive disorder and social phobia [6], but behavioural
disturbances and substance abuse are also a common place in such a situation. In addition, another
aspect to mention is that these patients have the highest mortality rate among those with mental
disorders, as well the highest suicide risk [7].

Case presentation

The patient has come for the first time to the Socola Institute of Psychiatry Iași, accompanied by
his mother, for a symptomatology that begun five years prior, with a chronic and long-term evolution.
These symptoms include restricted food intake, important weight loss, lack of vital drive, of energy
to accomplish various tasks, negative future projection, feelings of helplessness and mixed sleep
disturbances.
The patient does not have a psychiatric history, and he was previously assisted at the Clinic for
Diabetes, Nutrition and Metabolic Disorders, where a specific pathology was ruled out. The patient
was diagnosed with severe malnutrition vitamin D deficiency and he was recommended a
hypercaloric, normoglucidic, normoproteic, normosodic diet comprising 3,000kcal/day, 375g
carbohydrates/day, 100g proteins/day, 125g lipids/day, three main courses and two snacks, hydration
with at least 2-2.5l fluids/day, as well as sustained physical activity.
Clinic examination reveals influenced general status; the patient is little cooperative with all
medical staff members; his weight upon admission is 46kg at a height of 187cm; the body mass index
is 13.32kg/mp, and his waist measures 61cm. Furthermore, at the initial evaluation, blood pressure is
90/60 mmHg and the pulse 75b/min. As for his muscle system, the assessment concludes hypotonia,
hypokinesia and difficulty walking.

178
 The psychosocial evaluation highlights that the patient has lived with his mother and grandmother
for over five years and that he is unemployed; he denies consumption of alcohol, coffee, or other
psychoactive substances.
Paraclinical investigations show mild anaemia: erythrocytes=3.96 mil; Hb=12.8g/dl, Ht=38.3g%.,
positive anti Helicobacter pylori antibodies, vitamin D below 3mg/dl, normal hormonal assessment,
without altered metabolism of the lipids, proteins, and carbohydrates. He does not suffer from
malabsorption syndrome; he has normal Anti-tissue transglutaminase antibody, normal Anti-gliadin
antibodies, which rules out celiac disease. Cranio-cerebral native scan is normal. Abdominal
ultrasound points out the following: normal-size liver; regular reflectivity; postprandial contracted
gallbladder; non-dilated main and hepatic bile ducts; normally looking pancreas spleen, and kidney;
symmetric, homogenous prostate measuring 42/23/40mm; urinary bladder with normal contour.
Electrocardiography pathway shows sinus rhythm, intermediary electrical axis, minor bundle
branch block; for the rest, normal morphology.

Psychological examination
The psychological examination comprised the following psychodiagnosis instruments: semi-
structured interview for diagnostics on AXIS I, according to the criteria provided by DSM IV (SCID
II), structured interview, personality tests, evaluations scales for symptoms through self-assessment
questionnaires, and patient’s evaluation by the interviewer.
Interview questions and psychological tests targeted information regarding personality features
such as perfectionism, obsessiveness, nervousness, compulsive behaviours, behaviours regarding
nutrition, and concerns related to his physical appearance. Furthermore, special attention has been
paid to suicide risk. At the Hamilton Depression Rating Scale, the patient obtained a score of 22
points, accounting for an average level of depression. At Friedman’s Emotional Maturity Test, the
patient obtained a score of 15 points, accounting for emotional immaturity.
The SCL-90 R scale for psychiatric symptoms provided the following values:
Psychosomatization=18p;
Depression=26 p; Anxiety=24p; Obsessive-compulsive=21p; Phobic anxiety=19 p.
The FREIBURG personality inventory (12 personality factors), dominant personality factors
showed the following:
- Nervousness FP1-22 points – stanine 9, very high level;
- Emotional immaturity FP2-22 points – stanine 8, indicative of a high level of emotional
immaturity;
- Depression, low self-confidence, feelings of dissatisfaction, punitive tendencies FP4 -24 p,
stanine 9, very high level of depressive tendencies, of low self-confidence, of insufficiency
feelings;
- Excitability, low tolerance to frustrations FP4 -22 points, stanine 8, high level of emotionality;
- Sociability, relating skills FP5- 7 points, stanine 3, low level of sociability, relating
difficulties;
- Irritability, susceptibility, pessimism FP6 -5p, stanine 3, indicating a high level of irritability
and susceptibility;
- Inhibitedness FP8 -10 points, stanine 8, which suggests psycho-behavioural inhibitions,
decision-making difficulties, social anxiety;
- Extraversion – introversion FP10- 8 points, stanine 3, which suggests introversion;
- Emotional lability FP11-22 points, stanine 9, which suggests a high level of emotional lability;
- Masculinity/femininity FP12-10 points, stanine 3, which suggests a low level of masculinity,
psychomatization tendencies, reserved attitudes, inhibitions.
THE ANOREXIA NERVOSA SELF-ASSESSMENT SCALE (Garner and Garfield) for the
assessment of anorexia nervosa symptoms indicated a score of 69 points, underscoring a food
behaviour disorder. Out of the 40 items assessed on a 6-point LIKERT scale, 20 items scored 3 points,
while 8 items scored 2 points; hence, 28 items received scores showing high severity.
179
 THE EATING DISORDER INVENTORY (Garner) was used in order to evaluate the
psychopathological manifestations associated to eating disorders. It comprises 11 dimensions
evaluated on a 6-point LIKERT scale. Results indicated as follows:
- Drive for thinness: 20 p
- Body dissatisfaction: 15 p
- Negative self-evaluation: 40 p
- Interpersonal distrust: 20 p
- Interoceptive awareness: 21 p
- Maturity fears: 20 p
- Ascetism: 16 p
- Impulse regulation: 24 p
- Social insecurity: 22 p
The high scores obtained in the Eating Disorder Inventory were the elements used in the
psychological intervention within cognitive behavioural psychotherapy sessions, as well as in the
evaluation of its evolution after initiating medication.
Psychodiagnostic: Depressive configuration with obsessive-interpretive manifestations, in an
unstable – emotional context. Psychopathologically loaded personality with major adaptive-
integrative risk (eating disorders).
During the psychiatric interview, the patient is partially cooperative; he displays psychomotor
calmness; he is relatively communicative; he sets and inconstantly maintains eye contact with the
examiner. The voice has average intensity, high tonality, and affective modulation. He is properly
dressed; he looks neat and he takes care of his hygiene. The patient displays negative hyperthymic
mood, anhedonia, hypobulia, minimal involvement in daily activities, social isolation, decreased
personal efficiency and vital drive. From the perspective of sleep disturbances, we note mixed
insomnias with fragmented, non-relaxing, superficial sleep. Thought is coherent, flow of ideas
slightly slower, diminished verbal rhythm, demobilizing speech, negative perspective on the future.
He also displays attention deficit issues. Concerning eating instinct, we mention decreased
appetite, presence of routines, and refusal to eat certain types of foods, especially meat.

Diagnostic and treatment

The positive diagnostic is Anorexia nervosa – Restricting type. During the last three months,
the individual has not engaged in recurrent episodes of binge eating or purging behaviour (i.e., self-
induced vomiting or the misuse of laxatives, diuretics, or enemas), considering the diagnostic criteria
of DSM IV.
The medication comprises Mirtazapine 30mg/day, administered in the evening, vitamin
therapy, hydroelectrolytic rebalancing. Throughout hospitalization, the patient’s evolution was
slightly favourable; he had difficulties relating to the other patients and to the medical staff and he
barely accepted to take the medication. Initially, the patient vehemently denied any kind of food
intake; he maintained this strong refusal concerning meat until the end of the hospital days.
He eventually accepted to eat only puréed food, such as mashed potatoes or puréed vegetables.
Throughout hospitalization, the patient gained two pounds. We made great efforts to
administer Mirtazapine, by gradually increasing the dose up to a dose of 30mg/day. Subsequently,
medication was doubled by cognitive behavioural psychotherapy. Its objectives were the following:
- Getting the patient committed to therapy and to the need to change, and maintaining this
engagement in the future;
- Increasing awareness concerning his eating disorder:
* by creating a personalized phrasing regarding the processes that maintain the eating
condition;
* by getting him committed to self-monitoring relevant psychopathology in real time;
* by providing relevant personalized psychoeducation to the patient.
- Reducing weight-related concerns;
180
 - Introducing and settling a regular food intake pattern.

Furthermore, the patient is explained that normal food intake does not mean counting the calories,
weighing the food, or following a strict diet, easting low-caloric foods, such as diet biscuits instead
of bread. He is also explained that it is not healthy to consider that he can control better than his own
body what amount or type of foods it requires, or to weigh himself frequently in order to control
weight and food intake. He is told that a normal diet does not mean suing various tricks to restrict
food intake, such as “Diary makes me throw up,” “I am a vegetarian, for my own health.” Finally, he
is told it is not normal to divide foods into “GOOD” or “BAD.”
In this situation, we have focused on motivation, on weight gain, and on the fact that cognitive
intervention starts earlier, accompanying behavioural modifications, in order to change the rigid
attitudes and beliefs that prevent the implementation of food behaviour modifications (of food
restriction).
Finally, the relapse prevention plan concerned the risk situations and the warning signals, by using
techniques and exercises throughout therapy, such as a food- and thought-monitoring diary and a
healthy eating plan. Furthermore, we must highlight the factors leading to the eating disorder of
anorexia nervosa and to its maintenance, which really helps therapy. As future plans, we point out
the over-evaluation of form and weight, food intake, compulsive eating, etc.

Conclusions

As a conclusion, this case supports the need of a multidisciplinary treatment team, which optimally
includes a psychiatrist, a nutritionist, a gastroenterologist, and a psychotherapist. Each of them has
their own responsibilities in the patient’s care. The priority was represented by medical care per se,
in order to restore a bodyweight that enables the patient’s survival, which was only subsequently
accompanied by psychotherapeutic intervention.

REFERENCES

1. American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition:
DSM-5.
2. American Psychiatric Association. (2000). Diagnostic and Statistical Manual of Mental Disorders, Fourth
Edition: DSM-4 TR.
3. Mitchell, J.E., Crow, S. (2006). Medical complications of anorexia nervosa and bulimia nervosa. Curr Opin
Psychiatry.Jul;19(4):438-43.
4. Pomeroy, C., Mitchell, J.E. (2002). Medical complications of anorexia nervosa and bulimia nervosa. In: Brownell
KD, Fairburn CG, editors. Eating Disorders and Obesity: A Comprehensive Handbook. The Guilford Press; New
York, pp. 278–285.
5. Hudson, J.I., Hiripi, E., Pope, H.G., Kessler, R.C. (2007). The Prevalence and Correlates of Eating Disorders in
the National Comorbidity Survey Replication. Biological psychiatry;61(3):348-358.
6. Kaye, W.H., Bulik, C.M., Thornton, L., Barbarich, N., Masters, K. (2004). Comorbidity of anxiety disorders with
anorexia and bulimia nervosa. Am J Psychiatry. Dec;161(12):2215-21.
7. Franko, D.L., Keel, P.K. (2006). Suicidality in eating disorders: occurrence, correlates, and clinical implications.
Clin Psychol Rev. Oct;26(6):769-82. Epub 2006 Jul 27.

181
Gastrointestinal Symptoms and Alcohol Withdrawal Syndrome

BONEA Maria1, MICLUȚIA Ioana2

1Psychiatry Resident, PhD student, Children's Emergency Hospital, Cluj Napoca (ROMANIA)
2Professor Doctor, Head of Psychiatry Department, University of Medicine and Pharmacy “Iuliu Hațieganu” Cluj-Napoca
(ROMANIA)
Email: Bonea.Maria@umfcluj.ro

Abstract

Introduction
Alcohol use disorder, because of its prevalence, is one of the most important public health
problems. Frequently, on the medical departments, the discovery of these patients is related to trauma,
gastrointestinal and liver disease. Nausea and vomiting are often present in alcohol withdrawal treated
on psychiatric wards. In addition, chronic ethanol use influences intestinal motility and structure, with
the possibility of diarrheic syndrome.

Objective
Evaluation of digestive symptoms through a retrospective observational study in patients admitted
with a diagnosis of alcohol withdrawal.

Methods
We reviewed the medical charts of patients with a diagnosis of alcohol withdrawal, hospitalized
in January and February 2017 in the First and Second Psychiatric Clinic of the Emergency County
Hospital Cluj-Napoca. We recorded the demographics, the type of withdrawal, the presence of
digestive symptoms like nausea, vomiting and diarrhea.

Results
Of the 53 patients hospitalized with this diagnosis, 89% male and 11% female, with a mean age of
47.7 years, 69% with uncomplicated withdrawal, 15% withdrawal with convulsions and 25%
withdrawal with delirium. 70% had nausea, 25% vomiting, one patient suffered a diarrheal episode.

Conclusion
Mild digestive symptoms are common in patients treated on the psychiatric ward for alcohol
withdrawal. The more severe gastrointestinal pathology is the prerogative of the Gastroenterology
department.
Keywords: Alcohol withdrawal, diarrhea, gastrointestinal

Introduction

Alcohol use disorders generate a great burden of disease (globally, around 4%), especially in the
developed countries, where up to 80% of males and 60% of females drink at least once during the
course of their lives. [1] The 10th edition International Classification of Diseases (ICD-10) requires
the presence of at least three criteria to establish the diagnosis of alcohol dependence. The patients
must demonstrate a strong desire, even a compulsion to drink, they become unable to stop or at least
control the consumed quantities, neglecting other interests or pleasures. In time, they develop
tolerance, so they gradually increase the intake, in spite of the harmful psychiatric (such as depressive

182
mood states, cognitive impairment) and physical consequences (frequently, liver disease) and develop
a withdrawal state when the ethanol is reduced or ceased. [2]
The withdrawal syndrome is a very specific proof of dependence. Within several hours to a few
days after the alcohol consumption was stopped, the patient develops autonomic hyperactivity, such
as sweating and tachycardia, increased tremor of the extremities, insomnia, transient visual, tactile,
auditory hallucinations or illusions, psychomotor agitation, anxiety, nausea or vomiting. Alcohol
withdrawal can be complicated with grand mal seizures or delirium, in severely dependent, long time
users. Delirium tremens is a life-threatening condition, presenting with marked tremor, oneiroid state,
confusion, vivid hallucinations, fear, delusions, sleep-cycle reversal and excessive neurovegetative
activation. [3]
Alcohol can affect every level of the digestive tract. It favours the development of esophageal
varicosities secondary to liver cirrhosis, and may cause Mallory-Weiss syndrome (tearing due to
vomiting). It delays gastric emptying, stimulates acid regurgitation and diminishes the pressure of the
lower esophageal sphincter, leading to gastroesophageal reflux. [4] Studies show that the higher the
number of drinks in consumption period, the greater the risk of developing esophagitis. [5] Wine was
the only one, which used in moderation, had a protective effect on the esophageal mucosa. It was
inversely related to reflux esophagitis and thus with its complications, Barrett’s esophagus and
adenocarcinoma, probably due to the antioxidant effect of resveratrol and polyphenols. [5, 6] Several
studies, conducted on mice, suggested that not only the motility is low, but even the response to
carbachol and other parasympathetic substances is significantly decreased after chronic ethanol
intake. [7] Alcohol stimulates gastric acid secretion, especially in the case of beverages with lower
ethanol concentrations (less than 5%). The higher the concentration, the greater inhibition or damage
of the parietal and G cells, thus the less influence on acidity, but. [4] Regarding the gastric emptying,
studies show that alcoholic beverages lag this process, regardless of their concentrations. [8]
Also, alcohol disrupts small bowel motility, causing malabsorbtion and diarrhea. Alcoholics
frequently present with malnutrition, protein, minerals, group B vitamin deficits and a higher risk of
gastrointestinal tumors. [4] Occasional drinking causes constipation, as opposed to chronic use which
leads to increased intestinal motility. [9]

Methodology

The aim of the study was the evaluation of digestive symptoms through a retrospective
observational study in patients admitted with a diagnosis of alcohol withdrawal. We reviewed the
medical charts of patients with a diagnosis of alcohol withdrawal, hospitalized in January and
February 2017 in the First and Second Psychiatric Clinic of the Emergency County Hospital in Cluj-
Napoca. We recorded the demographics, the type of withdrawal, the presence of digestive symptoms
like nausea, vomiting and diarrhea.

Results

Of the 53 patients hospitalized with this diagnosis, 47 males (89%) and 6 females (11%), with a
mean age of 47.7 years, 69% had with uncomplicated withdrawal, 15% withdrawal with convulsions
and 25% withdrawal with delirium. 70% presented nausea, 25% vomiting, one patient suffered a
diarrheal episode. (Table 1)

Table 1. Distribution of gastrointestinal symptoms

Withdrawal type Nausea Vomiting Diarrhea

Male Female Male Female Male Female

Uncomplicated 24 1 9 1 0 0

183
 Convulsions 5 2 1 0 0 0

Delirium 5 1 3 0 1 0

As expected, nausea and vomiting were common symptoms of alcohol withdrawal. With only one
case of diarrheic syndrome we can assume that this kind of gastrointestinal motility disorder is not
typical for alcoholics in withdrawal. On the other hand, psychiatric treatment, such as typical
neuroleptic agents (Tiapride, Levomepropazine, Haloperidol) frequently used as adjunct therapy, that
slow the intestinal transit and have an additional antiemetic effect, could prevent such digestive
symptoms.

Conclusions

Since the chronic use of large amounts of alcohol leads to the acceleration of gastrointestinal
motility, there is no surprise that mild digestive symptoms, such as nausea and vomiting are common
in patients treated on the psychiatric ward for alcohol withdrawal. Diarrheic syndrome is less
frequent, but may complicate the somatic status, leading to hydroelectrolytic imbalance. The more
severe gastrointestinal pathology is the prerogative of the Gastroenterology department

REFERENCES

1. Schuckit MA. Alcohol-use disorders. The Lancet.373(9662):492-501.

2. Hoffmann NG, Kopak AM. How Well Do the DSM-5 Alcohol Use Disorder Designations Map to the ICD-10
Disorders? Alcoholism: Clinical and Experimental Research. 2015;39(4):697-701.
3. Sadock, B.J, Alcott Sadock, V., Ruiz, P. (2009). Kaplan and Sadockʼs Comprehensive Textbook of Psychiatry,
9th Edition. Lippincott Williams & Wilkins, pp. 1278.
4. Bujanda L. The effects of alcohol consumption upon the gastrointestinal tract. The American journal of
gastroenterology. 2000;95(12):3374-82.
5. Anderson LA, Cantwell MM, Watson RG, Johnston BT, Murphy SJ, Ferguson HR, et al. The association between
alcohol and reflux esophagitis, Barrettʼs esophagus, and esophageal adenocarcinoma. Gastroenterology.
2009;136(3):799-805.
6. El-Serag HB, Lagergren J. Alcohol drinking and the risk of Barrettʼs esophagus and esophageal adenocarcinoma.
Gastroenterology. 2009;136(4):1155-7.
7. Yazir Y, Tugay M, Utkan Z, Utkan T. Effects of chronic ethanol consumption on rat upper gastrointestinal system:
functional and histologic findings. Alcohol (Fayetteville, NY). 2012;46(7):649-55.
8. Franke A, Nakchbandi IA, Schneider A, Harder H, Singer MV. The effect of ethanol and alcoholic beverages on
gastric emptying of solid meals in humans. Alcohol and alcoholism (Oxford, Oxfordshire). 2005;40(3):187-93.
9. Grad S, Abenavoli L, Dumitrascu DL. The Effect of Alcohol on Gastrointestinal Motility. Reviews on recent
clinical trials. 2016;11(3):191-5.

184
Significance of C-Reactive Protein and Lysozyme in Crohn’s Disease
and Ulcerative Colitis Treated with Infliximab and Adalimumab

IONESCU Andra Consuela1, GAMAN Laura2, VASILESCU Alina3,

ATANASIU Valeriu4, STOIAN Irina5, IONESCU Lucian6, DICULESCU Mircea7
1 Fundeni Clinical Institute (BUCHAREST)
2 “Carol Davila” University of Medicine and Pharmacy (BUCHAREST)
3 International Centre of Biodynamics (BUCHAREST)
4 “Carol Davila” University of Medicine and Pharmacy (BUCHAREST)
5 “Carol Davila” University of Medicine and Pharmacy (BUCHAREST)
6 “Grigore Alexandrescu” Children Emergency Hospital (BUCHAREST)
7 Fundeni Clinical Institute (BUCHAREST)

Emails: andraionescu20@yahoo.com, glauraelena@yahoo.com, amvasilescu@yahoo.com, atanasis2003@yahoo.com,

irina_stoian64@yahoo.com, uce.lucian@gmail.com, mmdiculescu@yahoo.com

Abstract

Inflammatory bowel diseases (IBD), namely Crohn’s Disease and Ulcerative Colitis, are intestinal
disorders that cause chronic inflammation of the digestive tract. The pathogenesis of the diseases is
determined by environmental and disturbed immunological response on genetically predisposed
persons. IBD causes physical and psychosocial consequences that can decrease the quality of life.
Laboratory tests are of value in the management of IBD, such as C-Reactive Protein (CRP) and
serum lysozyme. CRP levels serve as a marker for detecting IBD, differentiating it from functional
bowel disorders, setting the disease severity and risk, and monitoring treatment’s effectiveness.
Lysozyme is a biomarker that can be used for additional screening in the diagnosis, prognosis, and
management of IBD.
Keywords: C- reactive protein, Lysozyme, inflammatory bowel disease

Introduction

Inflammatory bowel diseases (IBD), Crohn’s Disease (CD) and Ulcerative Colitis (UC), are
chronic disorders that affect the digestive tract, with unknown ethiology.
They are caused by a combination of environmental, immune and bacterial factors in genetically
susceptible individuals [1]. The annual incidence for CD is 12.7/100.000 person-years in Europe,
5.0/100.000 person-years in Asia and the Middle East, and 20.2/100.000 person-years in North
America. The annual incidence of UC was 24.3/100.000 person-years in Europe, 6.3/100.000 person-
years in Asia and the Middle East, and 19.2/100.000 person-years in North America [2]
Crohn Disease occur anywhere in the digestive tract and has chronic transmural inflammation, in
contrast to the Ulcerative Colitis, that affects only the colon’s mucosa, and has continuous lesions.
Both diseases evolve with periods of remissions and exacerbations.
They are life-long conditions that affect young people with ages between 15 and 25 years [1].
The predominant symptoms of IBD are diarrhoea, abdominal pain, gastrointestinal bleeding,
weight loss, malnutrition and fatigue. These symptoms can have substantial psychosocial
implications and cause sufferers to limit their lifestyles, with consequent impact on quality of life [3].
Laboratory markers have been investigated in IBD for diagnostic and differential diagnostic
purposes, for determining disease severity and risk of complications, to help predict disease relapse,
and for monitoring the effect of treatment [4].
C- Reactive Protein (CRP) is the most studied marker, and performs a major role in IBD.

185
 CRP is a pentameric protein consisting of five monomers and an acute-phase protein of hepatic
origin that increases following interleukin-6 secretion by macrophages and T cells [5]. Has a short
half life, 19 hours and will rise early after the onset of inflammation and rapidly decrease after
resolution of the inflammation.
Several studies had shown that CRP is very effective in detecting IBD and differentiate it from
other intestinal disorders, in monitoring disease activity and predict the disease course [3].
Another studied marker, lysozyme, also known as muramidase or N-acetylmuramide
glycanhydrolase, is a glycoside hydrolase which catalyze the hydrolysis of 1,4-beta-linkages between
N-acetylmuramic acid and N-acetyl-D-glucosamine residues in peptidoglycans – the major
component of gram-positive bacterial cell wall, then the hydrolysis destroy the integrity of bacterial
cell walls causing lysis of the bacteria [6].
Lysozyme is a biomarker that can be used for additional screening in the diagnosis, prognosis, and
management of IBD [7].
Several studies had shown that the concentrations of serum lysozyme were higher in patients with
Crohn’s disease and ulcerative colitis compared with normal controls, and levels tend to be slightly
higher in those with Crohn's disease than in those with ulcerative colitis [8].

Materials and methods

Measurements were made of serum CRP and lysozyme in fifteen patients with IBD treated with
Adalimumab and Infliximab.
Determination of lysozyme in human serum was done by a turbidimetric method based on the lytic
activity of lysozyme on Micrococcus lysodeikticus cells [9]. To determine the enzymatic activity of
lysozyme, 490 µL of a suspension of 1mg/mL Micrococcus lysodeikticus in 50 mM phosphate buffer
pH 7 were mixed with 10 µL of human lysozyme standard or human serum samples and the decrease
of absorbance at 450 nm was measured.
The decrease in absorbance at 450 nm due to the lysis of cellular walls is correlated with the
concentration of lysozyme in the sample. One unit of enzymatic activity is defined as the amount of
lysozyme required to produce a decrease in absorbance at 450 nm of 0.001 AU/min.
The amount of lysozyme in serum was determined by interpolation on a calibration curve obtained
with standard solutions of human lysozyme with concentrations in the range 1-10 µg/mL.

Results

8 patients had CD (75% males, 25% females - Table 1), 37,5% with ileocolonic CD, 50% with
ileal and 12,5% colonic damage Fig.1. 75% were treated with Adalimumab, 25% with Infliximab.
CRP was elevated in 50% of patients, lysozyme levels elevated in 75% Table 2. 87,5% of them
were in remision and 12,5% had mild disease.
From all patients, 12,5% had high levels of CRP and lysozyme and mild disease, and 25% with
both markers elevated were in disease remision Fig. 2.
In the UC group were included 7 patients (57,14% males, 42,86% females), 85,71% were treated
with Infliximab and 14,29% with Adalimumab.
In disease remision were 71,43%, with moderate disease were 14,29% and with severe were
14,29%.
High levels of CRP were found in 42,86%, lysozyme was elevated in 85,71% Table 2. Both levels
of CRP and lysozyme were elevated in 28,57% of patients with remision, 14,29% had moderate
disease and both markers elevated Fig. 2.
The results are summarised in the tables below. [Table 3, 4]

186
 Table 1. CD and UC sex distribution
CD 8 patients UC 7 patients

Male 75% 57,14%

Female 25% 42,86%

Fig. 1. CD phenotype

Table 2. CRP and Lysozyme levels in CD and UC

CRP Lysozyme

CD 50% 75%

UC 42,86% 85,71%

Fig. 2. High levels of PCR and Lysozyme

MILD DISEASE

CD

UC

0 7,5 15 22,5 30

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 Table 3. PCR and Lysozyme in CD
Disease localisation PCR mg/l Lysozyme Treatment

Ileocolonic 1,86 6,5 Adalimumab

Ileal 12,3 4,12 Infliximab

Ileal 4,04 5,45 Adalimumab

Ileocolonic 4,13 2,69 Adalimumab

Ileal 6,2 5,35 Adalimumab

Colonic 2,7 3,43 Adalimumab

Ileocolonic 0,91 5,37 Infliximab

Ileal 1,91 2,8 Adalimumab

Table 4. PCR and Lysozyme in UC

Disease severity PCR mg/l Lysozyme Treatment

Moderate 7,91 4,17 Adalimumab

Remision 86,8 7,31 Infliximab

Remision 1,92 4,21 Infliximab

Remision 0,77 2,57 Infliximab

Severe 0,51 5,18 Infliximab

Remision 1,06 3,03 Infliximab

Remision 4,15 5,29 Infliximab

Conclusion

Laboratory markers are useful and should be part of the management of IBD patients.
CRP and lysozyme markers should be used as a tool to clinical observation and disease activity
monitoring.

REFERENCES
1. Bing, X., Crusius JBA, Meuwissen SGM, Pena AS. Inflammatory bowel disease: definition, epidemiology,
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Psychosomatic Disorders in Chronic Diffuse Liver Diseases

LUPASCO Iulianna1, BEREZOVSCAIA Elena1,2, DUMBRAVA Vlada-Tatiana1

1 Laboratory of Gastroenterology, State University of Medicine and Pharmacy “icolaeTestemitanu”, Chisinau, (REPUBLIC OF
MOLDOVA)
2 Laboratory of Neurosanocreatology, Institute of Physiology and Sanocreatology of the Academy of Sciences of Moldova, Chisinau,

(REPUBLIC OF MOLDOVA)
Email: elenaberezovskaia69@gmail.com

Abstract

The article is devoted to the life issues in patients with CDLD as one of the most acute problems
of national health systems, presenting in almost all countries of the world. Frequent association
between chronic liver disease and mental health problems was noted in many scientific researches.

The purpose of this study was to explore the theoretical backgrounds of PSD comorbidity in patients
with CDLD and systematization of existing data.

Methods
A review of the literature was carried out, using the PubMed, Google Scholar database (2000-
2016) 148 sourses.

Results
Analysis of published studies shows a high comorbidity of CDLD with a lot of emotional, asthenic
and behavioral disorders. Most of patients with CDLD had one or more PSD. Three-quarters of
studied articles was devoted to emotional disorders: the main attention was paid to depression and
anxiety in patients with CDLD. In addition, asthenic disorders, addictions and behavioral disorders,
as well as a decrease in the quality of life were studied in patients with liver diseases. The incidence
of Depression and Anxiety in patients with CDLD (17-85% and 13-41%, accordingly) was reported
to be much higher compared to general population, and the incidence of Fatigue in patients with
CDLD is between 7 and 87%. Exist two hypotheses explaining the increase data of PSD prevalence
in patients with CDLD: somatic, suggesting that this could be induced by some neurotoxic substances
as a result of pathologic modifications of synthesis and biotransformation mechanisms, that are going
on in the affected liver, and psychosocial, that explain the exogenous social factors of understanding
the disease per se, as well as stigmatization etc.

Conclusion
Comorbidity of PSD in CDLD is common. However, remains unclear the pathogenesis of such
high comorbidity. Missing data about typology and phenomenology of PSD specific for different type
CDLD. Further research is needed for the formation of an individual approach in management of
support and treatment in patients with CDLD and prevention of PSD.
Keyword: psychosomatic disorders, Chronic Diffuse Liver Diseases, comorbidity

Introduction

The relationship issue between the psychic and somatic spheres represent major, complex and at
the same time unsolved problem of contemporary medicine. Chronic Diffuse Liver Diseases (CDLD)

190
are associated with a wide spectrum of extrahepatic manifestations including Psychosomatic
Disorders (PSD), which occupy an important place in clinical diagnosing and correction approach.
The mental health changing appears in many medical disorders. Among the chronic pathology,
accompanied by pronounced psycho-emotional disorders an important place is occupied by liver
diseases. Mental Disorders in patient with Liver Diseases were firstly noted in the IV century B.C by
Hippocrates, the father of modern medicine, who described in his treatise “Epidemics” different types
of jaundice as an independent disease that occurred with the increase of bile under the skin, coming
out of the liver, accompanied in some cases with fever, as well as with mental disorders, bleeding
and/or death of patients [29]. In the ancient medical literature, liver had a leading role in the
maintenance of mental health, and terms such as “melancholy” and “hypochondria” that reached us
from the past era are a vivid confirmation of medical interest to psychologic status of patients [30].

Epidemiology
CDLD present one of the most important problems of modern hepatology. It was recorded a steady
increase of liver pathology incidence and continuous increasing frequency of chronic hepatitis caused
by viral B and C infection worldwide during the past half of the century, wich in recent decades has
taken shape of pandemia. According to WHO data, the virus of hepatitis B (HBV) infected almost
every third person in the world (approximately 2 billion of people), with evolution in chronic form of
infection in 240 million people. The chronic hepatitis C (caused by HCV virus) affected about 150
million, while chronic hepatitis D (HDV virus) – more than 10 million. As a result, every 12th person
on Earth lives with chronic viral hepatitis. The pathology of the liver is one of the main causes of
death in the world: because of acute infection flare and liver insufficiency or of the consequences of
chronic viral hepatitis (CVH), such as liver cirrhosis and cancer, being the reason of about 1.4 million
people death each year [5].
The Liver Pathology more than a quarter of a century occupies one of the leading places in terms
of incidence, severity, frequency of chronization, disability, and economic damage to Moldova.
According to the WHO data, Moldova in 2014 became a leader in prevalence of chronic hepatitis
in Europe. Mortality from liver cirrhosis in our country is one of the highest in the world, ranking
first in Europe. Liver cirrhosis (LC) present third cause of death in the adult population structure
mortality in Moldova after the cardiovascular system and oncology pathology [4; 14; 20]. Thus,
CDLD are one of the most serious and urgent medical and social problems of our time.
The article is devoted to problems of life in patients with CDLD as one of the most acute problems
of national health systems in almost all countries of the world. Frequent association between chronic
liver disease and mental health problems was noted in a lot of studies.
The purpose of this study was to explore the theoretical backgrounds of comorbidity of PSD in
patients with CDLD and systematization of existing data.

Methods

A review of the scientific literature was carried out, using the Medline (PubMed) and Google
Scholar website databases (from 2000, until February 2017) using relevant keywords: Chronic Liver
Disease, Chronic Hepatitis, Liver Cirrhosis, Mental Disorders, Depression, Anxiety, Fatigue,
Aggression, Dysphoria, Mental Health, Quality of Life.
The analysis included all published empirical studies (reviews were excluded), having a summary
in English and relevant topics.
A total of 148 articles were found for these keywords. The total number of selected according to
the criteria of the studies was 45, which represents a sufficient amount of data for generalization.

191
Results and Discussion

Analysis of published studies shows a high comorbidity of CDLD with a lot of emotional, asthenic
and behavioral disorders. The majority of patients with CDLD had one or more PSD.
Three-quarters of the articles (Fig. 1) included the study of emotional disorders in patients with
CDLD: the main attention was paid to depression and anxiety. In addition, asthenic disorders,
addictions and behavioral disorders, as well as a decrease in the quality of life were studied in patients
with liver diseases.
Emotional disorders
A lot of attention was paid to depression and anxiety in patients with CDLD. The published
literature and routine clinical practice inform us that depression and anxiety are characteristic
comorbid disorders in patients with CDLD.
The prevalence of depression is very variable (Fig. 1), according to different studies, the incidence
of depression in patients with CDLD was between 16.5 and 85.0% [1, 22], which varied in different
nosologies from 3,7 to 100% [10, 23].
The prevalence of anxiety was found in patients with CDLD in 13.4 to 40.5% (Fig. 2), being
different in liver diseases between 5 and 49% [1, 15, 18, 27].

Disorders of Mental
Health in patients with
CDLD

Emotional Asthenic Addictions Psychiatric

disorders disorders QoL
and behavioral diagnoses
[34 art.] [11 art.] [11 art.]
disorders [10 art.]
[12 art.]
Depression Fatique
[33 art.] [7 art.]

Anxiety Headache
[13 art.] and Dizziness
[3 art.]

Sleep
disorders [4
art.]

Fig. 1. Distribution of Mental Health Disorders in CDLD

According to some authors, the type of the virus (Fig. 2) influenced the prevalence and severity of
depression: persons infected with HCV significantly more often suffered from depression compared
to patients with chronic HBV infection [3, 21, 23].

192
 Depression
Alavian, 2007, Iran 16,5 36,7
Anxiety

Ozkan, 2006, Turkey 22,4 14,0

38,7 40,5
Zhang, 2016, China

62,9 13,4
Popović, 2015, Serbia

Romanciuc, 2012, Moldova 85,0

0,0 20,0 40,0 60,0 80,0 100,0

Fig. 2. The Prevalence of Depression and Anxiety in patients with
CDLD
However, studies conducted by S. Alian (2012) in patients with CDLD of viral etiology did not
reveal a significant difference between HCV and HBV infected [2].
It needs to be mentioned that such a high prevalence of emotional disorders is of great clinical
importance, because the depression as weel as anxiety may limit the tolerability of standart regimens
of treatment with low answering outcome and significantly reduce patints’ quality of life [3; 15; 16].
The relationship between CDLD and emotional disorders is complex and ambiguous.
On the one hand, patients with depression and anxiety may have a higher incidence of CDLD of
viral and alcool ethiology in particular in intravenous drug users and alcool dependent patients, many
of whom have lifetime anxiety and depression [5, 6, 8, 21, 25, 28].
80 72,6

58,6
60 HBV HCV
33,3
40 33,3 32,6

% 17,1
20
3,7
0

Fig. 3. The Prevalence of Depression (%) in patients with CDLD of HBV and HCV
etiology

On the other hand, depression may exist as a secondary phenomenon of CDLD. This may take the
form of a reactive depression related to the distress, followed the information about the diagnosis or
concerns and fear over reduction in working capacities, as well as possible long-term health issues
and/or invalidization; or may be secondary due to clinical course of the disease symptoms,
biochemical parameters changes caused by the affected liver [9, 12, 16; 24].
The correlation between depression and anxiety in CDLD has been known for a long time, as well
as the fact that patients with CDLD had a significantly higher incidence of depression compared to
healthy population. However, causes and pathogenesis of depression and of anxiety in patients with
CDLD is clarified insufficiently.

193
Asthenic disorders
Nearly half of the patients (47.8%) with chronic HCV hepatitis considered fatigue the worst or
initial symptom of their disease. The total fatigue score of these patients was significantly higher in
comparison to healthy volunteers. Fatigue in patients with HCV was significantly more pronounced
in women [17].
The prevalence of fatigue was very variable (Fig. 3), according to different studies, the incidence
of fatigue in patients with CDLD was between 7 and 87 % [11, 17, 19, 23, 26].

Weinstein AA, 2011, USA 5,8 1,1

HCV
Piche T., 2002, France 48,7 HBV

Poynard T, 2002, France 53,0

Zalai D., 2015, Hungary 60,9

Lang CA, 2006, Australia 85,6

0,0 20,0 40,0 60,0 80,0 100,0 %

Fig. 3. The Prevalence of Fatigue (%) in patients
with CDLD of HBV and HCV etiology

Other manifestations of asthenic disorders, such as dizziness, headache, sleep disturbances, were
considered in only a few articles. For example, C.A. Lang (2006) noted headache in 56% of patients
with Liver’s Pathology and diagnosed sleep disorders in 65% of patients with CDLD of HCV
etiology, and M. Liu (2017) in 23-34% of patients with different types of chronic hepatitis of HBV
etiology [11, 13].
Thus, asthenic disorders, in particular fatigue, are fairly common complaints of patients with
CDLD. Despite the major importance for the well-being and quality of life in patients with chronic
diffuse liver disease, only few studies have investigated this symptom. It remains unclear what causes
fatigue in patients with liver disease. One of the major obstacles in research is the extremely non-
specific nature of asthenic disorders. In addition, all experimental approaches have been hampered
by the absence of any serious objective tools to assess the subjective experience of both fatigue, in
particular, and asthenic disorders in general.
Conclusion

Comorbidity of emotional and asthenic disorders with CDLD is very common. The pathogenesis
of such high comorbidity, however, remains unclear. In the same time the PSD specificity of CDLD
comorbidity is insufficiently studied in different types of chronic diffuse liver diseases.
In addition, the systematization of approaches has been hampered by a variety of methodological
approaches in the diagnosis of depression and anxiety, as well as in the absence of any serious
objective tools to assess the subjective experience such as fatigue.
Further research is needed for the formation of a uniform methodological approach to diagnosis
and treatment of patients with CDLD and prevention of PSD.

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195
The Role of Fecal Calprotectin in Investigating Inflammatory Bowel
Diseases
MĂRGINEAN Cristina1, VLĂDAIA Mihai2, POPESCU Marian-Sorin2,
MILOTIN Nicoleta2, PETRESCU Florin1
1 UMF Craiova, Spitalul Clinic Județean de Urgenta, Clinica Medicală II
2 Spitalul Clinic Județean de Urgență Craiova, Clinica Medicală II

Abstract

Although recently there is growing data regarding inflammatory bowel disease progression,
diagnosis, and treatment options, we still are looking for easy, accurate, non-invasive and not
expensive methods to estimate disease activity and differentiate IBD symptoms from the symptoms
of irritable bowel syndrome (IBS). Faecal calprotectin is considered a marker high associated with
colorectal inflammation. Faecal calprotectin is a simple and non-invasive method for assessing
excretion of macrophages into the gut lumen. Faecal calprotectin values can be used to screen
asymptomatic patients, to predict inflammatory bowel disease relapses and to evaluate the response
to treatment in patients with IBD.
Keywords: fecal, calprotectin, marker, inflammatory, bowel, disease

Introduction

Inflammatory bowel diseases (IBD) are chronic intestinal diseases that progress with periods of
activation and remission. Although, recently there is growing data regarding disease progression, we
are still looking for easy, accurate, non-invasive and not expensive methods to estimate disease
activity, in order to realise an optimal management of these diseases. [1]
The determination of biological markers or biomarkers of intestinal inflammation play a crucial
role in the management of IBD, many biomarkers showing significant correlation with endoscopic
lesions, with response to treatment or with the risk of recurrence. [1]
Faecal calprotectin is considered a marker high associated with colorectal inflammation, a
powerful correlation being already studied between faecal calprotectin excretion and intestinal
permeability in IBD, although it is not sure whether increased intestinal permeability is followed or
preceded by intestinal inflammation [2].
Calprotectin is a 36 kDa calcium- binding protein belonging to the S100 family and occurring in
large amounts in neutrophil granulocytes, macrophages and ileal tissue eosinophils [3], [4]. In vitro
experiments it was demonstrated that calprotectin has antibacterial, antifungal, immunomodulation
and antiproliferative effects [3], [5], [6].
Calprotectin is classified as a damage associated molecular pattern protein (DAMP) [7] with
antimicrobial properties. DAMPs are released by the immune system from activated or damaged cells.
[7], [8]. Calprotectin extracellular release during periods of cell stress is a precise marker of intestinal
inflammation [7].

Methods for review

We have conducted this review based on a search of Pub Med, OxLIP+/SOLO (Bodleian
Libraries) database (from 1993 to 2015) of relevant articles based on the useful determination of
calprotectin level in gastrointestinal diseases, and in their references as well.

196
Discussions and results

Since 1992, subsequent studies [9-12]. confirmed that the level of faecal calprotectin is elevated
in patients with both ulcerative colitis (UC) and Crohn’s disease (CD); in fact, the release of
calprotectin is generated by any inflammatory process of gastrointestinal tract.
In 2002, Summerton and colab associated in their study the level of calprotectin with the
inflammation of whole gastrointestinal tract [13]. So, many conditions that include infection,
diverticulitis, colorectal cancer, untreated celiac disease, AINS therapy, microscopic colitis,
autoimmune enteropathy where associated with elevated level of fecal calprotectin [14], [15].
Tibble and colab considered that this non-invasive marker has a positive predictive value for 76%
of organic gastrointestinal diseases in patients with gastrointestinal symptoms [ 16], and a meta-
analysis of 30 studies on 5983 patients has shown a good correlation of the concentration of faecal
calprotectin with endoscopic and histological grading of IBD activity [17]. The accuracy of this
marker is superior to other markers as C-reactive protein, erythrocyte sedimentation rate and
perinuclear antineutrophil cytoplasmic antibody [17].

Table 1 Conditions associated with elevation of faecal calprotectin [18]

IBD- UC, CD Conditions associated with infectious diarrhoea
Young age (< 5 years) HIV
Microscopic colitis Neoplastic conditions- colorectal cancer, pancreatic cancer
Diverticular disease Iatrogenic- AINS, proton pump inhibitors, radiotherapy
Celiac disease Liver cirrhosis
Graft versus host disease Food allergy
Spondylitis ankylopoetica Gastroesophageal reflux disease
Systemic sclerosis Graft rejection following intestinal transplant
Pancreatitis Cystic fibrosis

These several conditions exposed in table 1 have been associated to an elevation of faecal
calprotectin [18] but the current clinical use of this marker is focused on diagnosis of IBD, monitoring
disease activity in IBD and on differentiating IBD from irritable bowel syndrome (IBS) [18].
The most important systematic reviews and meta-analysis showed the diagnostic value of fecal
calprotectin in diagnosis of IBD [19], [20], [21].
Konikoff et al conducted a review of published articles regarding the correlation between faecal
calprotectin level and neutrophilic intestinal inflammation in IBD and demonstrated the correlation
with histological lesions, as they have been detected by colonoscopy [22].
A study performed in 2006 by Gaya et al showed a precise correlation between faecal calprotectin
leukocyte scintigraphy (the method considered the gold standard in quantifying inflammation) and
estimated that in fact faecal calprotectin is more accurate in proving intestinal inflammation than
leukocyte scintigraphy [23].
Roseth et al, in 2003 correlated the level of faecal calprotectin before and after treatment in IBD,
showing decreasing values of faecal calprotectin over a 3-4 weeks period after treatment. The study
concluded that faecal calprotectin is a substantial and significant marker of disease activity and
response to treatment in patients with IBD [24].
Many studies compared the value of faecal calprotectin with other markers of inflammation (like
C-reactive protein and stool lactoferin) for assessment the disease activity in IBD, quantified by
endoscopy [25]. Faecal calprotectin was more sensitive than C-reactive protein both in CD and UC
with an increased correlation of this marker with ulcerative colitis than Crohn’s disease [25].
The correlation between faecal calprotectin, C-reactive protein and other markers with endoscopic
activity was studied by Schoepfer AM et al. in 2013, in a study performed on 228 patients with UC;
this study underlined a better correlation of faecal calprotectin with endoscopic disease activity than
C-reactive protein blood leukocytes, platelets and haemoglobin, suggesting that faecal calprotectin
could represent a useful biomarker in order to reflect a non-invasive monitoring of IBD disease
activity [26].

197
 Faecal calprotectin has been also used to demonstrate the presence of subclinical intestinal
inflammation in patients with first-degree relatives of CD. This study performed by Thjodleifsson B
et al in 2003 showed a significant higher level of faecal calprotectin at these patients [27].

Conclusions

The best available evidence supports the role of faecal calprotectin in the screening and monitoring
IBD.
The simplicity of this not expensive and accurate test could help in decreasing the use of invasive
procedures.
This method is a simple way to evaluate neutrophils and macrophages excretion into the gut lumen,
strongly associated with intestinal inflammation.
There are growing evidences that related the correlation between faecal calprotectin and mucosal
disease activity. Faecal calprotectin provides better results than other biomarkers of intestinal
inflammation, so these surrogate markers should be evaluated in combination with clinical,
histological and endoscopic parameters in order to assess the management of IBD patients.
Future studies should gather superior information to define the validation of the role of faecal
calprotectin in managing IBD patients.

Abbreviations:
IBD – inflammatory bowel disease
IBS – irritable bowel syndrome
DAMP – damage associated molecular pattern protein
UC – ulcerative colitis
CD – Crohn disease
AINS – anti-inflammatory non-steroids
HIV – Human immunodeficiency virus

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faecal calprotectin as non-invasive marker of intestinal inflammation. Dig Liver Dis.2003; 35:642-647.
12. D’Inca R, Dal Pont E, Di Leo V, Ferronato A, Fries W, Vettorato MG, Martines D, Sturniolo GC. Calprotectin
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Diagnostic precision of fecal calprotectin for inflammatory bowel disease and colorectal malignancy. Am J
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19. Waugh N, Cummins E, Royle P, et al. Faecal calprotectin testing for differentiating amongst inflammatory and
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Digestive Manifestations in Wilms’ Tumor

NEDELCUTA Ramona, POPESCU Mirela, CALIN Gigi

Romania, Hospital Filantropia, Craiova
Emails: ramnedelcuta@yahoo.com, popescumirela83@yahoo.com, gigicalin@yahoo.com

Abstract

Introduction
Renal Tumors is the fifth most common tumor in children, and Wilms’ tumor is the most frequently
occurring renal tumor in children. Nephroblastomatosis consist in stimulating the development of
neural blastoma, which can lead to abnormal immune stimulation due to no longer recognize non-self
cells that multiply abnormally.
Evolution is silent with poor clinical signs and is the basis for late diagnosis and correlates with
poor response to therapy.

Material and method

We conducted a retrospective study of 7 cases of nephroblastoma diagnosed in various stages of
evolution.
We studied history, anamnesis, child’s age, gender, mode of onset, staging, pre/postoperative
treatment, immunohistochemical typing.

Results
Dyspeptic syndrome can signal atypical disease in its early stages, when the tumor is confined to
the kidney without distant dissemination.

Conclusions
Symptoms like bloating, nausea, vomiting, anorexia, abdominal unorganized pain, constipation,
are quasi present onset.
Immunohistochemistry studies correlating tumor cells with various cells involved in immune
defense that could open a new phase of treatment. It is an individual correspondence between a
specific immunostimulant, immunohistochemical markers, disease stage, the stage of pre-or post
surgical treatment.
Stimulator specifically adapted treatment follows classic adage “The physician should not treat the
disease but the patient who is suffering from it” and ensure maximum therapeutic outcome,
specifically modulated.
Keywords: dispeptic syndrome, Wilms tumor, children

Introduction

WT (Wilms’ tumor) accounts for over 95% of cases of kidney malignancy in children, the second
most common intraabdominal cancer. The majority of cases, 75%, occur in children under 5 years of
age, with a maximum incidence of 2-3 years, but it can be uni or bilateral, 5% of cases, synchronous
or metachronous, and only 2% of the cases determined a family history. [1]
In 8-10% of patients, WT is seen in the context of hemihytrotrophy, anuria, genito-urinary
abnormalities and a variety of rare syndromes, including Beckwith-Wiedemann Syndrome and
Denys-Drash Syndrome. [2]

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 Etiologically, it is thought to derive from incompletely differentiated renal mesenchyme and
tumors are typically composed of reminiscent cells of undifferentiated and partially differentiated
cells. [3]

Genetic

The genetic etiology of Wilms tumor is heterogeneous and incompletely understood.

Wilms tumors may occur in sporadic forms or as a hereditofamilial form associated with in-utero
mutation of the WT1 gene and subsequent loss or mutation of the remaining normal WT1 allele.
Sporadic Wilms tumors may be associated with bi-allelic mutation of WT1 in up to 15% of cases
[4] Loss of WT1 is frequently accompanied by gain of function mutations of CTNNB1. [5], [6], [7]
Sporadic Wilms tumors without WT1 mutation frequently show loss of imprinting of IGF2 locus
and many genes within this region may be deregulated. [8]
The blastemal WT-1, TGF-a, VEGF, MIB-1 and p27Kip1 expression correlates with clinical
progression in untreated nephroblastoma. Therefore, their expression may be of value in identifying
patients with a high propensity to develop distant metastases. [9]

Clinical

The most common initial clinical presentation for WT is incidental. The discovery of an
asymptomatic abdominal mass by parents during bathing or dressing of an affected child or by a
doctor during a routine check. At the presentation, the tumour may be quite large, because the
retroperitoneal masses can grow unrestricted by limited anatomical limits. Functional defects of the
pair organs, such as the kidneys, with good functional reserve, are also unlikely to be detected early.
Hypertension is present in approximately 25% of the tumors at presentation and was attributed to
increased renin activity.
Abdominal pain, painless hematuria and fever are frequent findings at diagnosis. Occasionally,
rapid abdominal enlargement and anemia occur as a result of bleeding in the kidney or pelvis
parenchyma.
Anatomopatological, WT is characterized by a large histological variety. The macroscopic tumor
is bulky, it deforms the kidney, it is located in a renal pole or it is multifocal, single or lobular,
sometimes pseudocapsulated. On the section appears with necrotic and pseudochistic zones.
It determines metastases haematogenic and pulmonary, less commonly in the liver. Microscopic
examination: blastemal, undifferentiated tissue, epithelial differentiation tissue, going to glomeruli
and tuber skeleton, mesenchymal differentiation tissue, mesoblastic and muscular. As histologically
unfavorable elements were noted cellular anaplasia and sarcoma transformation. [10]
In terms of a possible immune hypothesis, nephroblastomatosis is a stimulus to the development
of neuronal blastoma, and may cause a change in immunity that no longer recognizes non-self-
abnormal cells. The hypothesis that it is a genetic transmission of an existing mutation in a parent is
not found in the percentage of 1-2% of so-called family clusters and has fewer followers.
The silent progression of the disease, poor in signs and symptoms, is at the basis of late diagnosis
and correlates with low response to therapy. However, based on these theories, when
immunostimulation is beneficial and when it is not and how it can be effective early diagnosis, before
metastasis?
Surgical pretreatment and chemotherapy do not logically indicate, nonspecific immune stimulation
can globally stimulate the embryonic tissue it multiplies uncontrollably, increasing the tumor mass.
Postoperative, post-chemotherapy or radiotherapy immune stimulation must be done with
discernment, with strict monitoring of the number of leukocytes, taking care to keep it around 5000-
8000/mm3.
The objective of the study was to study the complex mechanism of action of the different
immunostimulators with subsequent correlation with the immunohistochemical determinations of

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each patient with the disease state, the predictive marker pathway, in order to establish possible
associative protocols with the classical ones (surgery, radiotherapy, chemotherapy). [11]
A particularity of immunostimulation is related to the form of the disease: in stage 1, with unilateral
limited disease, it can be absolutely beneficial after surgery and cytostatic excision. [12]
In stage 4, with pulmonary metastases, even after total remission, the immunostimulation is risky,
which, due to its non-specific character, can multiply the exacerbated and aberrant clone of mutant
cells, with the risk of remote determinations with poor response to cytostatic treatment that resumes
on a body already traced by previous treatments. Several immunostimulators have been studied.
Isoprinosine is a purine derivative obtained by attaching a ribose to hypoxanthine with a glycosidic
linkage. In the body of inosine uric acid is a natural antioxidant. Nephrectomized children are not
recommended for artificial rise of uric acid, which may interfere with renal function and alter specific
tests. For 10 days, short-term cure can be used as antiviral, long-distance effects are not well known.
Kaloba-pelargonium sidoides has multiple roles: antiviral, stimulating macrophages, secreting
cytokines and stimulating oxidative reactions, inducing TNF alpha, involved in cellular apoptosis,
with cytoprotective, interferon-like effect, activates NK cells. [13] Another role is the antibacterial,
indirectly, stimulates bacterial adherence to infected and dead cells, inhibits adherence to healthy
cells in the mucosa, is secretory by increasing the frequency of ciliary movements, causing rapid
mucus removal. NK cells, unlike TNK, do not express surface receptors, TCR or CD3 marker, or
surface immunoglobulins. But NK expresses CD16 and CD56. Up to 80% of cells have CD8. [14]
NK cells are effector, playing an important role in adaptive immune response, adapting to the
environment and developing immunological memory. NK cells remove the infected and tumor cells
by creating pores in the cell membrane via perforins, subsequently causing apoptosis of the host cell
by degradation of nuclear DNA.
Echinacea works by increasing the enzymatic cleavage resistance of hyaluronic acid, an important
intercellular defense factor, as a binder in tissues, including kidney, respiratory, hepatic, sites of
choice for localization and metastasis of WT.
Luivac is a bacterial lysate (Staphylococcus aureus, Streptococcus mitis, pyogenes, pneumoniae,
Branhamella catarhallis, Haemophillus, Klebsiella). During childhood, 7-8 episodes of respiratory
infections/year, with an average duration of 5-8 days/episode are considered normal. In pediatric post-
chemotherapy and/or radiotherapy, the number of episodes may triple, summing 150-240 days/year.
There is a common lymphoid mucosal tissue that affects the body’s overall defense, including
respiratory and digestive levels. Gastrointestinal mucosa allows the absorption of antigens (Herbst
effect). The intestinal lymphoid tissue has specialized cells that absorb the antigen and transfer it to
the intraluminal lymphocytes released in the Peyer plaque region, then circulate as IgA precursors
via the lymphatic pathway, returning to the circulatory pathway after immunological maturation in
the mucosal immune system. This phenomenon allows immunization with gastrointestinal release but
also in other immune mucosal tissues (lacrimal, salivary, breast, respiratory).
Septilin works by increasing the antibody titer of macrophage activity; it is antiviral, expectorant,
immunostimulator. It works by increasing the number of leukocytes and granulocytes without a direct
cytotoxic tumor role. Studies in mice show a 70% increase in the life of animals with tumors,
explained by immunopotentiating activity.

Material and Method

A prospective study was conducted on 7 cases with WT, diagnosed at different stages of evolution.
We studied: the modality of the onset, signs and symptoms, applied therapy, post-operative evolution,
chemotherapy or radiotherapy, adjuvant treatment, immunostimulation, immunohistochemistry
studies A correlation between immunostimulation, immunohistochemistry, onset, stage of disease
with or without metastasis was attempted in order to establish possible associative protocols of the
“classical” ones: surgery, radiotherapy, chemotherapy. It has been studied the complex mode of
action of each immunostimulator, immunohistochemical typing of each case, and scientific

202
correlations as rigorous as possible. We investigated all patients pre-and post-operative or after the
chemotherapy protocol (vincristine, cosmetic). It was performed: CBC, total leucocyte count,
platelets, AST, ALT, urea, creatinine, uric acid, VSH, CRP, abdominal ultrasound, tomography, and
immunohistochemical markers.

Results

Nonspecific dyspeptic syndrome (nausea, bloating, vomiting, anorexia, unsystematized abdominal

pain) was present in all patients at the onset and could have a predictive impact later on in an eventual
screening program that associates ultrasound kidney in children. The digestive symptoms were
completely resolved after cessation of treatment of the underlying disease. The post-cytostatic
immunostimulation treatments were different in different patients after correlation with
immunohistochemical markers. NSE was diffusely positive in children with secondary pulmonary
determinations, being a marker characteristic of patients with neuroendocrine tumors, small cell lung
cancer, neuroblastoma, and differential diagnosis factor of the latter. 3 cases had WT1, a WT
suppressor, on chromosome 1, the cause of malignancy, and all presenting secondary pulmonary
determinations. The rest were WT1 + diffuse with unilateral disease in stage 1 and a good surgical
and chemotherapeutic response. One case showed severe palpebral ptosis in vincristine treatment,
with total recovery after cytostatic interruption. The CD99+ cases correlated with good prognosis due
to increased glycosylated transmembrane glycoprotein. 4 cases showed CD34, marker for
haematopoietic and endothelial progenitor cells, correlated with haematogenic invasion. WT1 – also
presented a P53-marker, correlated with progression and invasion.
The patients in stage 1, WT1+, CD99+ received Isoprinosine for 10 days, then Alvityl, Kaloba,
Septilin. WT1-, NSE+, with secondary metastases received cures of luivac, echinacea, septilin. The
6 cases were satisfactory at 1 year after the cessation of chemotherapy, the intersectional episodes
were reduced to an average of 5-8/year, overlapping the norms of the pediatric population. The
paraclinical and ultrasound examinations at the 3-6 month revelations did not notice variations from
the standard. There was a slight increase in ITU incidence in 3 children, coupled with bacteriostatic
and urinary antiseptic. One case showed a catheter infection, with a septic state, which required
extraction of the inserted catheter for chemotherapy. Another case developed a surgical upper right
pulmonary lobe and chemotherapy a viral induced bronchial asthma, controlled with ventolin
inhalator in the crisis and montelukast as a baseline treatment.

Conclusions

The correlation of immunohistochemical studies of tumor cells with different mechanisms

involved in immune defense could open up a new treatment stage, the individual correspondence
between a particular immunostimulator, specific markers, stage of the disease and stage of treatment.
The dyspeptic syndromes should be investigated completely, carefully, taking into account an
atypical manner of onset of a severe WT, abdominal ultrasound screening being mandatory.
The stimulating treatment, specifically adapted, fits on the classic dictum that “there are no
illnesses but illnesses” and ensures the maximum modulated therapeutic outcome.
The rare diseases, which allow immunohistochemical patterns, can be used as a platform for the
development of personalized treatments and the entry into a new era of therapy, compatible to
different forms of disease.

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Collaborative Care, Teamwork, Communication and Effectiveness

OPREA Liviu1
1University of Medicine and Pharmacy “Gr. T. Popa” Iasi, Medical Deontology and Bioethics
Email: liviu.oprea@umfiasi.ro

Abstract

Chronic diseases are pervasive and their prevalence is increasing worldwide. Functional
gastrointestinal disorders (FGIDs) are not an exception as they are the main conditions in
gastroenterology practice. In this paper, I argue that there is a need for a paradigm shift in clinical
practice from the actual lone doctor model of practice to a multidisciplinary team practice to improve
the health outcomes of FGIDs patients. This is so because FGIDs are multifactorial and therefore it
needs the conjugated efforts of multiple specialists. Multidisciplinary teams are rather focused on
shared care around the whole cycle of care than on discrete and fragmented health services.
This approach also implies significant communication changes at the level of teams. The actual
communication style in the health care systems is a negative reinforcement one focused on correcting
actual deficits in patient care. It leads to a negative culture with slow improvements, if at all, at the
level of chronic care. I show that there is a need to change this negative culture to positive one
characterised by a positive reinforcement style, which in turn, promotes mutual trust at the level of
health care teams and implicitly improves patients’ health outcomes. However, further research is
needed to understand how to produce this cultural shift.

Keywords: multidisciplinary care, mutual trust, collaborative care

Chronic diseases are pervasive globally and their prevalence is increasing worldwide. (1) Chronic
diseases now represent a major health burden in most advanced societies, at an estimated 46% of
global burden of disease and 59% of mortality. (2) Heart disease, stroke, diabetes, depression and
cancer are the major contributors. Individuals with chronic diseases have a poorer quality of life and
decreased longevity. (3) The functional gastrointestinal disorders (FGIDs) are not an exception, being
the most common disorders seen in gastroenterology clinical practice. (4, 5) There is also an impact
on patients’ economic security through the direct costs of their medical care and indirectly due to
reduced workdays and employment opportunities. (3, 6, 7)
Significant scientific advances regarding the diagnosis, monitoring and treatment of FGIDs have
been made. (8, 9) Despite these scientific advances the health outcomes of FGIDs-ill patients, (10)
and their quality of health care still lags behind these achievements. (11) Several studies have shown
that evidence-based health care for FGIDs is not the norm in most health care settings and, frequently,
patients do not get the care they need. It has been argued, that in the context of chronic conditions,
multidisciplinary care will improve the outcomes of chronic diseases compared with traditional
specialty oriented care through better attention to co-morbidities for patients with complex medical
problems and reduced medical errors. (12-14)
The actual primary and outpatient specialty care is a lone doctor model. Doctors of different
specialties do not share the care of chronic patients. (15, 16) This is not to say, that doctors do not
collaborate with other doctors or other health care professionals such as nurses or allied health
professionals. (5, 17) Doctors dole out tasks to other team members or refer patients to other doctors,
but they do not share the care and responsibility. Usually the health care system is organized around
discrete and fragmented health care services specialty-oriented and patient coordination in this
journey is rather an exception than the norm. (18) In most situations, patients view the doctor as the

205
only person who can solve their problems (16). This situation has a tremendous negative impact on
both patients and doctors. For instance, there are studies showing that in the US alone over 48% of
family doctors believe that their work pace is chaotic and 78% that they have little control over their
work. (19, 20) Similarly, patients have serious troubles in remembering what doctors recommended
them or in understanding therapeutic recommendations. This has a negative impact on patients’ health
outcomes. (21-23)
Patients with FGIDs do not improve their health through discrete and fragmented health care
services such as primary care services, gastroenterology, psychology, or from different procedures
such as echography or endoscopy, but through the cumulated health services organized around the
cycle of care of their diseases. (19, 20) That is care organized around screening, prevention, active
treatment, rehabilitation and monitoring and coordinated by a case manager who helps patients in this
journey. (18, 19)
Consequently, it has been argued that health care services should be organized following three
principles: (1) health care should provide added value for patients – that is improved health outcomes,
which is the only thing that matters for patients; (2) Care should be organized around the cycle of
care of a specific disorder (preventive, early detection, active care, rehabilitation and monitoring) –
multiple specialists should collaborate as a team; and (3) Outcomes must be measured. In what
follows I will focus attention on multidisciplinary care organised around the cycle of diseases. (18,
19)
Ideally, care teams are cohesive groups of high performing primary & specialist doctors focused
on the preventive, active treatment, rehabilitation and monitoring needs of patients with FGIDs. (15,
16, 24)
It has been argued that these teams should not be large “factories” of health care services, but
rather small teams of 5 to 10 primary care and specialist doctors (gastroenterologists, surgeons,
psychiatrists) working together with allied health professionals (nutritionists, psychologists) by
providing different health services based on individual patients’ needs. This is so, because large teams
are difficult to manage and energy and time spent with many team members having to communicate
information and coordinate tasks is overwhelming. (15, 16, 24) This is a significant issue because if
only one person does not cooperate in an integrative way, the entire team can fail. Smaller teams are
easier to function harmoniously on the one hand, and patients can see always the same doctors on the
other hand. In this way doctors learn to trust each other and patients to trust the team. (15, 16, 24, 25)
Although, multidisciplinary care has been advocated to become the norm in health care systems
in the last two decades, multidisciplinary care remained also fragmented and multidisciplinary teams
remain to earn true statute of teams by providing shared care. This is not to say, that everyone will be
responsible for everything. (15, 16, 24) Multidisciplinary teams should have shared goals, but each
individual in the team should also have clearly defined roles. This is not a simple issue, as different
medical specialties overlap in their scope. For instance, family doctors, gastroenterologists and
surgeons, all of them, manage patients with gastrointestinal disorders. Similarly, family doctors and
nurses counsel patients with gastrointestinal disorders with respect with lifestyle changes needed to
improve their health status.
One possible approach for overcoming this overlap in multidisciplinary care is to allow
professionals in the team to exercise their profession at a maximum and to delegate the overlapping
tasks to less specialized professionals in the team. (24) For instance, family doctors could limit their
practice to diagnosis and treatment procedures for patients with FGIDs by delegating counselling
tasks to their nurses or allied professionals such as nutritionists or psychologists. This approach may
improve not only the effectiveness of care through specialization for a specific task, but also the
access to care of chronically ill patients as professionals with sub-specialties are few and they could
focus on those takes for which they were specifically trained. (16, 24) Yet, this a theoretical argument
and there is a need for further research to understand whether this approach could have such outcomes
in patients with FGIDs.

206
 In addition to this managerial approach, there is a need to promote cohesiveness at the level of
multidisciplinary teams. (16, 24) Mutual trust between health care professionals in the team as well
as mutual trust between health care professionals and their patients play a crucial role in the
effectiveness of health care services. (1) Besides shared goals at the level of the team and clear roles
for everyone in the team for avoiding overlap, effective communication at the level of health care
teams is significant. Communication in health care is the vehicle through which evidence-based
approaches in health care are implemented at the level of patients and therefore it directly impacts on
patients’ health status through patients’ adherence to therapeutic recommendations. (26)
The usual communication at the level of health care teams and between health care professionals
is a managerial one that could be generally labeled as negative reinforcement style. This style is
focused on solving problems and is characterized by: (1) identifying the problem; (2) cconducting
root cause analysis; (27-29) brainstorming for solutions and analyzing, and (4) develop action plans
to solve the problem. This style focuses on deficit as it tends to correct negative outcomes.
This approach leads to a “negative culture” characterized by fragmented responses, slow
organization development as it focuses on past causes, lack of vision and positive images of the future,
leading to personnel fatigue and defensive practices, which in turn, have a negative impact on
patients’ health. (30, 31)
Recent health services research has shown that a positive reinforcement style could have a better
impact on the cohesiveness of health care teams. (32-35) This style is characterized by (1) building
partnership between health care professionals in the team, which is developed during the process of
setting shared goals and individual responsibilities in the team; (2) information giving and seeking –
which is the minute to minute communication between health professionals in the team as well as
staff meetings focused on discussing difficult patients. By contrast with the negative reinforcement
style this style focuses as well as to increase the mutual trust at a personal level by promoting a
communication that is nonjudgmental and autonomy supportive which provides moral support at the
level of teams. There is some evidence that this communication promotes mutual trust and
subsequently preventive care and timely patients’ access to care. (32-35) However, there is not
information on how to shift from the actual pervasive negative reinforcement style to a positive
approach at the level of teams. Further research is needed to understand what interventions are needed
for promoting this cultural shift.
In this paper, I have argued that multidisciplinary care should replace the actual lone doctor model
of practice in primary and outpatient specialist care. This may improve the outcome of FGIDs
patients. Multidisciplinary teams have also to earn the statute of true teams by increasing their
cohesiveness. This change implies as well a cultural shift from the actual negative culture
characterized by a negative reinforcement style of communication focused on correcting deficits at
the level of health care to a positive reinforcement style characterized by positive reinforcement style
focused on innovative services. Further research is needed to understand how this cultural shift could
be implemented.

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209
Psychopathological Comorbidities in Patients with Advanced
Digestive Oncologic Pathology

POJOGA Cristina1,2, FADGYAS STANCULETE Mihaela3,

DUMITRASCU Dan Lucian4
1 Babes-Bolyai University, Department of Clinical Psychology and Psychotherapy, International Institute for Advanced Study of
Psychotherapy and Applied Mental Health (ROMANIA)
2 Regional Institute of Gastroenterology and Hepatology O Fodor, Cluj-Napoca (ROMANIA)
3 UMF Iuliu Hatieganu Cluj Napoca, Department of Neurosciences, Psychiatry (ROMANIA)
4 UMF Iuliu Hatieganu Cluj-Napoca, Department of Internal Medicine (ROMANIA)

Emails: cristinapojoga@yahoo.com, mihaelastanculete@yahoo.com, dan_dumitrascu@yahoo.de

Abstract

Patients with advanced digestive oncologic pathology often have psychopathologic comorbidities,
their presence dramatically influencing quality of life, adherence and response to the treatment,
therefore having an important effect on the prognosis of the oncologic ailment. The most frequently
met are emotional distress, anxiety and depression.
The aim of the study was to assess the influence the emotional distress, anxiety and depression
have on quality of life of the patients with advanced digestive oncologic disease.
Keywords: quality of life, psychopathological comorbidities, advanced oncologic pathology

Introduction

Over the past years, the number of oncologic cases has increased, many of them being diagnosed
during advanced stages. In those cases, the aim of the treatment is no longer to cure the disease, but
to extend the lifespan, maintainig an acceptable quality of life.
The symptoms of cancer, the complications of the disease, the side effects and even the costs of
the treatment pervade all aspects of functioning and ultimately impact the quality of life of patiens
and their family. Patients must learn to cope with important psysical changes, loss of social life and
very frequently with chronic pain, all within the context of a potential threat to one’s life. From the
clinical point of view, emotional distress in response to such a diagnosis is to some degree expected,
but in fact many cancer patients do meet the diagnostic criteria for clinical psychiatric disorders.
Psychopathological comorbidities dramatically influence patients’ quality of life, adherence and
response to the treatment, therefore having an important effect on the prognosis of the oncologic
ailment. The most frequently met are emotional distress, anxiety and depression.
About half of the cancer patients had psychiatric morbidity either in the form of depressive disorder
or in the form of generalized anxiety disorder. Higher stage of malignancy (from early, advanced to
metastasis) was associated with higher prevalence of depressive disorder and anxiety (1).
Psychological distress (anxiety and depression) is associated with an increase of 27% of death risc
in oncological patients (2, 3).
Comorbid depression can potentially complicate the tretment of both conditions (4). The multiple
stressors associated with cancer can lead to the development of depression (or the exacerbation of an
existing depression) and depression in turn can impact the adherence to the treatment, resulting in
more negative outcomes in these patients (4, 5).
Prevalence rates of depression spectrum syndromes vary widely, ranging from 0 to 58% (4, 6).
There is an overlap between symptoms of depression and of cancer or treatment side effects, so it
is difficult to determine if symptoms like loss of apetite, insomnia, reduced energy, weight loss are
due to depression, cancer or both (7).
210
 Anxiety, like depression, can be found on a continuum from normal to clinical levels. Cancer
patients have a lot of things to be concerned about: practical (maintaining job, taking care of the loved
ones), medical (fears about painful investigations and treatments) and existential (possibility of
death). The findings suggest that death anxiety in patients with advanced cancer is common and
determined by the interaction of individual factors, family circumstances and physical suffering (8).
In some patients, the diagnosis will exacerbate an existing anxiety, but there are many cases when
the onset of this psychiatric disease occur after diagnosing cancer. Anxiety can put patients to a risk
of poor adherence to treatment and even to risk of ceasing the treatment. Similar to depression, it is
difficult to diferentiate between some cancer symptoms or treatment side effects and the presence of
anxiety: insomnia, increased muscle tension, difficulty in concentration.
Based on the data from literature, the aim of the study was to assess the influence the emotional
distress, anxiety and depression have on quality of life of the patients with advanced digestive
oncologic disease.

Methodology

We conducted a cross-sectional study on a sample of 32 patients recruited consecutively from a

tertiary gastroenterology centre in Cluj-Napoca. The diagnosis of advanced digestive oncologic
disease has been confirmed by physicians using clinical examination, laboratory findings, advanced
imagistic investigations and histopathology.
The criteria for inclusion in the study were: a) at least 18 years, b) have a new diagnosis of
advanced oncological disease c) not known with previous psychiatric pathology, d) the ability to read
and write in Romanian.
Participants were excluded if they did not meet the criteria mentioned above. This study was
approved by the Ethics Committee of the University of Medicine and Pharmacy Cluj-Napoca, all
participants signing an informed consent to participate in the study.
We used Quality of Life Questionnaire in Oncologic Pathology.
EORTC QLQ-C30 version 3.0, DASS-21 Distress Questionnaire with 3 subscales: stress, anxiety,
depression, and the Coping Mechanism Questionnaire. We followed a protocol that complies with
ethical rules on the confidentiality of data processing. After obtaining the participants’ agreement,
the scales were administered without the need for a time limit.
To test the study hypotheses, we used correlation analysis and regression analysis.
Intercorrelations were calculated using the Pearson correlation coefficient.

Results

On the global quality of life scale QL2, score values varied between 0 and 83.33%, mean value
37.19±26.10 (Fig. 1).
90

80

70

60

50
QL2

40

30

20

10

Fig. 1. Score distribution on the global scale of quality of life

211
 We administered to the subjects the questionnaire DASS 21, calculating the total score and the
subtotal scores: stress score, anxiety score and depression score.
We found a negative correlation between the total distress score and the global quality of life, with
a correlation coefficient of -0.60 (p<0.05) (Fig. 2).

90

80

70

60

50
QL2

40

30

20

10

0
0 10 20 30 40 50
DASS 21 total

Fig. 2. Negative correlation between global quality of life score (QL2) and DASS-21 total score

We found a negative correlation between the stress DASS-21 score and the global quality of life
score (QL2), with a correlation coefficient of -0.62 (p<0.05) (Fig. 3).

Fig. 3. Negative correlation between global quality of life score (QL2) and DASS-21 stress score

We found a correlation coefficient of -0.58 (p<0.05) between the score of depression DASS-21
subscale and the global quality of life score (QL2) (Fig. 4)

Fig. 4. Negative correlation between global quality of life score (QL2) and DASS-21 depression score

Correlation analysis between global quality of life score and the anxiety DASS-21 subscale score
resulted in a correlation coefficient of -0.50 (p<0.05). (Fig. 5).

212
 Fig. 5. Negative correlation between global quality of life score (QL2) and DASS-21 anxiety score

Discussions

The results of the regression analysis have highlighted that patients with advanced digestive
oncologic pathology have an altered quality of life and their quality of life is negatively correlated to
the degree of distress, anxiety and depression. These results confirm the study assumptions.
Specifically, the results of this study highlight the importance of assessing and managing the
psychopathological comorbidities in patients with advanced digestive cancer in order to improve their
quality of life.
The results of our research are in line with literature data showing that cancer patients have a low
quality of life and that it is inversely correlated with depression, anxiety and distress.
The limits of the study
Our results are obtained from a limited group of patients; therefore, our results can not necessarily
be generalized to all the patients with advanced digestive oncologic disease.

Conclusions

In patients with advanced oncologic disease, it is important to assess the presence of

psychopathological comorbidities in order to tailor an individual treatment.

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patients: An institutional experience. Indian J Cancer. Jul-Sep;53(3):432-434.
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cancer. BMJ Support Palliat Care. Dec;5(4):373-80.

213
Neutropenic Enterocolitis (Typhlitis) as a Complication of Acute
Lymphoblastic Leukemia
SUBOTNICU Mirabela1,2, TRANDAFIR Laura1,2, IVANOV Anca1,2,
MIRON Ingrith1,2
1“Grigore T. Popa” University of Medicine and Pharmacy Iasi (ROMANIA)
2Emergency Hospital for Children “St Mary” Iasi (ROMANIA)
Emails: Subotnicu_mirabela@yahoo.com, trandafirlaura@yahoo.com, anca_vi@yahoo.com, ingridmiron@hotmail.com

Abstract

Neutropenic Enterocolitis (Typhlitis) is a rare, life-threatening gastrointestinal complication seen

in patients with hematologic malignancies. Severe neutropenia, infections or chemotherapy alter the
bowel mucosal surface which can proceed to necrosis and perforation. We report 4 cases of pediatric
patients diagnosed with acute lymphoblastic leukemia treated with myelosuppressive chemotherapy,
who developed severe neutropenic enterocolitis. According to BFM ALL 2002 risk stratification, 3
patients were included in High Risk group and one in Standard Risk group. All children had received
chemotherapy before the diagnosis of typhlitis; at the time of the diagnosis, 2 patients had bone
marrow relapse, while the other 2 had chemotherapy induced bone marrow aplasia. 3 patients
presented the typical triad of neutropenia, fever and abdominal pain. Most frequent clinical features
included abdominal pain, diarrhea and abdominal distention. Abdominal ultrasonography scan
identified diagnostic features consistent with typhlitis. One patient presented surgical condition such
as bowel perforation. 3 patients died despite prompt diagnosis and treatment with broad spectrum
antibiotics, antifungal agents, granulocyte colony-stimulating factor, bowel rest, parenteral nutrition,
and platelet units concentrate and packed red cell transfusions. The diagnosis of typhlitis was
determined by clinical features and was supported by radiologic evaluation. The course can be
towards the sepsis syndrome, multisystem organ failure and death. Oncologic patients presenting with
fever, abdominal pain and neutropenia are more likely to develop typhlitis.
Keywords: neutropenic enterocolitis, leukemia, child

Introduction

Neutropenic enterocolitis (NE) also known as typhlitis or necrotizing enterocolitis occurs during
periods of severe neutropenia in patients with hematologic malignancies, solid tumors, aplastic
anemia or with immune compromised status [1, 2]. NE is a necrotizing inflammatory condition of the
mucosal barrier of the intestine as a result of chemotherapy or neutropenia and can rapidly progress
to intestinal perforation, bacteremia, sepsis and death. It is characterized by typical triad fever,
abdominal pain and neutropenia, but other clinical features such as diarrhea, abdominal distention
and tenderness, vomiting, occult or frank blood in the stools may occur. Aggressive chemotherapy
used in leukemia treatment such as cytarabine (ARA-C), vincristine, etoposide (VP16), doxorubicin,
cyclophosphamide, leucovorin and daunorubicin could be involved in the development of NE [3, 4,
5].
The incidence of NE in leukemia patients is increased during cytoreductive therapy and rarely seen
during maintenance chemotherapy [6, 7, 8].

214
Materials and methods

We report 4 cases of pediatric patients diagnosed with acute lymphoblastic leukemia treated with
myelosuppresive chemotherapy, who developed severe neutropenic enterocolitis. All patients were
treated according to ALL IC-BFM 2002 Protocol.

Case 1
The patient was a 15 years old female diagnosed with High Risk T-cell Acute Lymphoblastic
Leukemia. She was admitted for chemotherapy – consolidation therapy. Pallor and cervical
lymphadenopathy was found on physical examination. Laboratory testing revealed hemoglobin level
10.4g/dl, white blood cell (WBC) count 109x103/μL and platelet count 64x103/μL.
Also, elevated values of lactate dehydrogenase and uric acid were observed. Peripheral blood
smear and a bone marrow aspirate showed blast cells in blood and in bone marrow. It was considered
early bone marrow relapse (at the end of induction phase) and intensive chemotherapy with
dexamethasone, cytarabine high-dose, idarubicine was started.
Four days after she received the last dose of ARA-C, she developed diarrhea, abdominal pain,
abdominal distention. At this stage, the patient’s physical examination revealed pallor, oral mucositis,
overall sensitivity in the abdominal region; WBC was 0.68x103/μL, absolute neutrophil count (ANC)
0.14x103/μL, hemoglobin level 9.4g/dl and platelet count 25x103/μL. Stool cultures were negative
for Clostridium difficile toxin A/B and other enteric rods. Direct examination of fresh stool-presence
of Giardia lamblia. Antibiotics, antifungal agents and granulocyte colony-stimulating factor were
administrated.
Her condition deteriorated with severe hypotension (65/40mmHg), tachycardia (146 beats per
minute), vomiting and nausea. Abdominal radiography showed hydroaeric levels in hypogastric
region with no evidence of perforation or pneumatosis intestinalis and ultrasound scan showed
increased bowel wall thickness. The patient was believed to have severe neutropenic colitis with
associated sepsis and she was transferred in the intensive care unit (ICU).
The treatment included bowel rest, total parenteral nutrition, antibiotics (metronidazole,
ceftazidime, ciprofloxacine), antifungal (fluconazole), granulocyte colony-stimulating factor, platelet
concentrate. The patient died two days later because of multiple organ failure.

Case 2
A 6 years old boy was treated in our unit since February 2015 for Acute Lymphoblastic Leukemia
with B-cell precursors. This patient was considered standard-risk at the onset of the disease, but he
developed medullary relapse at the time he reached the consolidation phase of the treatment.
The relapse protocol was initiated with idarubicin and cytarabine high-doses. After that the patient
suffered severe aplasia and secondary he developed Clostridium difficile sepsis. Clinically, the child
presented severe abdominal pain, vomiting, liquid stools and fever. The abdomen was distended and
the plain abdominal x-ray showed gaseous dilatation of the ascending colon. Abdominal ultrasound
revealed presence of fluid of 26 mm, wall thickness of the cecum increased, low peristalsis; the
diameter of colon was approximately 20mm. The patient was transferred to the Intensive care unit.
There, he was treated with parenteral nutrition, bowel rest, broad-spectrum antibiotics, G-CSF and
transfusions. Despite the treatment the evolution was unfavorable, the aplasia was severe and
persisted for a period of approximately 2 weeks. The hemoleucograms repeated daily, showed a
leukocyte count under 100/mm³, constantly, without any neutrophils. The patient was released home,
at parents’ request and died within few days.

Case 3
13 years old female diagnosed with High Risk B-cell Acute Lymphoblastic Leukemia developed,
during consolidation therapy with Dexamethasone, Methotrexate high dose (HD-MTX), Ifosfamide,
Daunorubicin, tonic clonic seizures and she was transferred in ICU for close observation
and monitoring. Laboratory testing revealed bone marrow aplasia (WBC 0.4x103/μL, hemoglobin
215
level 8.7g/dl and platelet count 17x103/μL) and severe hyponatremia. At that time, she became febrile
and intense abdominal pain and diarrhea occurred. Plain abdominal radiography showed hydro-aeric
levels in the right lower quadrant. On examination, the patient had overall sensitivity in the abdominal
region and abdominal distention; it was considered neutropenic enterocolitis. Surgical intervention
was indicated if her condition deteriorated. The patient improved clinically with non-surgical
management: bowel rest, intravenous fluid, broad-spectrum antibiotic, granulocyte-colony
stimulating factor therapy, platelet concentrate. The chemotherapy was postponed until complete
recovery.

Case 4
16 years old boy diagnosed with High Risk B-cell Acute Lymphoblastic Leukemia – Philadelphia
Chromosome Positive developed, during consolidation therapy (Dexamethasone, HD-MTX,
Ifosfamide, L-Asparaginase, Daunorubicin) with concomitant imatinib administration, spontaneous
onset abdominal pain, abdominal tenderness and bilious vomiting. Physical examination revealed a
flat abdomen with marked guarding and generalized tenderness and normal stool. No fever was
reported. Blood investigations showed a WBC of 1.1x103/μL, with absolute neutrophil count of
0.02x103/μL, hemoglobin level 13.5g/dl and platelet count 12x103/μL. Also, an increased level of C-
reactive protein and severe acidosis were observed. Imagistic findings and clinical features suggested
peritonitis caused by neutropenic enterocolitis. The patient died in a few hours despite prompt
ventilatory support, intravenous fluid, broad-spectrum antibiotics, granulocyte-colony stimulating
factor therapy and platelet concentrate. The cause of death was fulminating gram-negative septicemia
by Escherichia coli.

Discussions

The diagnosis of NE can be challenging, consisting mainly in clinical observations. The most
frequent differential diagnosis is with appendicitis, but this symptomatology can also be caused by
veno-occlusive disease, pseudomembranous colitis or infectious colitis.
The data from the current literature suggest an increased incidence of NE among patients with
hematologic malignancies compared with those presenting solid tumors [2, 4, 8].
The majority of the reported cases describe the involvement of cecum or ascending colon in
neutropenic enterocolitis, probably due to distensibility and low vascularization of this segment.
It has been stated that the recovery of this patients is linked to neutrophil recovery [2, 9, 10].
Diarrhea is often the dose-limiting and major toxicity of regimens and in addition to conventional
cytotoxic drugs, several molecularly targeted agents are also associated with it.
Some chemotherapeutic agents seem to have involvement in the pathogenesis of the typhlitis.
Among these anthracyclines and cytosine arabinoside have been cited to induce mucosal injury, and
vincristine to lower peristalsis. The patients’ exposure to corticosteroids, especially dexamethasone
regimen before of the episode was precipitating the disease [2, 4, 9, 11, 12, 13, 14].
The literature provides only few data concerning Giardial infestation [4, 15] and Clostridium
difficile associated diarrhea in patients with neutropenia who have hematologic malignancies [16,
17].
We presented 4 cases of pediatric patients in treatment for acute lymphoblastic leukemia. At the
time of the diagnosis, 2 patients had bone marrow relapse, while the other 2 had chemotherapy
induced bone marrow aplasia. Before NE diagnosis, all patients received chemotherapy according to
ALL IC-BFM 2002 Protocol, induction or consolidation therapy. The typical triad of neutropenia,
fever and abdominal pain occurred in three cases. One patient presented Clostridium difficile toxins
positive and, in other case, Giardia lamblia was present in direct fresh stool examination. Despite
prompt diagnosis and treatment with broad spectrum antibiotics, antifungal agents, granulocyte
colony-stimulating factor, bowel rest, parenteral nutrition, platelet units concentrate and packed red
cell transfusions, 3 patients died of multisystem organ failure and sepsis syndrome.

216
 The high mortality rate in the three cases described reveal the fact that every patient should be
treated individually according to his particularities.

Conclusions

Neutropenic enterocolitis can evolve towards the sepsis syndrome, multisystem organ failure and
death. Oncologic patients presenting with fever, abdominal pain and neutropenia are more likely to
develop typhlitis. Early recognition and treatment are essential for survival.

REFERENCES

1. Katz, JA. et al. (1990). Typhlitis. An 18-year experience and postmortem review. Cancer 65, pp. 1041.
2. Sloas, MM. et al. (1993). Typhlitis in children with cancer: a 30-year experience. Clin Infect Dis 17, pp. 484.
3. Davila ML. (2006). Neutropenic enterocolitis. Curr Opin Gastroenterol 22, pp. 44–47.
4. Aksoy, DY. et al. (2007). Diarrhea in neutropenic patients: a prospective cohort study with emphasis on
neutropenic enterocolitis. Ann Oncol; 18 (1), pp. 183-189.
5. Rizzatti, M., Brandalise, SR., Azevedo, AC., Pereira Pinheiro, VR., Santos Aguiar, S., (2010). Neutropenic
enterocolitis in children and young adults with cancer: Prognostic Value of Clinical and Image Findings,
Pediatric Hematology And Oncology Vol. 27, 6.
6. Kaste SC, Flynn PM, Furman WL. (1997). Acute lymphoblastic leukemia presenting with typhlitis. Med Pediatr
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7. Cloutier (2010). Neutropenic enterocolitis. RL. Hematol Oncol Clin North Am. 24(3), pp. 577-584.
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9. Nucci, M., Bijay, N., Anaissie, E. (2011). Leukemias: Principles and Practice of Therapy. pp. 392.
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children with cancer Journal: Acta Paediatrica. 101: 3, pp. 308.
11. Gil, L., Poplawski, D., Mol, A., Nowicki, A., Schneider, A., Komarnicki, M. (2013). Neutropenic enterocolitis
after high-dose chemotherapy and autologous stem cell transplantation: incidence, risk factors, and outcome.
Transpl Infect Dis 15, pp.1–7.
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Baillie, C.T. (2009), Diagnosis, incidence, and outcomes of suspected typhlitis in oncology patients—experience
in a tertiary pediatric surgical center in the United Kingdom Journal of Pediatric Surgery 44, pp. 381–385.
14. Quigley, MM., Bethel, K., Nowacki, M., et al. (2001). Neutropenic enterocolitis:
A rare presenting complication of acute leukemia. Am JHematol 66; pp. 213-219.
15. MULHOLLAND, M.W., DELANEY, J.P., FOKER, J.E., LEONARD, A.S., SIMMONS, R.L., (1983).
Gastrointestinal Complications of Congenital Immunodeficiency States, Ann. Surg 198:6, pp. 673-680.
16. Bilgrami, S., Feingold, J.M., Dorsky, D., et al. (1999). Incidence and outcome of Clostridium difficile infection
following autologous peripheral blood stem cell transplantation, Bone Marrow Transplant, vol. 23, pp. 1039-42.
17. Gorschluter, M., Glasmacher, A., Hahn, C., Schakowski, F., Ziske, C., Molitor, E., Marklein, G., Sauerbruch,
T., Schmidt-Wolf, G.H. (2001). Clostridium difficile Infection in Patients with Neutropenia, Clin Infect Dis
33(6), pp. 786-791.

217
Pregnancy after Surgical Treatment in Ulcerative Colitis- Case Report

TOADER Oana1,2, MARGINEANU Catalina1, SUCIU N.1,2, VOICHITOIU A.1,2,

CIRSTOIU Monica2,3, BOHILTEA Roxana2,3, VINTEA Alexandra1,2
1 “Alessandrescu-Rusescu” National Institute for Mother and Child Health, Polizu Department, Bucharest, (ROMANIA)
2 “Carol Davila” University of Medicine and Pharmacy, Bucharest, (ROMANIA)
3 Bucharest Emergency University Hospital, (ROMANIA)

Email: oana.toader@yahoo.com

Abstract

Introduction
Ulcerative colitis is an inflammatory bowel disease with a high incidence during reproductive age
in females. The aim of the treatment is to control the symptoms and obtain remission. Pregnancy may
influence the evolution of the disease with repercussions on the mother and fetus. Pregnancy with
ulcerative colitis is categorized as high risk. The collaboration between the obstetrician and
gastroenterologist is important for a more favorable evolution.

Case report
We present the case of PA, 20 years old, who is admitted to hospital because of uterine
contractions.
The patient is 39 weeks pregnant. From her history, it is important to notice the total
proctocolectomy with ileostomy for ulcerative colitis at the age of 15. The antenatal care did not raise
any medical problems. The stoma was permeable and functional all over the pregnancy. Because
there were no contraindications, the patient underwent the labor, but the cervical dilatation stopped
at 6 cm, and it was performed the caesarean-section. The indication was: fail of progression of the
labor. A female, 2500g, Apgar score 8-7 baby was born. During the caesarian-section, there were not
found any intraperitoneal adhesions from previous surgeries and the ileostomy was checked for
potential complications.

Conclusions
Despite the right treatment, ulcerative colitis is a disease which can have a major influence on the
quality of life. The concerns about sexual health are very common, especially in the young ladies who
underwent surgical treatment. During pregnancy, the ileostomy may be affected by obstruction or
other complications. Lacking any contraindications, the patients should be encouraged for vaginal
delivery.
Keywords: ulcerative colitis, pregnancy, ileostomy

Introduction

Ulcerative colitis (UC), an inflammatory bowel disease, has a high prevalence during reproductive
years. Pregnancy can worsen the progress of the disease, and of course, the disease can complicate
the pregnancy, with side effects both to the mothers and fetus. The common symptoms are diarrhea,
abdominal pain and pyrexia [1]. The surgical treatment is proposed in cases of unresponsiveness to
medical therapy. In severe cases, the surgical treatment is represented by total colectomy with end
ileostomy. The pregnancy can affect the ileostomy, in most of the cases by displacement or
obstruction by the enlarged uterus [2]. In these cases, without prompt treatment, the prognosis can be

218
fatal. We present the case of a young woman, 39 weeks pregnant, with a history of extensive
abdominal surgery for UC.

Case report

A 20 years old primigravida was referred to our clinic at gestational age of 39 weeks, because of
uterine contractions.
Her history revealed that at the age of 12 she was diagnosed with a severe form of ulcerative colitis
and, because she did not answer to medical therapy, at the age of 15 she suffered proctocolectomy
with end ileostomy. After the surgery, it was not necessary to continue any other treatment for the
disease.
The clinical examination revealed a distended abdomen because of the enlarged uterus, with a
fibrous median scar. The ileostomy was functional, with normal appearance, in the right lumbar
region. The gestational ultrasonography showed a 2650g fetus in cephalic presentation with
symmetrical growth, without any sign of fetal distress.
The antenatal care showed no significant problems, except for a mild anemia which was treated
with oral iron supplements. In the first trimester, the patient reported nausea and vomiting which were
also related to pregnancy and which were treated with antiemetic drugs. The ileostomy was functional
throughout the pregnancy without any specific complications, such as obstruction, displacement,
enlargement or prolapse.
Because of the contractions, the labor began with spontaneous rupture of the membranes at 3 cm
cervical dilatation. The patient was proposed for vaginal delivery because her medical history did not
represent a contraindication. In fact, because of the previous extensive surgery for ulcerative colitis,
it was a great concern about possible intraperitoneal adhesions.
The labor was uneventful but the cervical dilatation stopped at 6cm and the caesarian section (C-
section) was proposed for delivering the baby. The operating team included a general surgeon.
An iterative midline incision was made and a healthy female, 2500g baby was born. The Apgar
score was 8-7. Despite the expectations, no adhesions were present. The stoma was examined for
potential complications. The small bowel was also checked for possible ischemic or inflamed
segments, but none of those were present.
The postoperative evolution went well with antibiotic, painkillers and low molecular weight
heparin therapy. The patient was discharged after 8 days because of the additional care for the baby.
The check up after one month showed an epithelized skin suture with the physiologic uterine
retraction and a functional ileostomy, without retraction or displacement.

Discussions

The usually cause of stoma during reproductive years is represented by inflammatory bowel
disease (IBD) with UC being the primary reported diagnosis. Other causes of stomas at an early age
are spina bifida, bowel carcinomas, idiopathic megacolon, colon injury or anomalies [2].
An ileostomy is the most common type of stoma, followed by colostomy and urostomy. Stoma
during pregnancy is not a frequent condition. Because the lack of cases, the management of these
patients is adapted according to the circumstances.
For a young patient trying to conceive, UC can be active or inactive at the time of conception or
the disease can arise during gestation or during puerperium [3]. It is very important to know the
patient medical history because the causes of acute abdomen (due to UC) during pregnancy differ in
operated patients compared to never operated patients [3].
The displacement, obstruction or even prolapse of the ileostomy are complications that can appear
during pregnancy. In the first trimester, these are rarely seen, but with the progression of pregnancy,
the enlarged uterus may have a mechanic effect on the bowel, mostly because of the fixed nature of
the stoma and distal ileum at the abdominal wall [4].

219
 Hyperemesis is a frequent cause of stomal prolapse probably because of the increased intra-
abdominal pressure secondary to excessive vomiting [2, 5]. The manual reduction can be tempted to
solve prolapse, but in cases of unsuccessful reduction, a laparotomy may be needed to rule out other
potential complications like parastomal herniation [6].
Intestinal obstruction is one of the most severe complications and it can appear even in
nonpregnant patients [2]. The causes are intestinal adhesions, volvulus or compression of the small
bowel by the gravid uterus.
Besides the abdominal pain, nausea and vomiting are the most frequent symptoms seen in cases
of complications of the stoma [1]. In the first trimester, the diagnosis is difficult to make because
these symptoms may mimic pregnancy induced nausea, or even hyperemesis gravidarum, conditions
that are usually seen in pregnant patients. The bowel movements can be reduced because of the
progesterone slow down effect or because of the iron ingestion and intestinal obstruction is not the
first differential diagnosis taken into consideration. It is important to remember that any colic pain in
pregnancy may not be secondary to uterine contractions and, on the other side, a preterm labor can
complicate an intestinal obstruction. In the case of doubt, the modern investigation techniques, such
as MRI, should be used to rule out the diagnosis [4]. The suspicion index must be very high in patients
with stoma and laparotomy should be considered for any unusual pain [7]. Any delay in diagnosis
can increase the maternal mortality, subsequently increasing the neonatal mortality [1]. The first
therapeutic maneuver consists of bowel rest and decompression, with hydro-electrolytic replacement.
Surgery is indicated in complete bowel obstruction, persistent symptoms or if the conservative
therapy fails. As a result, premature delivery is usually a consequence of laparotomy in the last
trimester of pregnancy [4].
The diet is important in a patient with UC in preventing bowel obstruction. Soft fibers and liquid
diet can be recommended to prevent constipation in cases of previous extensive surgery [8]. Anemia
is frequently associated and iron supplementation should be taken into consideration, with caution to
iron intolerance.
Ileostomy does not represent a contraindication to vaginal delivery [7]. More than that, in a patient
with previous extensive surgery it is the preferred method of delivery because of the potential
intestinal adhesions. Beside the obstetric indications, the Caesarian section has a few indications in
cases of ileostomy. It may be required as a part of laparotomy for intestinal obstruction or stomal
complications [2]. Instrumental delivery is often seen because some patients may not feel the desire
to push or because of the fibrous scar perineum secondary to previous extensive inflammatory
processes [7]. In these cases, a large episiotomy is needed. In puerperium, abdominal wound and
genital tract infection are the most common complications that may appear, without any special
considerations regarding the treatment [7].

Conclusions

Ileostomy does not represent a contraindication to pregnancy. It is related to specific complications

that can appear during gestation. Unrecognized and without an adequate management with prompt
intervention, the maternal and fetal mortality can be very high. We presented the case of a young
woman with end ileostomy after proctocolectomy for UC, whose pregnancy and delivery went well
under a multidisciplinary approach.

REFERENCES

1. A’Dair Herrington, Rajiv Gala, David E. Beck, Alfred G. Robichaux. Bowel Obstruction in a Pregnant Patient
with a Restorative Proctocolectomy and Ileoanal J-Pouch: A Case Report. The Ochsner Journal 12:170–172,
2012.
2. Nicholl MC, Thompson JM, GDC and Cocks PS. (1993), Stomas and Pregnancy. Australian and New Zealand
Journal of Obstetrics and Gynecology, 33: 322–324. doi:10.1111/j.1479-828X.1993.tb02099.x.
3. G. Augustin, Acute Abdomen During Pregnancy, 279. DOI 10.1007/978-3-319-05422-3_8.

220
4. Spring A, Lee M, Patchett S, Deasy J, Wilson I and Cahill RA (2012), Ileostomy obstruction in the third trimester
of pregnancy. Colorectal Disease, 14: e631–e632. doi:10.1111/j.1463-1318.2012.02972.x.
5. Shabbir J and Britton DC (2010), Stoma complications: a literature overview. Colorectal Disease, 12: 958–964.
doi:10.1111/j.1463-1318.2009.02006.x.
6. Olufunso Adedeji W.A.F. McAdam. Intussusception in ileostomy in a pregnant woman. Department of General
Surgery, Airedale General Hospital, Skipton Road, Keighley BD20 6TD, West Yorkshire, UK.
7. McEwan H P (1965) Journal of Obstetrics and Gynecology of the British Common wealth 72, 450.
8. M Phillips, P Curtis & N Karanjia. An elemental diet for bowel obstruction in pregnancy: a case study. The
British Dietetic Association Ltd 2004 J Hum Nutr Dietet, 17, pp. 543–545.

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Fungal Dysbiosis in Inflammatory Bowel Disease – Where Are We?

GÎLCĂ Georgiana-Emmanuela1,2, ŞTEFĂNESCU Gabriela1,2,

CIOCOIU Manuela1
1 “Grigore T. Popa” University of Medicine and Pharmacy, Iași, (ROMANIA)
2 “Sf. Spiridon” Emergency Clinical County Hospital, Iași, (ROMANIA)

Abstract

Since there is growing evidence supporting the role of dysbiosis in the pathogenesis of
inflammatory bowel disease (IBD), intensive researsch has focused on identifying key players among
bacterial components. However, available data on the role of fungal microbiota in IBD pathogenesis
is scarce.
We review important microbiome studies focusing on fungal dysbiosis in patients with IBD and
describe mechanisms of intestinal microbiota dysfunction resulting from both clinical and
experimental studies. We focus on recent results of fungal microbiota research from observational
studies to interventional studies regarding immune-mediated interactions between fungal microbiota
and intestinal inflammatory status.
In IBD, bacterial microbiota diversity is reduced, while fungal biodiversity is reduced only in
ulcerative colitis (UC) and not during Crohn’s disease (CD). Fungal depletion in experimental models
has proved to worsen acute colitis. As for identifying the fungal influence upon inflammatory
response, several species among Saccharomyces genera exert regulatory effect on dendritic cells,
modulating various anti-inflammatory cytokine production. In clinical observational studies, specific
associations between bacterial and fungal components were identified, both during flares and
remission periods, involving different changes for UC and CD, but specific mechanisms between
fungal components and host immune system are still under debate.

Conclusions
Interkingdom microbiome alterations are found in IBD, which suggest that fungi may also be
involved in disease pathogenesis, with different involment in UC and CD. Fungal dysbiosis is a
certain player in IBD, both through composition and biodiversity alteration and further studies are
needed to specify the fungi-host immune interactions.
Keywords: microbiota, fungi, IBD, dysbiosis

Introduction

Although the main components assumed to be involved in the pathogenesis of inflammatory bowel
diseases (IBD) have been outlined: the genetic background, environmental factors, immune response
and gut microbiota, the focus in past years has been laid mainly on immune abnormalities.
Considering the genetic predisposition is clearly stated as an important landmark to both Crohn’s
disease (CD) and ulcerative colitis (UC), there is however evidence of the lack of genetic associations
in more than two-thirds of CD and UC patients [1]. This does not disregard the role of the genetic
background, but rather highlights several limitations of genome-wide association studies (GWAS) in
identifying genetic variants and moreover emphasizes that – in most cases – genetic risk itself is not
sufficient in causing IBD [2]. Immune events need integration and interpretation, linking all the main
players in IBD pathogenesis, including the effects of other cells with a role in the complexity of the
inflammatory process, such as endothelial, mesenchymal cells and adipocytes [3] (Fig. 1).

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 Fig. 1. Landmarks in IBD pathogenesis
(adapted from de Souza H and Fiocchi C, 2016) [3]

In finding the link between genetic predisposition and disease, western disorders such as IBD are
likely related to dramatic changes in the microbiota, which are consequence of dietary changes,
increased rates of C-section and excessive use of antibiotics [4, 5]. Thus, understanding the gut
microbiome and the emerging metabolic and complex immune changes emerges as an essential step
in approaching IBD. With the advances in bioinformatics and the emergence of culture-independent
methods to characterize the structural and functional profile of the gut microbiota, important progress
has been done in describing host- microbial interactions and IBD pathogenesis. However, the focus
has been put on bacterial microbiota and less on the fungal component or bacterial-fungal interactions.
Our aim is to review current knowledge on the fungi role in IBD pathogenesis and on potential
developments in the field.

Fungi- immune system interaction

The focus in studying microbiota as a key player in IBD has been put on the bacterial dysbiosis,
characterized by a decrease in biodiversity, an imbalance between Firmicutes and Proteobacteria
phylum, in favour of the latter. Fungal influence on the gut microbiota as a whole and specific
interactions with the immune system have been previously neglected, although there is evidence even
from many years ago that antibodies directed against Saccharomyces cerevisiae mannan (Anti
Saccharomyces cerevisiae antibody (ASCA) were shown to be associated with CD. Furthermore,
IBD-associated genes, such as Card9, are proven to be engaged in immune responses to fungi [6] and
it has been demonstrated on animal models that fungal proliferation is stimulated by inflammatory
status in the gut [7]. In mice, gut inflammation promotes fungi proliferation; conversely, some fungi
can modulate susceptibility to inflammation in a negative (Candida albicans) or positive
(Saccharomyces boulardii) manner [6, 8].
Beyond ASCA association with CD, there are several antibodies recognizing fungal cell wall
elements, inclund anti- anti-chitobioside antibodies (ACCA) and anti-laminaribioside antibodies
(ALCA) associated with with CD [9]. There is a complex process behind the immune response against
fungi, involving various cell types and molecular events. Among the first steps is identifying the
receptors on which fungi cell wall components bind, with reference to the toll-like receptors (TLR)
(especially TLR2 and TLR4) and to C-type lectin receptors (CLR) (such as DECTIN-1 and 2,
MINCLE) [10]. However, the role of TLR signaling in the antifungal immunity is controversial, with
discrepancy in results, especially considering that their activity can be influenced by a variety of
factors, including dietary changes [11], and also by a variety of interactions with chemokines [12].

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 In what concerns CLR recognition, it has been shown that dectin 1 deficiency alters the immune
response to commensal fungi in the gut microbiota and therefore the inflammatory response is favored
[13].
CLR activation leads to tyrosine kinase SYK activation, followed by involvement of caspase-
associated recruitment domain 9 (Card9), determining NFkB and NLRP3 inflammasome activation
and consequent proinflammatory cytokine production. The produced cytokines favor the
differentiation of T cells to Th1 and Th17; Th17 mainly produce IL-17A and IL-22, while Th1
produce mainly IFN-gamma, determining neutrophil recruitment, defensin production and activation
of phagocytes, ensuing elimination of the fungi [6, 14] (Fig. 2).

Fig. 2. Overview on the immune response to fungi

(adapted from Richard ML, et al. 2015 [6])

On Card9 KO mice, recovery after dextran sulphate sodium (DSS)-induced colitis was impaired,
associated to deficient IL-17/IL-22 production and reduced level of Th17 in the colonic lamina
propria. Moreover, the Card9 KO mice were unable to regulate the fungal components of the
microbiota, with an encountered highly increased fungal load compared with the wild-type mice [15].
It is well established that following antigen stimulation, naive T cells develop in Th1 and Th17
cells, in a process including dendritic cells (DC) production of Il-12 and IL-23, during inflammatory
process in IBD, but the regulation of these effector cells is still incompletely understood. A study
conducted by Wu, et al. [16] demonstrated that miR-10a is involved in regulating the inflammatory
process in IBD, through inhibiting DC and consequently, Th1 and Th17 function, thus revealing
another level of regulation in chronic intestinal inflammation. The involvement of of miR-10a in
response to antigen stimulation was highlighted focusing on bacterial antigens, but further studies are
needed in order to confirm if this pathway is also relevant in the response to fungal antigens as well.
It has been stated that various fungi genera may have antiinflammatory potential and the role of S.
cerevisiae in this context has been questioned; it is assumed that S. cerevisiae could be poorly adapted
to an inflammatory environment and/or that it has an anti-inflammatory potential. A study performed
using an in vitro BMDC system suggested that S. cerevisiae may exhibit regulatory effects on the
host, notably by inducing IL10 production [17].
Currently, there are still many aspects to be clarified regarding the interactions of microbiota
components and the host immune system and intestinal epithelial cells, although significant progress
has been registered in what concerns the bacterial component. Since the role played by fungal
component is still under debate, it is not clear whether the identified elements in the fungi-immune

224
system components are purely a pathological process or are a key step in maintaining homeostasis
and development of host immune response, as it is applicable for some bacteria.

Fungal dysbiosis- imbalance in composition and diversity

Altered composition of fungal microbiota in IBD

There are significant differences in the fungal community diversity and composition between the
inflamed and noninflamed mucosa [18]. Li, et al. [19] studied fungal microbiota in patients with CD,
using 18S rDNA-based molecular fingerprinting techniques and characterized the commensal fungal
composition in the ileal mucosa and feces, identifying striking differences in fungal composition in
the inflamed mucosa, compared to healthy subjects, with a marked expansion of Candida spp.,
Gibberella moniliformis, Alternaria brassicicola, and Cryptococcus neoformans. The gut fungal
diversity positively correlated with mucosal inflammation and the disease activity of CD patients,
with a potential involvement in aberrant intestinal inflammatory status. In this study, the
inflammatory response at mucosal level was quantified by the production of TNF- alpha and IFN-
gamma, which were strikingly increased in the ileal mucosa of CD patients, whereas IL-10 showed
an opposite trend, revealing a potential pathway of fungi- gut immune system interaction, mediated
by the activation of CD4+ T cells [19]. Although the study performed by Li, et al included a limited
number of patients, it brings important insight into the differences of fungal microbiota which occur
in CD patients compared to healthy subjects and also opens the road to identifying the role of various
components of the fungal community. Previous studies identified C. albicans as a dual player,
promoting immune tolerance in certain conditions, and also determining mucosal candidiasis and
supporting gut inflammation, favouring excessive growth of various Candida species [20, 21].
It has been stated that the overgrowth of these fungal species at the inflamed sites probably results
from diminished competition of the commensal bacteria in intestinal mucosa [13]. It is also important
to determine whether there is a different fungal signature between CD and UC. Sokol, et al identified
decreased fungal biodiversity only in UC, whereas CD-specific environmental changes may favour
fungi at the expense of bacteria. These results were particularly observed in CD patients with ileal
involvement, while for patients without ileal involvement, the fungal signature was closer to UC
patients, with decreased fungal biodiversity [22]. An important issue arising in this context is whether
there is a significant microorganism-to-microorganism interplay, with potential in modulating
inflammatory response, and also which are the immunological landmarks at ileal level, possibly
responsible for such differences.

Intra- and interkingdom microorganism interplay

Focusing on microorganism-to-microorganism interaction, it is noteworthy that S. boulardii can
influence C. albicans behavior [23, 24]. S. boulardii has been showed to exhibit promising
antiinflamatory effect in experimental studies [23], but translating it into clinical practice, it did not
prove efficiency in maintaining remission in CD patients [24]. This might be due to microorganism-
to-microorganism interplay.
Another key point is identifying whether there is significant interkingdom relationship and
possible synergistic effects or on the contrary-antagonistic activity of various components. There is
insight from experimental studies that metabolic and immunologic connections can be identified
between bacteria and fungi, such as the capacity of lactobacilli to metabolize the tryptophan a
generating a IL-22 response of innate lymphoid cells, which consequently triggers the inhibition of
C. albicans colonization [26]. The importance of inter-kingdom interactions that may be involved in
the inflammatory process was also underlined by Sokol, et al. regarding UC, where restricted
biodiversity in both fungi and bacteria was identified, but also highlighted new interactions between
various microbiota components which may influence the inflammatory process [22].

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Conclusions

The role of fungi in IBD is still under debate and there are multiple questions that need to be
answered, especially considering the influence of standard medical therapy, diet, and other
environmental factors on microbial function in IBD patients. Another questionable issue is whether
the fungal microbiota changes which are already identified are stable and may be taken as reference,
or they have a disease-dependent evolution. Further insights into fungi-immune system are required,
a better understanding of intermicrobial interactions is essential and also understanding the impact
and causality sequence between fungal dysbiosis and gut inflammation. All these are key points in
obtaining an improvement in clinical outcome for IBD patients.

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Gut 60(12), pp. 1739–53.
2. Vora P, Shih DQ, McGovern DP, Targan SR. (2012) Current concepts on the immunopathogenesis of
inflammatory bowel disease. Frontiers in Biosciences (Elite Edition) 4, pp. 1451–77.
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chemically induced colitis and augments inflammatory responses through galectin-3. Journal of Infectious
Diseases 197, pp. 972–80.
8. Chen X, et al. (2013) Probiotic yeast inhibits VEGFR signaling and angiogenesis in intestinal inflammation.
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10. Calich VL, Pina A, Felonato M, et al. (2008) Toll-like receptors and fungal infections: the role of TLR2, TLR4
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11. Kim KA, Gu W, Lee IA, et al. (2012) High fat diet-induced gut microbiota exacerbates inflammation and obesity
in mice via the TLR4 signaling pathway. PLoS ONE 7(10), Article ID e47713.
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microbiota, and intestinal immunity can influence gastrointestinal pathology. Journal of Immunology Research
2015, Article ID 489821.
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1143, pp. 35–44.
16. Wu W, He C, Liu C, et al. (2015) miR-10a inhibits dendritic cell activation and Th1/Th17 cell immune responses
in IBD. Gut 64(11), pp. 1755-64.
17. Jawhara S, Habib K, Maggiotto F, et al. (2012) Modulation of intestinal inflammation by yeasts and cell wall
extracts: strain dependence and unexpected anti-inflammatory role of glucan fractions. PLoS ONE 7:e40648.
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in Crohn’s disease. Journal of Clinical Gastroenterology 48, pp. 513–523.
20. Moyes DL, Naglik JR. (2011) Mucosal immunity and Candida albicans infection. Clinical and Developmental
Immunology 2011, pp307–346.
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26. Zelante T, Iannitti RG, Cunha C, et al. (2013) Tryptophan catabolites from microbiota engage aryl hydrocarbon
receptor and balance mucosal reactivity via interleukin-22. Immunity 39, pp. 372–385.

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The Interrelation between Gastrointestinal Microbiota and
Schizophrenia
ISAC Andra1,2,*, POP Bianca1,2,*, LUPU Viorel1,2, ANDREICA Vasile1,3,
MICLUTIA Ioana1,4
1 Universitatea de Medicină și Farmacie “Iuliu Hațieganu”, Cluj-Napoca (ROMÂNIA)
2 Clinica Psihiatrie Pediatrică, Spitalul Clinic de Urgență pentru Copii, Cluj-Napoca (ROMÂNIA)
3 Institutul Regional de Gastroenterologie și Hepatologie “Prof. Dr. O Fodor”, Cluj-Napoca (ROMÂNIA)
4 Clinica Psihiatrie II, Spitalul Clinic Județean de Urgență, Cluj-Napoca (ROMÂNIA)

* equal contribution of authors

Emails: Isac.Andra@umfcluj.ro, 1biancapop@gmail.com, violupu14@yahoo.com, andreicav@umfcluj.ro, imiclutia@umfcluj.ro

Abstract

Introduction
Schizophrenia is considered the prototype of the psychiatric disorders, considering that it affects
the human being in its entirety – personality and intellect. It is a disorder that lasts for at least six
months, with at least a month in which delirious ideas, hallucinations, disorganized behavior, alogia,
avolition, anhedonia and disorganization in one’s functioning are present.
The most researched physiological mechanisms in schizophrenia, in the last decade, are:
dysfunction of immunologic and inflammatory processes, dysregulation of the gut-brain axis,
oxidative stress, the role of microglia and the action of environmental toxics.

Method
In the current study, the authors wish to analyze the publications that attest the interrelation
between schizophrenia and the digestive tract. The latter can be considered the biggest immunological
organ of the organism and can be the connecting link between schizophrenia, autoimmunity,
inflammation and gastrointestinal microbial homeostasis.

Results
Starting from researchers’ observations, which show the association between gastrointestinal
pathology (celiac disease, casein intolerance, gastritis, enteritis, colitis, etc.) and schizophrenia, one
can support the role of digestive microbiota in the etiology of schizophrenia. The effect of
antipsychotic medication on digestive tract motility is known, but there are studies that attest the
presence of gastrointestinal inflammatory changes in patients without medication.

Conclusions
Based on the studies that sustain the correlation between gastrointestinal pathology and
schizophrenia, this review proposes an investigation into the impairment of the gastrointestinal area
in patients with schizophrenia, the treatment of the digestive pathology imposing itself as a
supplementary part in schizophrenia treatment.
Keywords: microbiota, schizophrenia, gastrointestinal disorders

General aspects

Schizophrenia is considered to be the prototype of the psychiatric disorder, considering the fact
that it affects the human being in its entirety – personality and intellect [1]. It lasts for at least six
months, with at least a month in which delirious ideas, hallucinations, disorganized speech,

228
disorganized behavior, alogia, avolition, anhedonia and disorganized social/occupational functioning
are present [2].
The most researched pathophysiological mechanisms, in the last decade, in schizophrenia are:
dysfunction of immunological and inflammatory processes, oxidative stress, implication of microglia,
dysfunction of the gut-brain axis, metabolic imbalance and the action of environmental toxics [3, 4,
5].
Although the role of microbiota in the onset of mental pathology has been noted since the 19th
century [6], only recently research was conducted to explore the impact of the dysregulation of the
gut-brain axis in schizophrenia. The gut-brain axis is an integrative physiological concept, comprising
the total of communicating pathways between the central nervous system and the gastrointestinal
system [7]. To underline the role of microbiota, Rhee [8] proposed the term of microbiome-gut-brain
axis.
Human gastrointestinal microbiota is represented by over 1014 bacteria, yeast, fungi and viruses
[9], Bacteroidetes and Firmicutes, two bacterial phyla, predominating [10].
The objective of this review is to describe the interaction between gastrointestinal microbiota and
the brain, with an accent on the relation with schizophrenia. For this the EbscoHost, ProQuest,
Thomson Reuters ISI, Web of Knowledge, Science Direct and PubMed databases were accessed
using the key words: schizophrenia, gastrointestinal disorders, microbiome, and microbiota.

Communicating pathways between the gastrointestinal microbiota and the brain

The mutual influence between the gastrointestinal microbiota and the brain can be explained
through:
A. A change in diet. Wang [11] mentioned the fact that the peptides that signal satiety (for ex:
peptide YY) are key molecules that influence the nutritive input and, thus, the availability
of nutrients for the microbiota, thus changing its composition.
B. A neuronal mechanism, operational through the enteric nervous system and the vagus
nerve [11]. Maqsood [6] accentuated the role of intestinal feedback on the brain, specifying
that, although the vagus nerve has a sensitive and motor component, the majority of the
pathways are afferent. Verdu [12] showed that changing the intestinal microbiota through
probiotics influences the intestinal neuromotor function.
C. Imbalance of the hypothalamic-pituitary-adrenal axis (HPA). The involvement of the HPA
axis is sustained by the following elements: a) control of HPA axis development by
postnatal microbial colonization, b) dysfunction of HPA axis in germ-free mice, c)
rebalance of the axis after bacterial transplant (from healthy mice), d) bacterial
translocation influences HPA axis [13], e) probiotics can influence the response of the HPA
axis [14], f) early stress leads to an increase in corticosteroid levels in the blood,
immunologic activation and changes in intestinal microbiota in mice [13, 15], g) the
indirect action of gastrointestinal microbiota on HPA axis by stimulating the vagus nerve
[16], h) changes in microbiota and HPA activation as an effect of induced depression in
mice [17].
D. Involvement of the immunological system. In patients with chronic schizophrenia high
levels of pro-inflammatory cytokines were identified (Il 6, IL 1β, TNF α) and a reduction
of IL 10 levels [6, 18, 19]. Probiotics can modify pro and anti-inflammatory cytokines [13].
The intestinal vasoactive peptide (synthetized intestinally and by the brain) can mediate
the immunological intervention in case of central nervous system inflammation [20].
E. Neurotransmitters’ action. The microbiome synthetizes neurotransmitters and their release
in the intestine leads to a release of modulators by the epithelial cells, acting on the enteric
nervous system or primary afferent neurons. Lactobacillus brevis and Bifidobacterium
dentium produce gamma-Aminobutyric acid, Escherichia, Saccharomyces and Bacillus–
norepinephrine, Lactobacillus–acetylcholine, Streptococcus, Escherichia, Candida and

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 Enterococcus–serotonin, and Bacillus and Serratia–dopamine [21, 22, 23].

Alteration of the microbiota in schizophrenia

Despite the differences in oropharyngeal and gastrointestinal microbiota, Segata [24] showed the
existence of superimposing metabolic pathways. The oropharyngeal samples from patients with
schizophrenia had a higher percentage of Firmicutes compared to controls, where Bacteroidetes and
Actinobacteria predominated. The control group had a higher number of species (Castro-Nallar, cited
by Dickerson) [25]. The bacteria that produce lactic acid are frequently found in patients suffering
from schizophrenia, with Lactobacillus gasseri having the greatest percentage, being over 400 more
abundant (Castro-Nallar, cited by Dickerson) [25].
In a subset of patients with schizophrenia a low intensity inflammatory process was found,
attributed to gastrointestinal dysbiosis, generating bacterial translocation [25]. Thus, antibodies
against Saccharomyces cerevisiae were found in patients with recent onset and chronic schizophrenia
[26], with higher values than antipsychotic naïve patients [27]. Severance [27] has identified a
significant increase of anti-Candida Albicans antibodies in patients with schizophrenia and
gastrointestinal symptoms.
Similarly, to bacterial translocation we can discuss about a translocation of digestive products [25].
In patients with schizophrenia the presence of an immune response against casein (before/after
diagnosis; high values of IgG antibodies showing a predictive risk of 18% in developing the disorder),
gliadin and intestinal inflammatory response were distinguished [4, 25, 26, 28]. Patients with recent
onset schizophrenia had higher levels of anti-gliadin antibodies than patients with multiple episodes
of schizophrenia [25].
Statistically significant differences were observed in the blood levels of D-lactic acid in patients
with schizophrenia [29]. D-lactic acid results from the processing of unabsorbed carbohydrates by
colonic bacteria and leads to cognitive deterioration and ataxia [30].
Fan [31] proposed using the number of leucocytes as marker for systemic inflammation in
schizophrenia and noted a directly proportional correlation between the high value of leucocytes and
the risk to develop metabolic syndrome and the severity of the psychiatric clinical picture. Schoepf
[32] discovered that a higher level of Lactobacillus in patients with schizophrenia is associated with
diabetes as comorbidity.

Gastrointestinal disorders and schizophrenia

Buscaino signaled in his study published in 1953, after the autopsy of 82 persons with
schizophrenia, the presence in 92% of cases of colitis, 88% of cases of enteritis and 50% of cases of
gastritis [33]. The reversed situation was observed, Dickerson [25], mentioning Gupta’s study, 1997,
remarked the presence of schizophrenia as comorbidity in 20% of the cases of irritable bowel
syndrome, and mentioned Whitehead’s study, 2002, which showed the prevalence of psychiatric
comorbidities in 54-94% of patients suffering from irritable bowel syndrome. Jackson, cited by
Dickerson [25], noted that in 1953, Bender observed that adolescents suffering from schizophrenia
were predisposed to celiac disease.
Severance et al. [26] found a significant correlation between anti-Toxoplasma antibodies and
markers of food sensitivity. Toxoplasma produces gastrointestinal inflammation, leading to a
decrease in bacterial diversity in the large intestine, modifying the gut barrier and increasing bacterial
translocation in blood circulation [23].
Numerous researchers sustain the role of gastrointestinal microbiota in the induction of weight
growth in patients with antipsychotic medication [6, 13, 34], which can lead to metabolic syndrome
and insulin resistance. Chrobak [13] noted that administering olanzapine, in female mice, leads to a
change in bacterial phyla, with a decrease in Bacteroidetes and an increase in Firmicutes and pro-
inflammatory markers.

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 Antipsychotic medication leads to numerous changes in the intestinal tract, from abdominal
discomfort, intestinal motility disorders, anorexia to paralytic ileus [35]. Hypomotility given by
clozapine is present in 50-80% of patients under treatment, with three times higher than that of
agranulocytosis [36].

Potential adjuvant interventions in schizophrenia

Considering the possible causality relation between changes in gastrointestinal microbiota and
schizophrenia, there have been several attempts to include in the treatment of schizophrenia
substances that act on microbiota.
The anti-inflammatory effect of antibiotics leads to them being tested as adjuvant medication in
the treatment of schizophrenia. Thus, tetracycline is considered to have neuroprotective action and
intensifies the transmission of glutamate, while minocycline is considered to decrease negative
symptoms [4].
Probiotics stabilize the barrier represented by the gastrointestinal mucosa, regulate the immunity,
the synthesis of antioxidants [34], they have an anti-nociceptive effect [11], improve the behavior
generated by stress or anxiety and ameliorate depressive symptoms [6, 34]. Treatment with
Bacteroides Fragilis administered to mice with schizophrenia symptoms lead to an improvement in
communication deficiencies, stereotype movements and anxiety [37].

Conclusions

With obtaining a broader and more detailed perspective about the way in which the microbiota and
the brain interact, important steps are made in deciding the opportunity to associate antibiotics,
probiotics, prebiotics, certain special diets to the specific treatment of psychiatric disorders in which
intestinal permeability is modified, among which schizophrenia is included.

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