Sindrome dell'intestino

irritabile: diagnosi e terapia

Relatore: Prof. E. Corazziari (Roma)

FGID: DEFINITION

“ Variable combination of chronic orrecurrent gastrointestinal symptomsnot explained by structural orbiochemical abnormalities”

Drossman et al Gastroenterol Int 1990;3:159

FUNCTIONAL BOWEL DISORDERS ROME EVOLUTION

From the Irritable Colon Syndrome to

Functional Bowel DisordersIrritable Bowel Syndrome (Pain + Bowel Disorders)

Functional Constipation (+/- Pain)

Functional Diarrhea (no Pain)

Functional Abdominal Bloating

Unspecified bowel disorders

IBS PREVALENCE IN ITALY

4E Corazziari et al. Digest and Liver Disease 2008;40:944-950

FACE-FACE INTERVIEWPhysical Ex. & USRandom/Electoral Rollsn=46,139 Resp. R 63,2%

IBS ROME I CRITERIA

F= 10.7%M= 5.4%

LA DIAGNOSI DI IBS

IBS- DIAGNOSTIC CRITERIA

HOW TO MAKE A DIAGNOSIS OF A

CHRONIC FUNCTIONAL DISORDER

WHEN NO BIOLOGICAL MARKER

EXISTS ?

By exclusion

Positive-Symptom based

IBS- DIAGNOSTIC CRITERIAExclusion of the Diseases with

Detectable Diagnostic Markers

useful to detect relevant disorders in few patients

but

it requires to submit many patients to many

investigations with elevated costs and risks of iatrogenic

damage

and

it does not offer any certainty about the origin of

symptoms

IBS-DIAGNOSTIC CRITERIA

Positive symptom-based diagnosis

OFFER CONFIDENT DIAGNOSIS?

Reduce unneeded investigations

Plan treatment

Strengthen patient compliance to

treatment and coping ability with chronic

suffering and daily limitations

IBS-D47%

IBS-C22%

23%

12%

53%

12%

40%

60%

IBS SUBGROUPS ACCORDING TO ROME QUESTIONNAIRE AND DIARY CARD

N=68

K= 0.6

6%

75%

13%

6%

85%

6%

9%IBS-D

IBS-C

IBS-M

IBS-U

Piacentino D et al DDW 2010

ABDOMINAL PAIN AND BLOATING DIFFER IN RELATION TO EATING AND DEFECATION IN IBS PATIENTS

Carboni S, Cantarini R, Badiali D, Pallotta N, Corazziari E. DDW 2007

TWO YEAR (IN)STABILITY OF ROME II IBS

Williams et al APT 2006; 23: 197-205

30% IDENTICAL IBS subtypes

ROME II IBS

N= 697

18% ABD PAIN

37% BOWEL

45% NO

SYMPTOMS

52% NOT IBS

18% CHANGED SUBTYPES

D

C

M4%7%

IBS-C-CIC AND IBS-D-FD OVERLAP

Ford A.C. et al. Aliment Pharmacol Ther 2014;39:312-321

ONE YEAR (IN)STABILITY (%) OF ROME III IBS-C & FC

Wong et al. Am J Gastroenterol 2010;105:2228

FC

WELL

IBS-M

WELL

IBS- C

14 25.5

35.5

39

BOWEL CHARACTERISTICS IN IBS-C vs CIC

0

10

20

30

40

50

60

70

80

90

<3 ev/WK Hard Stools Straining Inc. Empty. Stool block Digital

IBS-C

CIC

%

* p<0.001

*

* * *

Ford AC et al. APT 2014;39:312-321

*

*

THE CONSTIPATION UNIVERSE

Rey E et al. Am J Gastroenterol advance online publication, 4 March 2014;doi:10.1038/ajg.2014.18

THE VANISHING FUNCTIONAL ORGANIC BOUNDARIES

Lactase deficiency

Celiac disease

Gluten sensitivity

Bacterial overgrowth

Bile salt malabsorption

Non specific minimal change inflammation

Subclinical intestinal inflammation

EXTRA-GI CONDITIONS IN DBF (>30%)

URINARY Interstitial cystitis Incontinence Detrusor instability

MUSCOLOSKELETAL Fibromyalgia Backache Headache

Whorwell et al 1986; Nyhlin et al 1993; Triadofilopoulos et al 1991

SEXUAL Dyspareunia Decreased libido Inhibited orgasm

PSYCHOLOGICAL Affective disorders Stress sensitivity Illness behavior Health seeking behavior

COMORBIDITIES ASSOCIATED WITH IBS

*p<0.05

Whitehead WE et al. Am J Gastroenterol 2007;102:2762

COMORBIDITY REPORTED PREVALENCE IN IBS

GI disorders

Gastritis, duodenitis 31.2%

Inflammatory bowel disease 27.9%

Gastroesophageal reflux disease 19.0%

Dyspepsia 17.4%

Oesophagitis 15.5%

Anal disease 15.4%

Psychiatric disorders

Depression 30.5%

Stress reaction 17.2%

Anxiety state 15.5%

Symptom-based somatic diagnoses*

Chronic fatigue, malaise 20.1%

Fibromyositis (myalgia) 14.5%

Pelvic pain, vulvodynia 8.6%

Temporomandibular joint disorder 3.3%

Dysmenorrhoea 2.3%

Cystitis 1.8%

STRESSFUL EVENTS PREDICT

Onset of FGIDs

Symptom exacerbation and health seeking

IBS symptom intensity

Bennett EJ et al. Gut 1998: 43:256Creed FH et al. Gut 1988; 29:235

PSYCHOPATHOLOGY IN IBS DYSPEPSIA COMORBIDITY

Piacentino D et al. 2014 Submitted for publication

IBS SEVERITY

DETERMINED BY PATIENT’S SYMPTOM REPORT AND BEHAVIOR

COMPOSITE OF

GI & EXTRA GI SYMPTOMS

DEGREE OF DISABILITY

ILLNESS-RELATED PERCEPTIONS

ILLNESS-RELATED BEHAVIOR

PSYCHOSOCIAL DISTRESS

GENDER / AGE

Drossman DA et al. Am J Gastroenterol2011;106:1759;doi:10.1038/ajg.2011.201;published online 12 July 2011

PSYCHOLOGICAL STATUS IN IBS-C vs CIC & IBS-D vs FD

0

5

10

15

20

25

30

35

40

IBS-C

IBS-D

CIC

FD

ANXIETY SOMATIZATION

%

* p<0.00

*

**

*

Ford AC et al. APT 2014;39:312-321

THE MULTIDIMENSIONAL DIAGNOSIS OF IBS

Symptom-based diagnosis of IBS

Diagnose IBS-Subtype

Assess IBS severity

Assess Stress and Psychological Status

Assess Gastrointestinal comorbidities

Assess extragastrointestinal comorbiditiesAnd

Related polytherapy

CONSIDERAZIONI SULLA DIAGNOSI DI IBS

I CRITERI DI ROMA

Categorizzano a fini classificativi le grandi sindromi funzionali

Non identificano tutti i sottotipi di pazienti

IBS-C E STIPSI FUNZIONALE, IBS-D E DIARREA FUNZIONALE FANNO PARTE DI

UNO STESSO SPETTRO

NELLA PRATICA

IDENTIFICARE LE SOTTOSINDROMI

E

AGGIUNGERE ALTRE VALENZE CLINICHE

DIAGNOSI MULTI DIMENSIONALE

LA SEVERITÀ DI IBS NON E’ MISURABILE SUI SINTOMO INTESTINALI, MA DA UN

COMPLESSO DI FATTORI. I FATTORI PSICOSOCIALI SONO FORTEMENTE ASSOCIATI ALLA SEVERITÀ DEL DOLORE

NELLA PRATICA

NECESSITÀ DI SISTEMATIZZARE UN METODO SEMPLICE PER VALUTARE IL GRADO

E LE COMPONENTI DELLA SEVERITÀ

LA TERAPIA DELL’IBS

IBS•GENETIC

•DISEASES

•STRESSORS

PATIENT BEHAVIOR

CNS

PSYCHOLOGICAL STATUS

GI PHYSIOLOGY

ENS

PHYSICIAN

THERAPY

What the Patient Hears

Doctor-Patient Relationship - FGIDs

23

Just to be sure . . .

Nothing to worry

about . . .

You have IBS . . .

Blah

Blah

CancerBlah

My symptoms

are worse

Do I have

cancer?

I’m under

more stress

They

think it’s

all in my

head

Why am I

not getting

better?

Will you believe me?

IBS - Patient’s Agenda

Am I crazy?

25

IBS - Doctor’s Agenda

Serious

disease

Recent

life stress

Psychologic

comorbidity

Hiddenagendanarcoticsdisabilitylaxatives

Referral

elsewhere?

Social and

cultural

factors

What do

I do?

26

IBS - RELAZIONE MEDICO-PAZIENTE

Acquisire la fiducia di un paziente stigmatizzato e che non capisce

l’origine dei disturbi

• Capire la sofferenza

• Spiegare i disturbi

• Educare il paziente

• Indicare obiettivi possibili

STRENGTH OF DOCTOR-PATIENT RELATIONSHIP

Owens et al Am Int Med 1995

Placebo Effect: 20-40%

Kathryn T et al. Plos One 2012;7; e48135

Number of FU Visits for FBDGenetics & Pl responseCathecol-O-Methyltransferase Val 108 Met Polym.

PFC

PLACEBO RESPONSE IN IBD

Response %

UC 17-28

CD 18-36

CD Fistula closure* 16-18

Sands B Dig Dis 2009;27:68-75

* Ford AC et al Clin Gastroenterol Hepatol 2014 S1542-3565(14)01315-9.doi 10,1016/j.cgh.2014

TREATMENTS FOR FBD

Bloating Diet

Abdominal pain/discomfortDiet

Diarrhea Diet

Constipation Diet

Bloating /

distention

Abdominal pain /

discomfort

Altered bowel

function

Brandt LJ et al. American J Gastroenterol 2009;104 Suppl 1

DIET IN IBS (EIGHT STUDIES)

FODMAP effects in the IBS patients

LOW-FODMAP STUDIESThree studies report symptom improvement with low-FODMAP diets in IBS patients

1. a significant number of IBS patients report gastrointestinal (GI) mmmmmmmmmmmmmmmmmmmmmsymptom foods containing

2. it has been hypothesized that gluten could act as a trigger for GI symptoms IBS and other clinical conditions s

3. GS is characterized by GI and extra-GI symptoms in the absence of the typical immunological and mucosal alterations caused by the ingestion of gluten

symptoms in GS patients are similar to those of IBS patients, even gluten hypersensitivity has been included among the possible etiopathogenetic or exacerbating factors for IBS symptoms

Staudacher et al, 2011: retrospective

De Roest et al, 2013: observational

Halmos et al, 2014:- accurate control of nutrients - 77% fructose malabsorption

- crossover with unblinding effect (only 17% of IBS patients did not

recognize the type of diet)

BLOATING

EFFECTS OF LOW FODMAP DIET IN IBS A

DOUBLE BLIND PARALLEL CONTROLLED CLINICAL TRIAL

PAIN

Piacentino et al. DDW 2014

TREATMENTS FOR FBD

Constipation Fibers (Ispaghula/psyllium)

Bloating /

distention

Abdominal pain /

discomfort

Altered bowel

function

EvidenceLevel

RecommendationGrade

Bran 3 C

Methylcellulose 3 C

Psyllium 2 B

Psyllium+Senna* 3 C

BULK LAXATIVES

Rankumar, Rao, AJGE 2005;

American College GE, AJGE 2005;

*Marlett et al AJGE, 1987

Aggravate Bloating, Dyspepsia, Bran Ineffective in Slow Rectal Transit,

*Aggravate Bloating & Cramps

TREATMENTS FOR FBD

Bloating Probiotics

Abodminal pain/discomfort Probiotics

Diarrhea Probiotics

ConstipationProbiotics

Bloating /

distention

Abdominal pain /

discomfort

Altered bowel

function

FLOW DIAGRAM OF IDENTIFIED STUDIES FOR

META-ANALYSIS OF PROBIOTICS IN IBS

NNT=7

AC Ford et al. Am J Gastroenterol 29 July 2014;doi:10,1038/ajg.2014,202

LIMITS OF PROBIOTIC STUDIES

LITTLE NUMBER OF PROPERLY-PERFORMED STUDIES

META-ANALYSIS POOL STUDIES WITH

Different Probiotics

Different Probiotic Species Combination

Different Dosages

Different Conditions

Different Patients

Few Patients

Direct-to-consumer marketing and lack of regulation are obstacles to proper clinical studies

43VERNA E.C. ET AL. THER ADV GASTROENTEROL 2010;5:307-319

FBD TREATMENT WITH PROBIOTICS

DIARRHEA PAIN BLOATING

GONFIORE DIARREA

CONSTIPATION BLOATING GONFIORE

Lactobacillus GGVSL #3 Lactobacillus

PlantarumLactobacillus Reuterii Bifidobacterium InfantisLactobacillus Casei

Saccharomyces Boulardii

B.Longum/Rhamnosus Acidophilus

L. Casei/Paracasei/Thermophilus

B. Lactis AnimalisL. Casei Shirota

TREATMENTS FOR IBS

Bloating Antibiotics

Diarrhea Antibiotics

Bloating /

distention

Abdominal pain /

discomfort

Altered bowel

function

EFFECT OF RIFAXIMIN ON NON-CONSTIPATED IBS

46

Pimentel M et al. N Engl J Med 2011;364:22-32

TREATMENTS FOR FBD

Abdominal pain/discomfort Antispasmodics Antidepressants

- TCAs/SSRIs/SNRIsBloating /

distention

Abdominal pain /

discomfort

Altered bowel

function

Poynard T. et al . Aliment Pharmacol Ther 2001;15:355-361

ANTISPASMODICS IN IBS

ANTIDEPRESSIVI NELLA SII

Jackson JL et al A J Med 2000

ANTIDEPRESSIVI

Studi controllatiDisordine dell’asse Cervello-Visceri

Alterata motilità GI

Ipersensibilità viscerale

Alterazione dei meccanismi centrali di regolazione

Neuroendocrino

Autonomico

Cognitivo

della percezione del dolore

EFFICACY OF ANTIDEPRESSANTS AND PSYCHOLOGICAL THERAPIES IN IBS

NNT 95%CI

TCA 4 3-6

SSRI 4 2.5-20

CBT 3 2-6

Hypnot 4 3-8

Ford AC et al. AJG 2014;109:1350-65

ANTIDEPRESSANTS FOR IBS CLINICAL CONSIDERATION

1. ACG Task Force on IBS. Am J Gastroenterol 2009;104(suppl 1):S1-S352. Ford AC et al. Gut 2009;58:367-3783. Grover M. Drossman A. Curr Opin Pharmacol 2008;8:715-723

TCAs in IBS-D, SSRIs in IBS-CSSRI/SNRI for anxiety

Poor response3 Satisfactory response3

Switch to different class antidepressant Combine treatments as augmentation Obtain psychiatry consultation

Continue at minimum effective dose for 6 to 12 months

Long-term therapy may be warranted for some patients

TREATMENTS FOR FBD

ConstipationSecretagogs Linaclotide

Bloating /

distention

Abdominal pain /

discomfort

Altered bowel

function

T53

Cl-Cl-

Na+

K+

K+

K+2Cl-

Tight

junction

H2O

Na+

H2O

Na+

Chloride Channels in Intestinal Transport

Ion Transport

Na+

CFTRchannel

EnterocytesCl C2

channel

Corsetti M, Tack J. UEG Journal 2013;1:7-20

AZIONE DELLA LINACLOTIDE SULL’EPITELIO INTESTINALE

Chey WD et al. AJG 2012;107:1702-12

EFFETTO DELLA LINACLOTIDE NELLA IBS-C

EFFECT OF LINACLOTIDE VS PLACEBO

IBS-C290gNNT

CC 145gNNT

CSBM(3/WK) 8 7

Abd. Pain/Disc. 8 9

CSBM+Abd Pain 12 5

Adequate Relief (>75%) 5 4

TREATMENTS FOR FBD

Bloating Diet Probiotics Antibiotics

Abdominal pain/discomfortProbiotics Antispasmodics Antidepressants

- TCAs/SSRIs/SNRIs

Diarrhea Diet Probiotics Antibiotics Colestyramine Loperamide

Constipation Diet Fibers (Ispaghula/psyllium) Probiotics LinaclotideWater-binding macrogol/Osmotic laxatives Prucalopride

Bloating /

distention

Abdominal pain /

discomfort

Altered bowel

function PsychotherapyCBT

Hypnotherapy

EFFECTIVENESS VS INVASIVENESS OF IBS TREATMENT

58Modified from Simrén M. et al Gut 2013;62:159-176

More Invasive

and/or Less Safe

Less Invasive

and/or Safer

Less Effective More Effective

Linaclotide

Loperamide

Probiotics

Loperamide

Prebiotics

TCA

Antispasm

Systematic

Exclusion Diets Low FODMAP DIET

Placebo

Antibiotics

FMT IN REFRACTORY IBS (N=13)

%

Pinn et al. Presented at AM College Gastroenterology 2013

EFFECTIVENESS VS INVASIVENESS OF IBS

TREATMENT

60Modified from Simrén M. et al Gut 2013;62:159-176

More Invasive

and/or Less Safe

Less Invasive

and/or Safer

Less Effective More Effective

Linaclotide

Loperamide

Probiotics

Loperamide

Prebiotics

TCA

Antispasm

Systematic

Exclusion Diets Low FODMAP DIET

Placebo

Antibiotics

• Valutare la storia medica, la personalità e la famiglia

Valutare la qualità di vita e il livello di attività quotidiana

Valutare la storia psicosociale

• Spiegare e rassicurare

• Istituire terapia appropriata

Stabilire una relazione terapeutica

Prescrivere test diagnostici Prescrivere test diagnostici

APPROCCIO MULTIDIMENSIONALE AL PAZIENTE CON MALATTIA CRONICA

Fare una diagnosi

IBS

GENETIC

HYPERSENSITIVITY

DIETARY FACTORS

INFLAMMATION

IMMUNE RESPONSE

STRESS

PSYCHOSOCIAL FACTORS

ALTERED MOTILITY

BEHAVIOR

DYSBIOSIS

CNS/ENS ALTERATIONS

GI SECRETION

IBS SEVERITY

DETERMINED BY PATIENT’S SYMPTOM REPORT AND BEHAVIOR

COMPOSITE OF

GI & EXTRA GI SYMPTOMS

DEGREE OF DISABILITY

ILLNESS-RELATED PERCEPTIONS

ILLNESS-RELATED BEHAVIOR

PSYCHOSOCIAL DISTRESS

GENDERE / AGE

Drossman DA et al. Am J Gastroenterol2011;106:1759;doi:10.1038/ajg.2011.201;published online 12 July 2011

CO MORBIDITY

SYMPTOM SEVERITY

QOL

EPISODE FREQUENCYIBS

COMORBIDITY

HYPERSENSITIVITY

BILE AC. MALABSORPTION

DIETARY FACTORS

ENVIRONMENTAL FACTORS

PSYCHOLOGICAL ALTERATIONS

SPASM

ILLNESS BEHAVIOR

DYSBIOSISS

RAPID TRANSIT

SLOW TRANSIT

IBS Pain Severity

Episode FrequencyEpisode Duration

QoL

MULTIDIMENSIONAL DIAGNOSTIC ASSESSMENT OF IBS PATIENT

POLY THERAPY

COLESTYRAMINE

PROPER DIET

TCA 5HT3 ANTAGONIST

RELAXATION TRAINING HYPNOSIS

SSRI SNRI PSYCHOTHERAPY

COGNITIVE BEHAVIORAL TH

STRESS

PROBIOTICS ANTIBIOTICS

SPASMOLYTICS

FIBER, LINACLOTIDE LAXATIVES, PRUCALOPRIDE

LOPERAMIDE, TCA

LONG DURATION

HIGH

SYMPTOM SEVERITY

LOW

SHORT DURATION

HIGH

FREQUENCY

LOW

IBS EPISODE

REASSURANCE ON DEMAND

CONTINUOUS

INTERMITTENT

CONSIDERAZIONI SULLA TERAPIA DI IBS

LE TERAPIA FARMACOLOGICHE SONO STATE TESTATE SU IBS, IBS-C E IBS-D. MANCANO STUDI SULLE SOTTOSINDROMI

FONDAMENTALE IL RAPPORTO MEDICO-PAZIENTE E L’EFFETTO PLACEBO

NELLA PRATICA

ESALTARE LE CAPACITÀ DEL MEDICO

LA DIETA LOW-FODMAP OFFRE NOTEVOLE BENEFICIO

LA LINACLOTIDE, PRIMO FARMACO CHE AGISCE TOPICAMENTE SULL’EPITELIO

SIA SU STIPSI CHE DOLORE

NELLA PRATICA

IDENTIFICARE CHI RISPONDE ALLA DIETA LOW-FODMAP E ALLA LINACLOTIDE