Dott. A. Costantino Dott.ssa Maria Giovanna Minissale Università ...

Dott. A. Costantino Dott.ssa Maria Giovanna Minissale Università degli Studi di Palermo

Scuola di Specializzazione in Gastroenterologia Prof. C. Cammà

Mi fa male la pancia Vado male di corpo

Ho spesso diarrea Ho la pancia gonfia

Nel mondo occidentale, molte persone lamentano cronicamente sintomi suggestivi di intestino irritabile (IBS)

9%

15%

23%

Drossman GE 1997 EPIDEMIOLOGY

EPIDEMIOLOGY

Prevalence estimates for IBS have varied from 3% to 20% in the United States, with similar results reported elsewhere; however, prevalence estimates are influenced substantially by the definition applied.

For example, in Olmsted County, Minnesota, the prevalence of IBS varied from 8% to 22% depending on the criteria used.

Saito YA, Talley NJ, Melton III LJ, et al Neurogastroenterol Motil 2003

EPIDEMIOLOGY Drossman NEJM al 1997

0

2

4

6

8

10

12

14

15-34 35-44 >45

MASCHIFEMMINE

%

Età (anni)

Gender-‐specific prevalence rates for IBS are approximately two female to one male in most studies, and all popula<on-‐based studies have reported a female predominance. Healthy women have: ü  greater rectal sensi<vity, ü slower colonic transit ü smaller stool outputs

Lee OY, Mayer EA, Schmulson M, et al: Gender-related differences in IBS symptoms

Am J Gastroenterol , 2001

EPIDEMIOLOGY

IMPATTO NELLA PRATICA GASTROENTEROLOGICA Mitchell & Drossman

IBS 28%

Fegato 10%

Altri disordini funzionali 13%

IBD 14%

Altre malattie gastrointestinali 15%

Malattia peptica 20%

Irritable bowel syndrome (IBS) and chronic constipation (CC) are 2 of the most common functional gastrointestinal disorders estimated to affect nearly 1 in 5 North Americans. • It has been estimated that the annual cost of IBS in the United States is between $1.7 and $10 billion in direct medical costs, excluding prescription and over-the-counter drugs, and up to $20 billion in indirect costs.

A Systematic Review of the Economic and Humanistic Burden of Illness in Irritable Bowel Syndrome and Chronic Constipation

Dave Nellesen, PhD, MBA; Kimberly Yee, MPH; Anita Chawla, PhD; Barbara Edelman Lewis, PhD, MHA; and Robyn T. Carson, MPH

November 2013 JMCP Journal of Managed Care Pharmacy

Direct costs of IBS ranged from $1,562 to $7,547 per year, and the indirect costs ranged from $791 to $7,737 per year, while the direct costs of CC ranged from $1,912 to $7,522 per year. Indirect costs for CC were not identified. • The distribution health care cost of IBS varied widely, particularly outpatient costs (12.7% to > 50% of total costs), inpatient costs (6.2% to 40.8%), and pharmacy or drug costs (5.9% to 46.6%). Neither study reported cost by standard categories of service. • In studies that compared IBS with a non-IBS control population, quality of life (as measured by SF-36) was significantly lower in IBS patients than in controls. Only 1 study of CC patients reported humanistic burden.

A Systematic Review of the Economic and Humanistic Burden of Illness in Irritable Bowel Syndrome and Chronic Constipation

Dave Nellesen, PhD, MBA; Kimberly Yee, MPH; Anita Chawla, PhD; Barbara Edelman Lewis, PhD, MHA; and Robyn T. Carson, MPH

November 2013 JMCP Journal of Managed Care Pharmacy

La sindrome del colon irritabile (IBS) costa 30 miliardi di euro in soli 10 Paesi dell'Ue. Solo in Italia ne soffrono oltre 3 milioni di cittadini e l'IBS risulta ad oggi tra le principali

cause di assenza dal posto di lavoro.

Il Sole 24 Ore, settembre 2012

Qualità di vita nella IBS: confronto con altre patologie

Wells NEJM, 1997

0 10 20 30 40 50 60 70 80 90

Punteggio medio

USA donne in salute (n=1.412) IBS (n=1.302) IBD (n=546) Cardiopatia congestizia (n=216)

Diagnostic criteria Symptoms, signs, and laboratory investigations

included in criteria

- Manning (1978) - Kruis (1984) - Rome I (1990) - Rome II (1999) - Rome III (2006)


included in criteria

•  Manning (1978): IBS is defined as the symptoms given below with no duration of symptoms described. The number of symptoms that need to be present to diagnose IBS is not reported in the paper, but a threshold of three positive is the most commonly used:

•  1. Abdominal pain relieved by defecation •  2. More frequent stools with onset of pain •  3. Looser stools with onset of pain •  4. Mucus per rectum •  5. Feeling of incomplete emptying •  6. Patient-reported visible abdominal distension


included in criteria Kruis (1984): IBS is defined by a logistic regression model that

describes the probability of IBS. Symptoms need to be present for more than two years. Symptoms: 1. Abdominal pain, flatulence, or bowel irregularity 2. Description of character and severity of abdominal pain 3. Alternating constipation and diarrhea Signs that exclude IBS (each determined by the physician): 1. Abnormal physical findings and/or history pathognomonic for any diagnosis other than IBS 2. Erythrocyte sedimentation rate >20 mm/2 h 3. Leukocytosis >10,000/cc 4. Anemia (Hemoglobin < 12 for women or < 14 for men) 5. Impression by the physician that the patient has rectal bleeding


included in criteria I) Rome I (1990): Abdominal pain or discomfort relieved with defecation, or

associated with a change in stool frequency or consistency, PLUS two or more of the following on at least 25% of occasions or days for three months:

•  1. Altered stool frequency •  2. Altered stool form •  3. Altered stool passage •  4. Passage of mucus •  5. Bloating or distension II) Rome II (1999): Abdominal discomfort or pain that has two of three features for

12 weeks (need not be consecutive) in the last one year: •  1. Relieved with defecation •  2. Onset associated with a change in frequency of stool •  3. Onset associated with a change in form of stool III) Rome III (2006): Recurrent abdominal pain or discomfort three days per month

in the last three months associated with two or more of: •  1. Improvement with defecation •  2. Onset associated with a change in frequency of stool •  3. Onset associated with a change in form of stool

Longstreth GF. et al, 2006

Dolore o fastidio addominale ricorrente per almeno 3 gg/mese negli ultimi 3 mesi associati a 2 o più:

Miglioramenti

con defecazione

Inizio associato con cambiamento

della frequenza delle defecazioni

Inizio associato con cambiamento della forma delle feci

* Criteri presenti negli ultimi 3 mesi con comparsa dei sintomi almeno 6 mesi prima della diagnosi

Diagnostic criteria Sign, Symptoms, and laboratory investigations

included in criteria : ROME III

Il dolore addominale è il sintomo principale dell’IBS, e correla con la severità della malattia e con la ridotta qualità di vita dei pazienti

Sandler et al., Gastroenterology 1984 Spiegel et al., Arch Int Med 2004

Dolore addominale Caratteristiche compatibili con IBS: - crampiforme, di intensità variabile e con esacerbazioni periodiche -  ampia variabilità di localizzazione e severità -  spesso esacerbato da agenti stressanti e dai pasti -  alleviato dalla defecazione nella maggior parte dei casi

Caratteristiche non compatibili con IBS: - Dolore associato ad anoressia, calo ponderale o malnutrizione - Dolore progressivo, o che non permette o impedisce il riposo notturno

Variazioni INTER ed INTRA INDIVIDUALI

Alterazioni dell’alvo DIARREA (IBS-D) -  Valutata secondo la scala di Bristol tipo 6-7 -  Evacuazioni frequenti, di modeste quantità di feci, spesso liquide o

cremose, nella metà dei casi con presenza di muco -  Spesso insorge al mattino o dopo i pasti -  Precedute da dolore addominale crampiforme o urgenza

all’evacuazione, fino all’incontinenza STIPSI (IBS-C) - Valutata secondo la scala di Bristol tipo 1 - Può durare da giorni a mesi, con intervalli di diarrea o alvo regolare - Spesso presente sensazione di evacuazione incompleta

SINDROME DELL’INTESTINO IRRITABILE: “Sottotipi”

-  IBS con stipsi (IBS C): feci dure in più del 25 % delle evacuazioni -  IBS con diarrea (IBS D): feci non formate in più del 25% delle evacuazioni -  IBS mista -  IBS non classificata (unsubtyped)

Altri sintomi

Gastrointestinali: Meteorismo, distensione addominale MRGE Disfagia Sazietà precoce Dispepsia intermittente Nausea

Extraintestinali: Disfunzione sessuale Dismenorrea Dispareunia Incontinenza urinaria Fibromialgia Cefalea Disturbi del sonno (insonnia)

Approccio diagnostico

-  Identificare il sintomo dominante (diarrea, stipsi, dolore) ESCLUDERE i sintomi di allarme (non compatibili con IBS) Rettorragia Dolore addominale notturno o progressivo Calo ponderale

Anemia, anormalità elettrolitiche e incremento degli indici di flogosi

Approccio diagnostico

Esami bioumorali di routine solitamente nei limiti

- Emocromo - Ormoni tiroidei - Calcio, elettroliti, glicemia - Indici di infiammaziome (VES; PCR) - Calprotectina e lactoferrina

Approccio diagnostico IBS- C

-Rx diretta addome (coprostasi altre cause di subocclusione?) -Colonscopia (se sospetto di cause organiche, o

comunque come screening nei pazienti di età superiore ai 50 anni)

-Manometria, defecografia, elettromiografia : se disturbi dell'evacuazione, alterazioni del pavimento pelvico.

Approccio diagnostico IBS-D

-  Coprocoltura (ruolo minore, ma attenzione alla Giardiasi!)

-  Screening per Malattia Celiaca -  UBT al lattosio se sospetto deficit di lattasi -  Cromogranina, serotonina, ormoni neuroendocrini in

caso di diarrea secretoria -  Colonscopia con biopsie (esclusione colite

microscopica)

IBS: EVOLUZIONE DELLE IPOTESI FISIOPATOLOGICHE

1950 1960 1970 1980 1990 2000

Alterata motilità

Ipersensibilità viscerale

Interazioni “brain-gut”

Infiammazione, infezione, fattori genetici

Psicosomatica

FISIOPATOLOGIA: 1- Disturbi Psicosomatici 2- Alterazione della motilità intestinale 3- Ipersensibilità viscerale 4- Risposta infiammatoria 5- Fattori genetici 6- IBS post- infettivo 7- Fattori dietetici 8- Microbiota

1- Disturbi Psicosomatici RISPOSTA MOTORIA ALLO STRESS

“Scoperta del cancro”

“Rassicurazione”

Motilità

3+

2+

1+

0 0 10 20 30 40

Minuti

Lo stress determina un'alterazione della motilità intestinale che si traduce in un aumento della contrattilità dell'intestino,

con la successiva sintomatologia algica Almy TP, Am J Med, 1951

1- Disturbi Psicosomatici IBS: VISITE MEDICHE

MEDICO DI FAMIGLIA 20%

“NON-CONSULTANO” 75%

GASTROENTEROLOGO 4%

CENTRI DI RIFERIMENTO 1%

~60% con disturbi psicologici:

"   Depressione e ansia "   Disordini somatici "   Disturbi della personalità "   Eventi stressanti nella vita

IBS: non tutto è nella mente!

2- Alterazione della motilità intestinale:

La motilità intestinale è incrementata da : somministrazione di acido deossicolico, CRH (situazioni di stress), colecistochinina, cibi grassi, distensione ileale.

- IBS- D: - aumento delle contrazioni segmentarie propulsive - Riflesso gastro colico al cibo - Ipersensibilità rettale

- IBS-C: -aumento delle contrazioni segmentarie non propulsive -Riduzione delle contrazioni propulsive -Riduzione della sensibilità rettale

IBS: TEMPI DI TRANSITO NEL TENUE

Cann PA et al, Gut 1983

0

2

1

3

4

5

6 Controlli IBS (diarrea) IBS (stipsi)

* p<0.01 *

*

Tempo (h)

AUMENTO DELLA MOTILITA’ COLICA POST-PRANDIALE NEI PAZIENTI CON IBS

Rogers et al., Gut 1989

0

500

1000

1500

2000

0 50 100 130

Indice di Motilità m

mhg

IBS

Normale

Pasto

Tempo (min)

Gangli delle Radici Dorsali

Corna posteriori midollo spinale

Tronco

Talamo

Corteccia somato-sensoriale

Lobo frontale Sistema limbico

SISTEMA INIBITORIO

DISCENDENTE

3- Ipersensibilità Viscerale

La sensibilità viscerale intestinale deriva dalla stimolazione di vari recettori sulla parete intestinale. Questi recettori trasmettono i segnali attraverso la via afferente neuronale alle corna dorsali del midollo spinale e infine al cervello.

Mechanisms Underlying Visceral Hypersensitivity in Irritable Bowel Syndrome G.Barbara, C.Cremon, R.De Giorgio. Curr Gastroenterol Rep (2011)

3- Ipersensibilità Viscerale

ATTIVAZIONE CEREBRALE EVOCATA DA STIMOLI INTESTINALI NELL’IBS

Verne et al., Pain 2003

ACC: anterior cingulate; PCC: posterior cingulate; PFC: prefrontal cortex; Ins: insula

Stimolo meccanico

Vascolarizzazione valutata tramite RM encefalo Attivazione dei Lobi Frontali (centro della vigilanza e dell'ansia) > attivazione della regione del Cingolo (sistema endogeno di inibizione del dolore)

RECETTORI SENSORIALI NELLA PARETE INTESTINALE

Chemorecettori

Meccanorecettori

Recettori "Silenti"

Muscolo Mucosa

"   Infiammazione "   Eccessiva contrazione "   Eccessiva distensione

3- Ipersensibilità Viscerale I neurotrasmettitori che favoriscono l'ipersensibilità viscerale sono: - serotonina (recettori 5HT3- 5HT4) - neurochinine - peptidi correlati alla calcitonina - N Metil D aspartato (NMDA)

Mechanisms Underlying Visceral HypersensiKvity in Irritable Bowel Syndrome Giovanni Barbaraat al. Curr Gastroenterol Rep (2011)

4- Risposta infiammatoria La risposta infiammatoria può essere associata a infezioni, ad una flora batterica anormale, alla bile, ad antigeni del cibo

Barbara Neurogastroenteroel Motil 2001

LINFOCITI: queste cellule rilasciano mediatori quali l' NO, l' istamina, le proteasi capaci di stimolare il sistema nervoso enterico , portando ad anormalità motorie e della risposta viscerale Linf T CD8+ Linf B -> con produzione di Ig G ( contro i flagelli batterici) MASTOCITI: vi è una correlazione fra il dolore addominale e la presenza di mast cellule in prossimità delle strutture nervose coliche

4- Risposta infiammatoria CITOCHINE PROINFIAMMATORIE (Che attivano i neuroni afferenti) - PREFORMATE: istamina, serotonina, triptasi

- DI NUOVA SINTESI: prostaglandine, leucotrieni e citochine ( IL1, IL6, TNFalfa)

Barbara Neurogastroenteroel Motil 2001

Genes related to mast cells and the intercellular apical junction complex (AJC) were expressed differently than in healthy subjects. The jejunal mucosa of IBS-D patients displays disrupted apical junctional complex integrity associated with mast cell activation and clinical manifestations. These results provide evidence for the organic nature of IBS-D.

Diarrhoea-predominant irritable bowel syndrome: an organic disorder with structural abnormalities in the jejunal epithelial barrier.

Martínez,Lobo. Gut. 2013

Barbara et al, 2012

CELLULE INFIAMMATORIE NELLA MUCOSA COLICA DI PAZIENTI CON IBS: MASTOCITI

C IBS

% O

F CE

LL

S / AR

EA

p<0.01

CELLULE INFIAMMATORIE NELLA MUCOSA COLICA

DI PAZIENTI CON IBS

0

5

10

15

20

25

30

35

CONTROLLI

IBS

% D

I CE

LL

UL

E / A

RE

A MASCHI

FEMMINE

p<0.01

Barbara et al, 2012

5- Fattori genetici

Gemelli monozigoti n = 117

Levy RL, Gastroenterology 2011

17.2% 8.4%

Gemelli dizigoti n = 164

Concordanti (entrambi affetti da IBS)

Discordanti (solo uno è affetto da IBS)

p = 0.03

5- Fattori genetici Nei pazienti con IBS si può avere: - Ridotto genotipo di IL10 → che predispone ad una maggiore infiammazione in risposta a stimoli non infettivi - Mutazione di uno specifico canale del sodio (SCN5A) -Polimorfismi del gene del trasportatore della serotonina - Varianti funzionali del gene del recettore tipo III della serotonina

Gonsalkorale et al, Gut 2003

RIDOTTO GENOTIPO DI INTERLEUCHINA-10 NEI PAZIENTI CON IBS

0

5

10

15

20

25

30

35

% pz con genotipo G

/G (high producer) IL

-10

* p=0.003

*

IBS (n=230)

HC (n=450)

Gonsalkorale et al, Gut 2003

THE IRRITABLE COLON SYNDROME

.....in 34 patients the symptoms dated from an attack of infective dysentery, either proven or strongly presumptive. The presumptive cases were those in which the patient had been involved in an epidemic of enteritis and had developed chronic symptoms thereafter.....

Quarterly Journal of Medicine 1962;123:307-322

.....examinations of the stools for pathogenic bacteria, amoebae, ova and cysts was negative at the time they came under our care..... ......it was observed that patients with the irritable colon syndrome invariably had a normal mucosa on histological examination....

•  Campylobacter •  Shigella •  Salmonella •  …

IBS post-infettiva (7-31%)

Sintomi acuti

Fattori di rischio

•  Patogeno (virulenza)

•  Severità episodio acuto

•  Fattori genetici

•  Fattori psicosociali

•  Età<29 aa.

•  Femmine

•  Antibiotici

6- IBS post- infettivo

6- IBS post- infettivo Teorie proposte: - Malassorbimento degli acidi biliari con sviluppo di diarrea (IBS D) - Incremento di cellule enteroendocrine/linfociti In particolare l'aumento della serotonina porta ad un incremento della motilità intestinale e della sensibilità viscerale - Uso di Antibiotici

Tornblom, Dunlop Gastroent 2007 Barbara J Neurogastroenterol Motil 2011

7- Fattori dietetici Molti pazienti attribuiscono i loro sintomi all'ingestione di alcuni alimenti, l'esclusione dei quali genera miglioramento. - Allergie alimentari: fra i soggetti con IBS c'è una maggiore quantità di soggetti con prick tes cutanei positivi e con IgG elevate verso taluni alimenti - FODMAP ( fermentable oligo-di- mono saccharides and polyols) Fermentano alivello del tenue distale e del colon causando i sintomi dello IBS, incrementando la permeabilità intestinale e forse anche l'infiammazione - Gluten sensitivity: possono sussistere degli overlap fra GS ed IBS

Atkinson Gut 2004 Austin Clin Gastroenterol Hepatol 2009

8- Microbiota - Nei pazienti con IBS vi può essere un' alterata flora microbica, responsabile di un'aumentata fermentazione ed eccessiva produzione di gas. Il microbiota determina inoltre attivazione di una risposta immune innata a livello mucosale, con incremento della permeabilità epiteliale, attivazione dei nocicettori e disregolazione del sistema nervoso enterico. Questi pazienti possono beneficiare dell'uso di probiotici

Intestinal microbiota in functional bowel disorders: a Rome foundation report. M. Simre, G. Barbara. Gut 2013

- Nel sangue periferico dei pazienti con IBS vi sono Ab contro Ag del microbiota (bacterial flagellin) ed elevati livelli di citochine evocando l'esistenza di un' anormale interazione fra ospite e microbiota con conseguente riposta immunitaria sistemica.

The Immune System in Irritable Bowel Syndrome

G. Barbara, C.Cremon, G.Carini. J Neurogastroenterol Motil 2011.

Dietary modifica<on •  Lactose •  Exclusion of gas-‐producing foods •  Fiber •  Food allergies ? •  Gluten sensitivity ? •  Carbohydrate malabsorption ?

FODMAPs One theory related to IBS suggests that symptoms may be at least in part related to impaired absorption of carbohydrates. The theory holds that fermentable oligo-‐, di-‐, and monosaccharides and polyols (FODMAPs) in patients with IBS or IBD enter the distal small bowel and colon where they are fermented, leading to symptoms and increased intestinal permeability (and possibly inflammation)

Evidence-based dietary management of functional gastrointestinal symptoms: The FODMAP approach. 2010 Journal of Gastroenterology and Hepatology

Physical ac<vity METHODS: We randomized 102 pa<ents to a physical ac<vity group and a control group. Pa<ents of the physical ac<vity group were

instructed by a physiotherapist to increase their physical ac<vity, and those of the control group were instructed to maintain their lifestyle. The primary end point was to assess the change in the IBS Severity Scoring System

APer 12 weeks, there was a trend toward more pa<ents in the physical ac<vity arm showing clinical improvement in the severity

of IBS symptoms compared with the control group (43 versus 26 percent, p = 0.07). In addi<on, pa<ents in the physical ac<vity arm were less likely to have clinically significant worsening of their IBS symptoms (8 versus 23 percent, p <0.01).

CONCLUSIONS: Increased physical ac<vity improves GI symptoms in IBS. Physically ac<ve pa<ents with IBS will face less symptom deteriora<on

compared with physically inac<ve pa<ents. Physical ac<vity should be used as a primary treatment modality in IBS

Physical activity improves symptoms in irritable bowel syndrome: a randomized controlled trial. Joanneson et al Am J. Gastroenterology,. 2011

Psychosocial therapy Psychotherapy, hypnotherapy, and cognitive behavioral therapy (CBT) have been proposed as useful treatments for IBS.

Based on the available literature, IBS patients with abdominal pain, diarrhea, and psychological distress appear most likely to have a beneficial response to such intervention, particularly if the symptoms have been of short duration and have waxed and waned

Psychosocial therapy 32 RCTs were eligible for inclusion: 20 compared psychological therapies with

control therapy or "usual management", 12 compared antidepressants with placebo.

The RR of IBS symptoms persisting with antidepressants versus placebo was 0.66 (95% CI, 0.57 to 0.78), with similar treatment effects for both tricyclic antidepressants and selective serotonin reuptake inhibitors. The RR of symptoms persisting with psychological therapies was 0.67 (95% CI, 0.57 to 0.79). The NNT was 4 for both interventions.

CONCLUSIONS: Antidepressants are effective in the treatment of IBS. There is less high-‐quality evidence for routine use of psychological therapies in IBS, but available data suggest these may be of comparable efficacy.

Efficacy of anKdepressants and psychological therapies in irritable bowel syndrome: systemaKc review and meta-‐analysis. Ford AC, Talley NJ, Schoenfeld PS, Quigley EM, Moayyedi

Gut, 2009.

Medica<ons Pharmacologic agents are only an adjunct to treatment in irritable bowel syndrome.

The chronic use of drugs be generally minimized or avoided because of the lifelong nature of this disorder and the lack of convincing therapeutic benefit.

Poche evidenze The difficulty in demonstrating efficacy may in part be due to

�  the heterogeneous population diagnosed with IBS �  the lack of disease markers �  the high placebo response rates

Jailwala J, Imperiale TF, Kroenke K Ann Intern Med. 2000

Risposta al placebo nell’IBS:

16% - 71%

Patel SM, Neurogastroenterol Motil 2005

OPZIONI TERAPEUTICHE NELL’IBS: IL PRESENTE

STIPSI DIARREA DOLORE

Formanti massa: •  Prebiotici •  PEG Lassativi osmotici •  Lattulosio

Antidiarroici: •  Loperamide •  Colestiramina

Antispastici: •  Anticolinergici •  Olio di menta Agenti oppioido-simili: •  Trimebutina Antidepressivi: •  Triciclici •  Serotoninergici




Antidiarroici: •  Loperamide •  Colestiramina •  Diosmectite

Antispastici: •  Anticolinergici •  Olio di menta Antidepressivi: •  Triciclici •  Serotoninergici

Razionale: riducono il transito intestinale, migliorano l’assorbimento di acqua ed elettroliti, aumentano il tono dello sfintere anale a riposo. •  RCTs positivi (loperamide): 4/4 (2/2 RCTs di alta qualità) •  Efficaci nei pazienti con diarrea (nessun beneficio per il dolore e la distensione) •  Differenza media vs placebo: +28% •  Da utilizzarsi al bisogno. •  Efficacia: loperamide > questran > diosmectite •  Effetti indesiderati

Loperamide: Imodium, Lopemid, Dissenten Colestiramina: Questran Diosmectite: Diosmectal

Antidiarroici Jailwala et al, Ann Intern Med 2000

Loperamide

Loperamide is an opiod-‐receptor agonist and acts on the opioid receptors in the myenteric plexus of the large intestine; by itself it does not affect the central nervous system .

It works similarly to morphine , by �  decreasing the activity of the myenteric plexus. �  increases the amount of time substances stay in the intestine,

allowing for more water to be absorbed out of the fecal matter. �  suppresses the gastrocolic reflex.

Loperamide RESULTS: Throughout the 5 weeks of treatment an �  improved stool consistency �  reduced defecation frequency were found in the loperamide group. An increase in nightly pain was observed in the loperamide group. CONCLUSIONS: The trial shows a benefit of loperamide in an unselected cohort of IBS patients with

regard to stool frequency, stool consistency, but with increased abdominal pain during the night.

A double-‐blind placebo-‐controlled trial with loperamide in irritable bowel syndrome. Efskind PS, Bernklev T, Vatn MH

Scand J Gastroenterol. 1999




Antidiarroici: •  Loperamide •  Colestiramina • Diosmectina


ParasimpaKcoliKci (AnKspasKci)

I parasimpaticolitici sono farmaci antagonisti del recettore colinergico muscarinico; bloccando il legame dell’aceticolina ai recettori post-‐gangliari colinergici muscarinici a livello dei siti neuroeffettori a livello di muscolatura liscia, muscolatura cardiaca e cellule ghiandolari.

Controindicazioni: �  glaucoma ad angolo chiuso non trattato, non controindicato in caso di glaucoma ad

angolo aperto (più comune) o in caso di glaucoma ad angolo chiuso sottoposto a iridectomia.

�  ipertrofia prostatica Effetti collaterali: disturbi dell’accomodazione visiva; vertigini, faticabilità,

secchezza delle fauci, impotenza.

Jailwala et al, Ann Intern Med 2000

Antispastici

Cimetropio bromuro: Alginor Mebeverina: Duspatal Pinaverio: Dicetel M. Scopolamina/joscina: Buscopan

Trimebutina: Debridat/Debrum(bzd)Otilonio bromuro: Spasmomen

Razionale: ridurre la tensione di parete •  RCTs con esito positivo 13/16 •  Differenza media verso placebo: +39% •  Maggior effetto in IBS con dolore addominale •  Effetti indesiderati •  Da usarsi al bisogno e non per periodi prolungati (tachifilassi)

METHODS AND TRIALS: A total of 23 randomized clinical trials were selected for meta-analyses of their efficacy and tolerance. Six drugs were analysed: cimetropium bromide (5 trials Alginor), hyoscine butyl bromide (3 trials Buscopan), mebeverine (5 trials) Duspatal) , otilium bromide ( 4 trials Spasmomen), pinaverium bromide (2 trials Dicetel ) and trimebutine ( 4 trials Debridat). The total number of patients included was 1888, of which 945 received an active drug and 943 a placebo. RESULTS: The mean percentage of patients with global improvement was 38% in the placebo group and 56% in the myorelaxant group, in favour of myorelaxants with a mean odds ratio of 2.13, P<0.001 (95% CI: 1.77--2.58. There was no significant difference for adverse events. CONCLUSION: Myorelaxants are superior to placebo in

tMeta-analysis of smooth muscle relaxants in the treatment of irritable bowel syndrome. Poynard T, Regimbeau C, Benhamou Y

Aliment Pharmacol Ther. 2001

Bulking agents, anKspasmodics and anKdepressants for the treatment of irritable bowel syndrome. Ruepert L, Quartero AO, de Wit NJ, van der Heijden GJ, Rubin G, Muris JW

Cochrane Database Syst Rev. 2011

MAIN RESULTS: A total of 56 studies (3725 pa<ents) were included in this review. There was a beneficial effect for anKspasmodics over placebo for improvement of • abdominal pain 58% of an<spasmodic pa<ents improved compared to 46% of placebo RR 1.32; 95% CI 1.12 to 1.55;P<0.001; NNT = 7, • global assessment 57% of an<spasmodic pa<ents improved compared to 39% of placebo RR 1.49; 95% CI 1.25 to 1.77; P<0.0001; NNT = 5 • symptom score 37% of an<spasmodic pa<ents improved compared to 22% of placebo RR 1.86; 95% CI 1.26 to 2.76; P<0.01; NNT = 3. Subgroup analyses for different types of an<spasmodics found sta<s<cally significant benefits for cimetropium/ dicyclomine (Alginor), peppermint oil, pinaverium (Dicetel) and trimebu<ne (Debridat). Adverse events were not assessed as an outcome in this review. AUTHORS' CONCLUSIONS: There is no evidence that bulking agents are effecKve for treaKng IBS. There is evidence that anKspasmodics are effecKve for the treatment of IBS. The individual subgroups which are effecKve include: cimetropium/dicyclomine, peppermint oil, pinaverium and trimebuKne.

ParasimpaKcoliKci (AnKspasKci)

Peppermint oil To determine the efficacy and tolerability of an enteric-‐coated peppermint-‐oil

formulation (Colpermin), we conducted a prospective, randomized, double-‐blind, placebo-‐controlled clinical study in 110 outpatients with symptoms of irritable bowel syndrome. Patients took one capsule (Colpermin or placebo) three to four times daily, 15-‐30 min before meals, for 1 month.

�  79% (vs 43%) patients on Colpermin experienced an alleviation of abdominal pain �  83 % (vs 29%) had less abdominal distension �  83% (vs 32%) had reduced stool frequency �  73% (vs 31%) had fewer borborygmi �  79% (vs 22%) had less flatulence.

Enteric-‐coated peppermint-‐oil capsules in the treatment of irritable bowel

syndrome: a prospective, randomized trial. Liu JH, Chen GH, Yeh HZ, Huang CK, Poon SK J.Gastroenterol. 1997

Peppermint oil Peppermint oil does appear to be efficacious in IBS for abdominal pain, and it is usually well tolerated; The NNT is 2.5. The usual dose is 0.2 mL three times a day 30 minutes before meals (swallowed not chewed).

American College of Gastroenterology Task Force on IBS: Am J Gastroenterol 2009




Antidiarroici: •  Loperamide •  Colestiramina • Diosmectina


An<depressants Antidepressants have analgesic properties independent of

their mood improving effects and may therefore be beneficial in patients with neuropathic pain. The postulated mechanisms of pain modulation with tricyclic antidepressants (TCAs) and possibly serotonin reuptake inhibitors (SSRIs) in IBS are facilitation of endogenous endorphin release, blockade of norepinephrine reuptake leading to enhancement of descending inhibitory pain pathways, and blockade of the pain neuromodulator, serotonin . TCAs, via their anticholinergic properties, also slow intestinal transit time, which may provide benefit in diarrhea-predominant IBS.

Effetti indesiderati:

Rischio da overdose:

Efficacia:

Aggiustamento della dose:

Triciclici Serotoninergici

Sedazione, secchezza delle fauci, ipotensione, aritmie, aumento peso, stipsi

Insonnia, agitazione, sudorazione notturna, perdita di peso, diarrea

Moderato Minimo

Discreta Discreta

Necessario Inusuale

Costo / mese: $ 5-30 $ 60-100

Antidepressivi

Amitriptilina: Laroxyl, Triptazol Imipramina: Tofranil Sertralina: Zoloft

Paroxetina: Seroxat, Sereupin Fluoxetina: Prozac

An<depressants 32 RCTs were eligible for inclusion: 20 compared psychological therapies with control

therapy or "usual management", 12 compared antidepressants with placebo. The RR of IBS symptoms persisting with antidepressants versus placebo was 0.66 (95% CI,

0.57 to 0.78), with similar treatment effects for both tricyclic antidepressants and selective serotonin reuptake inhibitors. The RR of symptoms persisting with psychological therapies was 0.67 (95% CI, 0.57 to 0.79).

The NNT was 4 for both interventions. CONCLUSIONS: Antidepressants are effective in the treatment of IBS.

Efficacy of antidepressants and psychological therapies in irritable bowel syndrome: systematic review and meta-analysis.

Ford AC, Talley NJ, Schoenfeld PS, Quigley EM, Moayyedi Gut, 2009.

An<depressants MAIN RESULTS: There was a beneficial effect for antidepressants over placebo for improvement of �  abdominal pain (54% of antidepressants patients improved compared to 37% of placebo;

RR 1.49; 95% CI 1.05 to 2.12; P = 0.03; NNT = 5 �  global assessment (59% of antidepressants patients improved compared to 39% of placebo;

RR 1.57; 95% CI 1.23 to 2.00; P<0.001; NNT = 4 �  symptom score (53% of antidepressants patients improved compared to 26% of placebo;

RR 1.99; 95% CI 1.32 to 2.99; P = 0.001; NNT = 4 Subgroup analyses showed a statistically significant benefit for selective serotonin releasing inhibitors

(SSRIs) for improvement of global assessment and for tricyclic antidepressants (TCAs) for improvement of abdominal pain and symptom score.

Adverse events were not assessed as an outcome in this review. AUTHORS' CONCLUSIONS: There is good evidence that antidepressants are effective for the

treatment of IBS. The subgroup analyses for SSRIs and TCAs are unequivocal and their effectiveness may depend on the individual patient

Bulking agents, antispasmodics and antidepressants for the treatment of irritable bowel syndrome.

Ruepert L, Quartero AO, de Wit NJ, van der Heijden GJ, Rubin G, Muris JW Cochrane Database Syst Rev. 2011

SSRIs vs TCAs , POSOLOGY The selective serotonin reuptake inhibitors (SSRIs) cause fewer side

effects than the TCAs, and a meta-‐analysis of the randomized, controlled trials in IBS has reported a global benefit of SSRIs with an NNT of 3.5

If an antidepressant is chosen for the treatment of IBS, low doses should

be administered initially and titrated to pain control or tolerance. Because of the delayed onset of action, three to four weeks of therapy should be attempted before considering treatment insufficient and increasing the dose.

American College of Gastroenterology Task Force on IBS: Am J Gastroenterol 2009

OPZIONI TERAPEUTICHE NELL’IBS: IL FUTURO

MOTILITA’ SENSIBILITA’ SNC FATT. LUMINALI

Antagonisti M3 Antagonisti CCK •  Dex-Loxiglumide Modulatori 5-HT •  Tegaserod •  Alosetron Agenti a2 •  Clonidina

Analgesici viscerali •  Anti-sostanza P •  CGRP Modulatori 5-HT •  Tegaserod •  Alosetron

Encefaline Endorfine

Probiotici Antibiotici topici •  Rifaximina Anti-allergici •  DSCG •  Anti-istaminici Anti-infiammatori •  Mesalazina • Stabilizzatori Mast cell • Ketotifen

Serotonin (5-‐HT) Serotonin (5-‐HT) is a key neurotransmitter and paracrine signaling molecule in the bidirectional

communication between the brain and the gut. Approximately 90% of 5-‐HT in the human body is produced within the gastrointestinal tract, where it is mainly synthesized by enterochromaffin cells, a subtype of enteroendocrine cells. The remaining 10% is present in the brain, where it represents an important neurotransmitter. Peripherally produced 5-‐HT does not substantially interfere with central 5-‐HT since 5-‐HT cannot cross the blood–brain barrier. 5-‐HT, whose activity is terminated by the serotonin reuptake transporter (SERT) located on enterocytes, activates multiple receptors (5-‐HT1-‐7) expressed primarily by different neurons supplying the gut, including extrinsic afferent sensory nerves (vagal and spinal) and intrinsic primary afferent neurons (limited comment about some of what is known of central serotonin and its relation to peripheral 5-‐HT might be made here). 5-‐ HT modulates visceral sensation via both 5-‐HT3 receptor and non 5-‐HT3 receptor-‐dependent mechanisms on vagal or spinal afferents. In the small intestine, 5-‐HT activates predominantly vagal fibers while activation of spinal afferents is relatively less. Conversely, in the colon, 5-‐HT has been shown to activate spinal afferents particularly via 5-‐HT3 receptors.

The 5-‐HT3 receptor antagonist, alosetron, inhibits spinal cord c-‐fos expression in response to noxious colorectal distension , suggesting that 5-‐HT plays a role in the transmission of noxious information within the spinal cord.

Mechanisms Underlying Visceral Hypersensi4vity in Irritable Bowel Syndrome

Giovanni Barbara et al. Curr Gastroenterol Rep (2011)

Serotonin (5-‐HT) 3 receptor antagonists

We found 14 eligible randomized controlled trials of alosetron (n = 3024) or cilansetron (n = 1116) versus placebo (n = 3043) or mebeverine (n = 304).

Random-‐effects meta-‐analyses found 5-‐HT(3) antagonists more effective than the comparators in �  achieving global improvement in IBS symptoms (pooled relative risk, 1.60; 95% confidence

interval [CI], 1.49-‐1.72; I(2) = 0%) �  relief of abdominal pain and discomfort (pooled relative risk, 1.30; 95% CI, 1.22-‐1.39; I(2) = 22%). Nine patients (0.2%) using 5-‐HT(3) antagonists had possible ischemic colitis versus none in control

groups. CONCLUSIONS: 5-‐HT(3) antagonists significantly improve symptoms of D-‐IBS in men and

women. There is an increased risk of constipation with 5-‐HT(3) antagonists, although the risk is lower in those with D-‐IBS

Effects of 5-hydroxytryptamine (serotonin) type 3 antagonists on symptom relief and constipation in nonconstipated irritable bowel syndrome: a systematic review and meta-analysis of randomized

controlled trials. Andresen V, Montori VM, Keller J, West CP, Layer P, Camilleri M

Clin Gastroenterol Hepatol. 2008, Mayo Clinic

Alosetron (Lotronex ®)

Because the drug was associated with ischemic colitis and serious complications related to severe constipation, the Food and Drug Administration (FDA) removed it from the market in the United States , then it was returned to the U.S. market, It was the first drug ever returned to the U.S. market after withdrawal for safety concerns.

An article published in the BMJ noted: "By allowing the marketing of alosetron, a drug that poses a serious and significant public health concern according to its own terms, the FDA failed in its mission

Keto<fen (Mast-‐cell stabilizer) BACKGROUND: Mast cell activation is thought to be involved in visceral hypersensitivity, one of the

main characteristics of the irritable bowel syndrome (IBS) METHODS: 60 patients with IBS underwent a barostat study to assess rectal sensitivity before and

after 8 weeks of treatment. After the initial barostat, patients were randomised to receive ketotifen or placebo. IBS symptoms and health-‐related quality of life were scored.

RESULTS: Ketotifen but not placebo increased the threshold for discomfort in patients with IBS with visceral hypersensitivity. Ketotifen significantly decreased abdominal pain and other IBS symptoms and improved quality of life.

CONCLUSIONS: This study shows that ketotifen increases the threshold for discomfort in patients with IBS with visceral hypersensitivity, reduces IBS symptoms and improves health-‐related quality of life.

(The study did not achieve statistical significance) The mast cell stabiliser ketotifen decreases visceral hypersensitivity and improves intestinal

symptoms in patients with irritable bowel syndrome. Klooker TK, Braak B, Koopman KE, Welting O, Wouters MM, van der Heide S, Schemann M,

Bischoff SC, van den Wijngaard RM, Boeckxstaens Gut. 2010

Keto<fene fumarato (Zaditen®) � Ketotifene è un antistaminico ad azione inibitoria non competitiva sui recettori istaminici H1. Il farmaco ha anche un’attività stabilizzante i mastociti, ostacolandone la liberazione di istamina

�  In Italia in commercio con la sola indicazione della rinite allergica

Effetto della mesalazina sui sintomi in pazienti con IBS

0

2

4

6

8

* p = 0.018 *

Benessere generale

VA

S (0-10)

0

2

4

6

8

VA

S (0-10)

Dolore addominale

T0 8 settimane T0 8 settimane

Placebo Mesalazina (800 mg t.i.d.)

A recent randomized, double-blind, placebo-controlled pilot trial assessed the effect of mesalazine on intestinal immune cells and symptom perception in patients with IBS. Mesalazine markedly reduced mucosal immune cells and mast cells in particular, compared to placebo. In addition, mesalazine significantly improved general well-being. Mesalazine may enhance epithelial barrier function, and preliminary data suggest that it may alter faecal bacterial profiles in IBS patients. Nevertheless, the exact mechanism through which this drug affects immune activation in the intestine of patients with IBS remains unknown

Aminosalicylates and other anti-‐inflammatory compounds for irritable bowel syndrome Dig. Dis. 2009, Barbara et al.

Probiotici

•  Prodotti farmaceutici: miscela di singoli o multipli ceppi di microrganismi vitali usati per trattare o prevenire le malattie umane.

•  Prodotti nutrizionali: microrganismi aggiunti o

presenti naturalmente negli alimenti (cibi funzionali).

Lattobacilli

•  L. acidophilus •  L. paracasei F19 •  L. crispatus •  L. gasseri •  L. johnsoni La1 •  L. reuteri •  L. rhamnosus GG •  L. salivarus

(UCC118)

•  B. adolescentis •  B. animalis •  B. bifidum •  B. longum •  B. infantis •  B. lactis (Bb12)

•  E. faecalis •  E. faecium •  L. lactis •  P. acidilactici

•  B. cereus •  B. subtilis •  S. cerevisiae •  S. boulardi

Lactobacillus species

Bifidobacterium species

Microrganismi non LA-produttori

Altri batteri

Probiotici comunemente utilizzati

Efficacia stabilita ü  Diarrea da antibiotici ü  Gastroenterite acuta (diarrea da rotavirus nei

bambini) ü  Diarrea del viaggiatore ü  Maldigestione di lattosio ü  Profilassi della pouchite

Efficacia probabile

ü  Prevenzione di gastroenterite acuta

ü  Infezione da C.difficile ü  Sintomi associati

all’eradicazione dell’H. pylori

Efficacia potenziale ü  Infezione cronica da

Salmonella o Campylobacter ü  Sindrome dell’intestino

irritabile ü  Dispepsia funzionale ü  Malattia di Crohn ü  Rettocolite ulcerosa ü  Sovraccrescita batterica ü  Irradiazione della pelvi ü  Diarrea HIV-relata

Indicazioni all’utilizzo dei probiotici nelle malattie gastrointestinali

Probiotici nell’IBS: tials clinici controllati

Autore, anno # Pts Criteri Probiotici Sett. Outcome

Positivo

Halpern, 1996 29 ? L. acidophilus 14 Sì

O’Sullivan, 2000 25 Roma L. casei 20 No

Nobaek, 2000 60 Roma L. plantarum 4 Sì

Niedzielin, 2001 40 Manning L. plantarum 4 Sì

Sen, 2002 12 ? L. plantarum 4 No

Kim, 2003 25 Roma II VSL#3 8 Sì/No

Saggioro, 2004 50 Roma II L. plantarum LP0 1 & B. breve BR0 4 Sì

O’Mahony, 2005 77 Roma II L. salivarius UCC4331

& B. infantis 35624* 8 Sì*

An<bio<cs As the microbiota may be disturbed in functional GI disorders, a

potential treatment approach is to try to correct dysbiosis either by

the administration of an antibiotic

Despite evidence that previous antibiotic use may be related to the development of IBS, and the fact

that antibiotic treatment may increase the development of long-‐term digestive symptoms after

bacterial gastroenteritis, poorly absorbable antibiotics might still have therapeutic potential in

this condition. There are three fully-‐published, double blind, placebo controlled trials of rifaximin

in FBD and the data suggest an improvement in symptoms, especially bloating and flatulence for

approximately 10 weeks following treatment.

Intestinal microbiota in functional bowel disorders: a Rome foundation report. Simrén, Barbara et al Gut 2013.

Rifaximin In two identically designed, phase 3, double-‐blind, placebo-‐controlled trials (TARGET 1 and TARGET

2), patients who had IBS without constipation were randomly assigned to either rifaximin at a dose of 550 mg or placebo, three times daily for 2 weeks, and were followed for an additional 10 weeks.

RESULTS: Significantly more patients in the rifaximin group than in the placebo group had adequate relief of global IBS symptoms during the first 4 weeks after treatment (40.8% vs. 31.2%, P=0.01, in TARGET 1; 40.6% vs. 32.2%, P=0.03, in TARGET 2; 40.7% vs. 31.7%, P<0.001, in the two studies combined). Similarly, more patients in the rifaximin group than in the placebo group had adequate relief of bloating (39.5% vs. 28.7%, P=0.005, in TARGET 1; 41.0% vs. 31.9%, P=0.02, in TARGET 2; 40.2% vs. 30.3%, P<0.001, in the two studies combined).

CONCLUSIONS: Among patients who had IBS without constipation, treatment with

rifaximin for 2 weeks provided significant relief of IBS symptoms, bloating, abdominal pain, and loose or watery stools.

Rifaximin therapy for patients with irritable bowel syndrome without constipation.

Pimentel M, Lembo A, Chey WD, Zakko S, Ringel Y, Yu J, Mareya SM, Shaw AL, Bortey E, Forbes WP, TARGET Study GroupN Engl J Med. 2011

Rifaximin �  Meta-‐analysis found rifaximin to be more efficacious than placebo for

global IBS symptom improvement (OR=1.57; 95% CI=1.22, 2.01; therapeutic gain=9.8%; number needed to treat (NNT)=10.2), with mild heterogeneity (P=0.25, I(2)=26%).

�  Rifaximin was significantly more likely to improve bloating than placebo (OR=1.55; 95% CI=1.23-‐1.96; therapeutic gain=9.9%; NNT=10.1), with no significant heterogeneity (P=0.27, I(2)=23%).

�  Serious AEs were rare (<1%) and similar with rifaximin and placebo

The efficacy and safety of rifaximin for the irritable bowel syndrome: a systematic review and meta-analysis.

Menees SB, Maneerattannaporn M, Kim HM, Chey WD Am J Gastroenterol. 2012

Edith Lahner, Stefano Bellentani et al. on behalf of the Study Group Primary Care in Gastroenterology of the Italian Society of Gastroenterology A survey of pharmacological and nonpharmacological treatment of funcKonal gastrointesKnal disorders

United European Gastroenterology Journal October 2013

Management RecommendaKons for Irritable Bowel Syndrome

�  Make a positive diagnosis based on symptoms and the absence of alarm features

�  Determine if there is a comorbid psychiatric disease or an unresolved major loss or trauma.

�  Provide education, including an understandable explanation of why symptoms might arise, emphasizing that the patient is not alone in his or her suffering and the prognosis is benign.

�  Provide firm reassurance, emphasizing that the symptoms are known to be real (not just “in the patient's head”) and that irritable bowel syndrome is a recognized bowel disease.

�  Set realistic treatment goals. �  Organize a continuing care strategy if symptoms have been chronic or

disabling. �  Consider psychological treatments for patients with moderate to severe

symptoms. Irritable bowel syndrome, a little understood organic bowel disease? Talley N. Spiller RC

Lancet 2002

Caso Clinico Signora M. L. T., 67 anni, F 10 anni di sintomi attribuiti come IBS, finché non arriva in DH a settembre 2013: COLONSCOPIA: l'ileo in tutto il tratto osservato, di calibro regolare, si presenta con multiple

ulcere irregolarmente ovalari di dimensioni comprese tra 5 e 20 cm, depresse, a fondo fibrinoso, con eritema a mosaico della mucosa circostante nel contesto di mucosa normale. Colon: Valvola ileo-‐cecale beante ed eritematosa. Cieco, ascendente, trasverso, discendente e sigma con multiple ulcere aftoidi di 2 mm circa, lievemente depresse, a fondo fibrinoso e margini rilevati ed eritematosi.

ENTERO TC: Ispessimento delle pareti dell'ultima ansa ileale che si estende per 20 cm circa con iperdensita' della mucosa dopo mdc cui si associa iperdensita' dell'adipe mesenteriale periviscerale (comb sign) e presenza di alcuni sub-‐centimetrici linfonodi.

BIOPSIE INTESTINALI: A) ILEO B) CECO C) TRASVERSO D) DISCENDENTE E) SIGMA F) RETTO A) Multipli frammenti superficiali di muocosa di piccolo intestino sede di un ntenso infiltrato flogistico cronico, attivo, della lamina propria con isolati ascessi criptici e riduzione della componente ghiandolare. Si segnala la presenza di isolati frammenti costituiti esclusivamente da tessuto di granulazione in fase florida, coerente con la sede ulcerosa del prelievo. B,C,D,E) Frammenti di mucosa di grosso intestino sede di lieve flogosi linfogranulocitaria eosinofila, focalmente attiva, della lamina propria con isolati ascessi criptici. F) Frammenti sede di lieve flogosi cronica inattiva della lamina propria.

Take home messagges IBS deve essere una diagnosi di esclusione IBS sembrerebbe avere cause organiche, ancora non del tutto conosciute

IBS va trattata adeguatamente: ad oggi le linee guida dell’ACG sono un buon aiuto per un approccio EBM.

Bring at home

Mi fa male a panza M’attuppavi!

Me maritu fa piritunaaa! C’aiu siempre u cacarune!

Nel mondo occidentale, molte persone lamentano cronicamente sintomi suggestivi di intestino irritabile (IBS)

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