IRRITABLE BOWEL SYNDROME (IBS) CHRONIC CONSTIPATION Susan Lucak, MD

IRRITABLE BOWEL SYNDROME (IBS) CHRONIC CONSTIPATION Susan Lucak, MD

IBS: Definitions IBS:  Definitions • Functional disorder=absence of organic  abnormalities, i.e. no discernible biochemical  or structural changes • Syndrome not Disease complex biopsychosocial disorder of  disorder of • A complex biopsychosocial unknown cause, characterized by abdominal  pain/discomfort and bowel irregularities (C D pain/discomfort and bowel irregularities (C, D,  C/D), gut interacts withCNS

IBS: Epidemiology IBS: Epidemiology Up to Up to 22% Americans report IBS Sxs 22% Americans report IBS Sxs ~70% IBS patients are women Age : less than 40 l h 0 Not directly lethal, associated with suicidality (SI, SA, suicides) p Q y ( , p ) • Impacts on Quality of Life (~DM, depression) • Reduces productivity (13.4 v. 4.9 days missed  at work) at work) • • • •

Pathophysiology of IBS Proposed Pathophysiology of IBS Acute Gastroenteritis

• Gastrointestinal (GI)  Motor Disturbances

Food

• Visceral  Hypersensitivity

Genetic Factors Environment Abuse History Other Precipitating Factors

• Abnormal Central  Processing of  Sensations • Psychological  Disturbances

Symptoms

Stress

Consultation

Adapted from Rome Foundation Functional GI Disorders Specialty Modules.

IBS: Pathophysiology, Predisposing Factors Genetic Factors IBS aggregates in some families Gene polymorphisms: 5‐HT, IL‐10, COMT – pain sensitivity Twin studies : monozygotes – increased concordance Environmental Factors – Early Life Children of adults with IBS,  more health care visits, social learning of illness  behavior Children with recurrent abdominal pain, higher levels of anxiety +  depression, more Sxs Abuse Historyy Sexual, physical abuse (30‐56% in referral centers in US + Europe, less  frequent in primary care centers) Childhood abuse (~50%) Ab Abuse affects health outcomes (more severe pain,  greater impairment in   ff h lh ( i i i i functioning Precipitating Factors – Adult Life Breakup of a relationship Breakup of a relationship Stressful life events (war, loss of loved one) Chronic life stress (unhappy marriage, war), more severe Sxs

IBS:Pathophysiology, Brain‐Gut Interactions +  Other Possible Modifying Factors Other Possible Modifying Factors Enhanced perception Psychosocial factors

Food

Altered motility

Genetic predisposition

5‐HT

Infection / inflammation

Visceral hypersensitivity Adapted from Camilleri et al, Aliment Pharmacol Ther 1997; 11: 3 

IBS: Functions of the GI tract‐outline IBS: Functions of the GI tract outline Chemical/physical stimulation in the mucosa releases  mediators, stimulate intrinsic neurons in ENS, afferent  nerves synapse with: Sensory: afferent neurons to spinal cord, to brain, • Sensory: afferent neurons to spinal cord, to brain,  descending inhibitory pathways back to ENS  • Motor: interneurons,in ENS,  synapse with motor  neurons in ENS peristalsis (cycles of contraction+ neurons in ENS, peristalsis (cycles of contraction+  relaxation) • Secretory:  interneurons, release of mediators  stimulate chloride secretion i l hl id i • Mediators: 5‐HT, tachykinins, CGRP, enkephalins, Ach,  NO, substance P, VIP, cholecystokinin , , , y

CNS Activation (fMRI) of Normals and IBS Subjects to Rectal Distension

IBS: Brain functional MRI during rectal distention, differential activity in IBS v. C

IBS

80

IBS Controls 60

Active pixels (# per ROI) 40

*

Control PFC ACC IC Thalamus

20

0 Prefrontal

Mertz et. al., Gastroenterology 2000; 118:842

Insula

ACC

Thalamus

Descending Pain Pathways

Descending Visceral Pain Pathway

ACC

Thalamus PAG Locus coeruleus Amygdala

Caudal raphe nucleus

Noradrenergic

Rostral ventral  medulla

Serotonergic Opioidergic

Colon

IBS: Pathophysiology Secretion via Chloride Channels hl d h l Luminal

Abluminal K+ CI– Na+

Cl– channel

CI–

Na+

~

K+

K+

Na+/K+/2CI– Cotransporter Na+ pump N K+ channel

Na+ paracellular path

Adapted from Cuppoletti J, et al. Am J Physiol Cell Physiol. 2004;287:C1173‐C1183.

IBS: Pathophysiology, Secretion via Chloride Channels (ClC‐2) i i hl id h l ( l )

Pathophysiology of IBS Proposed Pathophysiology of IBS Acute Gastroenteritis

• Gastrointestinal (GI)  Motor Disturbances

Food

• Visceral  Hypersensitivity

Genetic Factors Environment Abuse History Other Precipitating Factors

• Abnormal Central  Processing of  Sensations • Psychological  Disturbances

Symptoms

Stress

Consultation

Adapted from Rome Foundation Functional GI Disorders Specialty Modules.

Gut Flora in IBS Postinfectious IBS (PI IBS) Postinfectious IBS (PI‐IBS)

SIBO

Normal Intestinal Microflora Duodenum 101–103 cfu/ml

1011–1012

Stomach 101–103 cfu/ml

Colon cfu/ml Jejunum/ileum 104–107 cfu/ml

Most common bacteria Anaerobic genera

Aerobic genera

Bifidobacterium

Escherichia

Clostridium

Enterococcus

Bacteroides

Streptococcus

Eubacterium

Klebsiella

O’Hara AM. EMBO Rep. 2006;7:688‐693.

• 10 10 trillion nonpathogenic trillion nonpathogenic bacteria in  bacteria in the GI tract (1‐2 kg) • Exert protective function by creating  a barrier against pathogenic by  producing various anti‐microbial  factors • Influence the development and  f ti function of the mucosal immune  f th li system

Risk of PI‐IBS Increases 7‐fold After  Infectious Gastroenteritis* Protective Effect

Increased Risk

Study (year/bacteria) 

OR (95% Cl) 

Ji (2005/Shigella) 

2.8 (1.0‐7.5)

Mearin (2005/Salmonella) 

8.7 (3.3‐22.6) 

W Wang  ( (2004/Unspecified)  / ifi d)

10 7 (2 5 45 6) 10.7 (2.5‐45.6) 

Okhuysen (2004/Unspecified) 

10.1 (0.6‐181.4) 

Cumberland (2003/Unspecified)

6.6 (2.0‐22.3) 

llnyckyj (2003/Unspecified) 

2.7 (0.2‐30.2) 

Parry (2003/Bacterial NOS) 

9.9 (3.2‐30.0) 

Rodriguez (1999/Bacterial NOS) 

11.3 (6.3‐20.1) 

Pooled estimate 

7.3 (4.8‐11.1) 0.1               0.5    1                         10               50    

OR

*Systematic review of 8 studies involving 588,061 subjects; follow‐up ranged from 3 to 12 months. Halvorsen HA et al. Am J Gastroenterol. 2006;101:1894‐1899.

9.8% IBS in  cases  vs  1.2% IBS in  controls

Increased Inflammatory Cells Found in PI‐IBS Rectal Biopsies

Ente eroendocrine Ce ell Countss/100 Epithelial Cells

30

CD8 Lymphocyte Counts

A *

* 20

* *

10

0

Visit 1

Visit 2

Visit 3

Control

PI‐IBS‡

Intraepitheiial CD8 Lymphocytes/100 EEpithelial Cells

Enteroendocrine Cells 8

6

*

4

†

2

0

Visit 1

Visit 2

Visit 3

Levels at 52 wk Levels at 52 wk

25th to 50th Percentile           50th to 75th Percentile          Median (50th Percentile)

*P