Enteric Neuropathy and Diverticular Disease€¦ · Enteric Neuropathy and Diverticular Disease Why...

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EntericEnteric NeuropathyNeuropathy and and DiverticularDiverticular DiseaseDisease

ClassicClassic pathogeneticpathogenetic conceptsconcepts

Ageing

Smooth muscle disorder

Connective tissue disorder

low fiber intake

myochosis

elastosis

predominant in the elderly

Enteric neuropathy ?

WhyWhy shouldshould entericenteric nervesnerves bebe involvedinvolved ??

increased intraluminal pressure

final common pathway for mucosal herniation

segmental hypercontractility („bladder colon“ / „concertina colon“)

increased motor activity

high amplitude propagated contractions

increased motility indices (manometric + myoelectric studies)

most evident after postprandial + pharmacological stimulation

increased painfull sensations

abdominal bloating

intestinal spasms

WhyWhy shouldshould entericenteric nervesnerves bebe involvedinvolved ??

intraluminal pressure motor activity painfull sensations

... ... mediatedmediated byby thetheentericenteric nervousnervous systemsystem (ENS)(ENS)

StructuralStructural alterationsalterations of of thethe ENSENS

MacBeth, J MacBeth, J ClinClin PatholPathol, 1965, 1965

• increase of nerve tissue

• glial cell proliferation

• ectopic ganglia

control diverticular disease First evidence in the literature

„Neuromuscularderangement“

Stoss & Stoss & MeierMeier--RugeRuge, , SurgSurg EndoscEndosc, 1991, 1991

• submucous giant ganglia

• submucous nerve fiber hypertrophy

Intestinal neuronal dysplasia

diverticular disease

Wedel et al., Wedel et al., ViszeralchirViszeralchir, 1999, 1999

• decreased ganglionic size• decreased nerve cell content• increased glial cell content

myenteric hypoganglionosis (25% of cases)

control diverticular disease

Wedel et al., Wedel et al., ViszeralchirViszeralchir, 1999, 1999• submucous giant ganglia• submucous nerve fiber hypertrophy

Intestinal neuronal dysplasia (20% of cases)

Simpson et al., Simpson et al., GastroenterolGastroenterol, 2002, 2002

• increased intramuscularnerve fibers

• increased mucosalnerve fibers

proliferative nerve remodelling

regenerative hyperinnervation

control chronic diverticular disease

FunctionalFunctional alterationsalterations of of thethe ENSENS

Neurotransmitters

• increased VIP-positive neuronsMilnerMilner et al., et al., GastroenterologyGastroenterology, 1990, 1990

• upregulation of tachykinins (substance P, neuropeptide K)• upregulation of galanin• in patients with painfull diverticular disease

Simpson, Simpson, SchofieldSchofield & & SpillerSpiller, , BritBrit J J SurgSurg, 2003, 2003

„„ ......visceralvisceral hypersensitivityhypersensitivity originatesoriginates locallylocally, , possiblypossibly as a as a resultresult of nerve of nerve damagedamage followingfollowing acuteacute diverticulitisdiverticulitis..““

Neuroreceptors GolderGolder et al., et al., LancetLancet, 2003, 2003

• decreased cholinergic innervation• increased muscarinergic receptors

„... cholinergic hypersensitivity due to upregulation of muscarinergic receptors.“

in-vitro contractility

GolderGolder et al., et al., LancetLancet, 2003, 2003

• increased contractionsafter exogenous acetylcholine

HuizingaHuizinga et al., et al., ScandScand J J GastroenterolGastroenterol, 1999, 1999

• uncoordinated contractionsafter exogenous acetylcholine

in-vitro contractility

• decreased ability to relaxafter electrical field stimulation

• decreased ability to relaxin response to VIP / NO

Tomita et al., Tomita et al., RegulRegul PeptPept, 1993, 1993

SummarySummary of ENS of ENS alterationsalterations

Structural alterations

Functional alterations

• myenteric hypoganglionosis• submucosal hyperganglionosis• mucosal nerve fiber hypertrophy

• upregulation of neurotransmitters• upregulation of muscarinergic receptors• hypercontractility• insufficient relaxation

Enteric neuropathy ?

Structural alterations

Functional alterations

• myenteric hypoganglionosis• submucosal hyperganglionosis• mucosal nerve fiber hypertrophy

• upregulation of neurotransmitters• upregulation of muscarinergic receptors• hypercontractility• insufficient relaxation

Enteric neuropathy !

intraluminal pressure

motor activity

painfull sensations

development of diverticula

generation of symptoms

TheThe openopen questionquestion::Primary lesion ?

Secondary lesion ?

• enteric neuropathy causes colonicmotor disturbances

• enteric neuropathy predisposes to diverticular disease

• enteric neuropathy = causative event

• enteric neuropathy results frominflammatory injury

• enteric neuropathy generates symptoms

• enteric neuropathy = concomittant event

ConclusionsConclusions

Enteric neuropathy...

• is associated with diverticular disease

• is characterized by both structuraland functional alterations

• could account for the disturbed motilityand symptom generation in diverticulardisease

• should be considered in a targetedtherapeutic approach (e.g. spasmolytics,muscarinergic antagonists, antinociceptiva)

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Enteric Neuropathy and Diverticular Disease€¦ · Enteric Neuropathy and Diverticular Disease Why...

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