Disorders of ENS Flashcards
What is the ENS?
Extensive ganglionic network of neurons & glia
400-600 million neurons in humans
1.2 million in mice
ENS activities
Propulsive and mixing motility patterns- getting stuff through the GIT and making sure food is mixed and comes in contact with walls for absorption
Fluid movement across epithelium- esp wrt submucosal plexus
Gastric acid secretion- hormones, other elements
Blood flow
ENS Cell Types
Interstitial cell of Cajal (ICC)-type of interstitial cell in GI tract
Myenteric [ICC-MY]-pacemaker which creates the bioelectrical slow wave potential that leads to contraction of smooth muscle.
Intramuscular [ICC-IM]- involved in the stimulation of smooth muscle cells, neurotransmitters act through them.
Intrinsic primary afferent neurons [IPAN]s
Have cell bodies in walls of intestine
Specialised neurons that encode information about the state of the gut that transduce mechanical and chemical stimuli that reflect tension in gut wall and chemical nature of lumen
They connect with interneurons and motor neurons in the gut to form intrinsic muscle motor, secretomotor and vasomotor reflexes
Aid reflex loops in the gut- connect interneurons with motor neurons in gut to form intrinsic motor reflexes
Disorders of ENS
Disorders of colonisation by migrating neural cells
Aganglionosis- Hirschsprung’s disorder, related to RET, GDNF and END3 genes
Disorders of differentiation
Hyperganglionosis
- Intestinal dysplasia- A” form affecting the sympathetic innervation, and “B” version affecting parasympathetic innervation
- Dysplasia - expansion of immature cells (such as cells of the ectoderm), with a corresponding decrease in number & location of mature cells; typically used when cellular abnormality is restricted to originating tissue
Ganglioneuromas-rare tumors that most frequently start in the autonomic nerve cells, which may be in any part of the body-usually noncancerous
Disorders of Survival / maintenance of neurons
Hypoganglionosis- reduction in ganglia
Neuronal intranuclear inclusion and apoptosis
Neuronal degeneration
Hirschsprungs Disease
Complete absence of ganglion cells in mucosal and myenteric plexuses
Failure of ENCCs to colonise gut fully
Aganglionic region is obstructed- accumulation of contents- megacolon
Results in decreased motility in the affected bowel segment, lack of propagation of peristaltic waves into the aganglionic colon, and abnormal or absent relaxation of this segment and of the internal anal sphincter
Congenital, polygenic disorder-mutations affecting a wide array of genes
Control tyrosine kinase function, neurotrophins-crucial role
RET mutations -50% of familial forms and 17-20% of sporadic
Occurs as a sole disease or part of a syndrome
E.g. Waardenburg-Shah syndrome-pigmentary disorders and neural deafness
Clinical Signs of Hirschsprungs
Diagnostic evaluation- plain abdominal radiography, followed by a contrast enema examination of the colon to confirm the diagnosis of HD
Occasionally, ultrasonographic findings may also suggest the diagnosis
Rectal biopsy of submucosa-absence of submucosal ganglia, hypertrophic submucosal nerves
Stains for more densely packed, large, AChE-positive fibers through the full thickness of the muscularis mucosae.
In addition, prominent AChE-positive fibers are often present in the lamina propria
Treatment of Hirschprungs
Surgery removes area of large intestine (no nerve cells)-first months of life
Enemas-remove stool from the intestine until surgery
End of large intestine is removed; colostomy bag placed there
Allows the remaining normal intestine time to recover
After a few weeks or months, colostomy is closed & healthy intestine is reattached
Stool will again pass from the body through anus
Complications: leak where the intestine is re-joined (anastomotic leaks) and scar tissue formation (strictures)
After surgery
No further intestinal blockages are expected
Long-term outcomes are variable
Fecal incontinence
Recurrent or chronic abdominal pain or constipation
Some may persist into adulthood
Hirschsprung’s-associated enterocolitis
Inflammation-a perforation may form in the large intestine, causing stool to leak inside the abdomen- emergency surgery needed
The cause of symptoms that won’t go away is often unclear
Hypertrophic pyloric stenosis
Pyloric sphincter (btw oesophagus and stomach) won’t relax in an appropriate manner When hypertrophic, won't contract or expand appropriately- can lead to reflux
Achalasia AS an ENS disorder
NT disorder
Symptoms: dysphagia (difficulty in swallowing), regurgitation of undigested food, chest pain behind the sternum, and weight loss
Incomplete lower oesphageal sphincter (LES) relaxation, increased tone, lack of peristalsis
Cause of most cases unknown
Pressure and relaxation- normally regulated by excitatory (e.g., acetylcholine, substance P) and inhibitory (e.g., nitric oxide, vasoactive intestinal peptide) neurotransmitters
Imbalance in excitatory and inhibitory neurotransmission
Diagnosis-barium swallow, manometry (catheter from mouth to oesophagus with baroceptors on it), biopsy (hypertrophied musculature and absence of certain nerve cells of the myenteric plexus)
Treat: lifestyle changes, calcium channel blockers, botox, surgery
Irritable bowel syndrome as ENS disorder
Disturbances of anal pressure activity, colonic motor function, small-bowel motility, gastric motiltity, & visceral sensitivity
Causes are unclear
But enteric infections precede the development of IBS (post-infectious IBS)
& IBD in remission express IBS-like symptoms
Inflammation
Lots of lymphocytes in GI tract, including infiltration into myenteric ganglia
If inflammation continues, causes enteric neuropathy- destruction of ENS tissue and neurons die
Molecular dysregulation of peristalsis
Tend to be acquired rather than congenital
Disturbances in ENS nerves and neurotransmitters- altering the peristaltic reflex
Slow colonic transit disorders (e.g. gastroparesis, pseudoobstruction, constipation, megacolon)
IPANs-activated by neurotransmitters released
Treating ENS disorders
Depends greatly on basis of disorder Surgery Steroids & immunosuppressives Neurotrophic factors NGF, BDNF, NT-3, 4, 6 Bind to plasma membrane bound molecules-signal activation of RET Lead to survival of enteric neurons; modulates neurotransmitter synthesis; increases neuronal excitability; provides long-term synaptic potentiation of neurons (ie direct and indirect actions) Transplanting progenitor cells
Diagnosing of ENS disorders
Current steps in clinical evaluation
Exclusion of mechanical obstruction
Endoscopy (tube with camera attached used to visualise what’s going on in the GIT) & barium studies
Assessment of motility
Transit profile of tagged molecule through GIT
Manometry- pressure measured through GIT
Identify complications of motility disorder
Bacterial overgrowth, dehydration, malnutrition (esp diarrhoea)
Identify pathogenesis
Neuropathic causes with uncertain aetiology often seen
Further testing- looking at autonomic nervous system; brain/brainstem lesions; neurologic autoimmunity if etiology not discovered
Biopsies
No definite indications of when to collect- taken from patients with unknown origin of dysmotility
