00:01
Welcome.
00:02
This talk is all about
Hirschsprung disease.
00:05
You may not have heard about
this before but now you will.
00:09
Hirschsprung disease is also
called congenital megacolon.
00:13
And basically it's
caused by the failure
of neural crest
derived ganglion cells
to migrate all the
way along the length
of the colon down to the anus.
00:25
The epidemiology,
this is kind of interesting,
about 1 in 5,000 live
births in the US and that
same frequency happens
pretty much around the world.
00:35
It is much more common entity
in baby boys than in baby girls.
00:40
There may be a more,
a greater predilection
in certain populations
of Asian descent.
00:48
The pathophysiology involves
mutations in the
RET tyrosine kinase.
00:55
So, in these genes, that would
normally
control the growth and differentiation
of neural crest cells there's a loss of
function in these genes.
01:04
Most commonly,
it is the RET gene.
01:07
So RET stands for rearranged
during transfection gene
and as a receptor tyrosine
kinase loss of function of the RET tyrosine kinase
in the neurons
leads to the Hirschsprung disease.
01:22
Interestingly,
there are other diseases
associated with gain of
function so constitutive
activation of the
RET tyrosine kinase.
01:30
That gain of function
mutation in other tissues
associated with
various cancers including
the multiple endocrine
neoplasias, types lla and llb.
01:42
Interestingly, RET mutations,
the loss of function mutations
associated with Hirschsprung disease
may also be influenced
by environmental factors,
some of which may be sex linked,
and those can then modify
the severity of the final disease.
02:03
In Sporadic
Hirschsprung's disease,
which is most common,
about 70% of cases,
a third of those may
have RET mutations.
02:13
There are other mutations
and that may lead to similar
loss of normal
migration of the neurons.
02:21
In familial disease,
approximately half
of the cases will
have RET mutations.
02:25
And again, there are other known
signaling molecules
that may be involved in the
normal migration of these neurons.
02:34
When it's part of the
genetic syndrome,
the RET mutations or other
mutations are frequently
associated with Down
syndrome or Trisomy 21.
02:45
The Waardenburg
syndrome which is
associated with abnormal
melanocyte migration
and melanocytes are
neural crest-derived cells.
02:53
So, it makes kind of
sense that defects
in melanocyte migration
might also be associated with
defects in the neural migration
in Hirschsprung disease.
03:05
Additional congenital
malformations are present
in about a quarter
of individuals,
again, speaking to syndromic
genetic changes.
03:14
And frequently there is
congenital heart disease.
03:17
And in fact, in those who have
Down syndrome, trisomy 21,
there's a very high prevalence
of cardiac heart anomalies.
03:29
So normal peristaltic
movement within the GI tract.
03:33
This is normal movement squeezes
the bowel contents from proximal-to-distal.
03:37
This top-to-bottom
trajectory requires
the coordinated activity
of parasympathetic ganglia
and nerve plexi that sit within
the layers of the muscularis propria.
03:47
So the major layers of smooth
muscle around the bowel,
and in particular,
we're going to be
talking about Auerbach
Myenteric Plexus.
03:55
During development,
the nerves responsible for this activity
must migrate from the original
location in the neural crest,
and traffic all the way
along the elongating
bowel
eventually reaching
completely to the rectum.
04:09
In Hirschsprung's disease,
mutations and again,
chiefly in the RET
tyrosine kinase gene
cause the cells to lose their ability to have
the normal cellular proliferation
and movement and you
have an incomplete migration.
04:23
Sometimes, fortunately,
this only involves
just the very last
bit of the rectum
at the most distal end
of the migratory path.
04:31
But sometimes it can
affect the entire large bowel
and even parts
of the small bowel.
04:36
In most cases, the migration
of the neurons ends somewhere
in the sigmoid
colon in patients who
are going to have
Hirschsprung disease.
04:44
When this happens,
the affected portions of bowel
are no longer able to
transmit a peristaltic wave
and they tend to just kind of sit
there in a hyper contracted state,
so they don't relax and they
don't move the peristaltic wave.
04:57
That hyper contracted state
of that portion of the bowel
interferes with the
passage of stool contents.
05:03
Depending on how much
of the bowel is affected,
therapy can range from just
dilating the rectum to complete
surgical resection of the
affected portion of the bowel.
05:13
Gross pathology is pretty
obvious when you think about
what's going on at the
molecular and cellular level.
05:20
So there is muscular
hypertrophy and dilation
of the bowel proximal
to the obstruction.
05:24
Clearly, the bowel is trying to
squeeze past the area of obstruction.
05:30
With that hypertrophy,
and then dilation
due to the obstruction,
you may progress to a megacolon,
and even rupture,
which typically would
occur in the cecum.
05:40
In Hirschsprung disease,
the rectum is always involved,
that's the most distal end
of the migratory pathway.
05:46
In short-segment disease,
you'll have involvement
of the rectosigmoid colon,
and that's going to be the
most common manifestation.
05:54
And if we have extension
more proximal to the sigmoid,
so called long sigmoid
disease that occurs
in about 15% to 20% of patients.
06:03
It's relatively rare to have
total colonic aganglionosis,
and that's only
5% of cases or less.
06:12
So what's being demonstrated
on the right in the histology,
on the top is the normal
layers of smooth muscle,
we have an inner circular
layer of the muscularis propria.
06:24
And we have an outer longitudinal
layer of the muscularis propria,
and in between are ganglia
of the Auerbach's Plexus,
that's going to be responsible
for coordinating their movement.
06:35
In the bottom slide,
on the right hand side,
So this portion
of the bowel is not
innervated and can't
undergo peristalsis.
06:46
And so now we're going to
have that hyper contracted
bit of smooth muscle
in that location.
06:51
This is what's been
shown on the left.
06:53
So all the way down on the
kind of the bottom on the right,
we have the Rectosigmoid
which is a little
shriveled kind of worm-like
structure that has
never been able to have
a normal peristaltic wave.
07:07
That hyper contraction
of the smooth muscle
in that location due to
the loss of the ganglia
is going to cause more
proximal bowel dilation.
07:17
And you can see that
massively dilated segment
all the way over into the small
bowel on the left hand side.
07:25
The clinical presentation.
07:27
There's a classic triad,
so babies don't pass meconium.
07:31
That's the early
bowel contents of
within the typical
two days after birth.
07:38
Because there is
now this proximal
dilation due to
the distal stenosis,
you will have expanded
abdominal contents
and abdominal distension.
07:49
And because the baby
is not able to move,
bile, and anything that's
ingested more distally,
it tends to eject with
forceful bilious vomiting.
08:00
Additional signs and symptoms.
08:01
So depending on the
degree of obstruction,
if there's just a little bit
at the very distal rectum,
you can actually do
a digital rectal exam
and allow massive
release of air so there'll be
an explosive expulsion
of gas and stool.
08:21
Depending on inflammation
that may be associated
with the dilation
depending on ischemia,
you may have an enterocolitis.
08:30
And typically,
if there's going to be a perforation,
it's going to be at the level
of the appendix or cecum.
08:37
So how do we make the diagnosis?
Not too hard.
08:41
So if we don't have the
normal passage of meconium,
we have distension
of the abdomen.
08:46
If we have bilious vomiting,
we're kind of suspicious
that there may be
obstruction someplace.
08:51
If we do a contrast enema,
the lumen of the bowel is there,
we just can't get
stool to go through it
because there is no relaxation.
09:01
It's a hyper contracted
bit of smooth muscle
in that portion of the bowel.
09:06
So if we do a contrast enema,
going from below up,
we will see a stenotic segment
into dilated loops of bowel
which is what you're
seeing on the right hand side.
09:18
You can also do
anorectal manometry.
09:20
So just put a pressure sensor up
and see that there's a
hyper contracted segment.
09:25
We can confirm our diagnosis
by doing a rectal biopsy,
a rather deep rectal biopsy
into the muscularis propria.
09:33
And we can demonstrate
there the absence
of ganglion cells which
will confirm the diagnosis.
09:39
In most cases,
although I would always advocate
for biopsy being a pathologist,
we won't do this.
09:46
Managing the disease.
09:48
So, one, the most important
thing is to recognize that it's there.
09:53
Once you have identified it,
we also want to
make sure because
there are many
syndromic manifestations.
09:59
Associated with
Hirschsprung disease,
you want to be sure there's
nothing else wrong with the baby.
10:04
So we'll do a
genitourinary ultrasound
to assess for urinary
system malformations.
10:08
We'll screen for
hearing impairment,
we'll screen for
visual impairment.
10:13
We should also be looking to see
whether there are
any cardiac anomalies.
10:16
Remember that
cardiac malformations
are going to be
commonly associated.
10:21
We should definitely get a
clinical geneticist involved.
10:24
In cases where there may
be mutations that would
lead to multiple endocrine
neoplasia types lla or llb.
10:33
Clearly,
if there's a long segment of bowel,
we can't just dilate it,
we're going to have
to surgically resected.
10:38
So we'll do a primary
anastomosis from the normal
functioning portion of
the colon into the anus.
10:46
If there's really ultra short
segment Hirschsprung disease,
so just the last 3-4 cm from
the internal anal sphincter,
we can manage this with diet,
stool softeners, laxatives,
even botulinum toxin
injections to cause
a relaxation of
the smooth muscle.
11:06
But in many cases,
even that short segment
will require some degree
of surgical management
with myomectomy cutting
incising the smooth muscle
so that we can get
passage of stool.
11:19
With that, we've kind of
covered all the way down
to the very end of the colon
with Hirschsprung disease.