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DISEASES OF THE ESOPHAGUS, KEVIN McGRATH, MD
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My topic of discussion is diseases of the esophagus and I tried to list as many as I could think of, it
would be a daunting task to try to get through all of these in 30, 35 minutes, so buckle up, we are
going to move quick. Because it’s a CME course I thought I’d talk about the new kid on the block,
and if you are like myself and we graduated medical school in the last century we didn’t learn about
this one, so hopefully I can update some of you on a relatively new disease, and I’ll start with a case
presentation.
A 25 year old male was referred for solid dysphagia, he’s had food impaction twice in the past 3
years, no weight loss, asthma as a child, had a barium swallow that was interpreted as normal. What
would your diagnosis be?
(Inaudible)
I heard it. Okay, eosinophilic esophagitis. By a show of hands if you didn’t have my presentation
sitting in front of you how many would have known that? One, maybe two, three? Good, okay.
Correct. Eosinophilic esophagitis, what is this? This was previously thought to be a very rare
disorder, however it’s emerged as one of the most common causes of dysphagia and esophageal food
impaction in adults, and generally these are young healthy adults, there is a male predominance and
you can glean a history of chronic solid dysphagia from these patients.
The formal definition as brought out just 3 months ago in the updated guidelines is that it’s a chronic
immune and/or antigen mediated esophageal disease characterized clinically by symptoms related to
DISEASES OF THE ESOPHAGUS, KEVIN McGRATH, MD
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esophageal dysfunction, generally sensations of dysphagia and histologically by eosinophil
predominant inflammation. So hence it’s a clinical pathologic diagnosis. It’s a new player, it was
first described in the late ‘70s and first described in the pediatric population. The first case series was
published in 1993 and in the last 10 years we’ve seen a logarithmic increase in the number of
publications and I think we have a much better understanding of this.
There’s been a paucity of epidemiologic studies and I think a lot of that relates to just inadequate
recognition, we did not know what we were looking at, and just going back 10 years ago, and I’m as
guilty as any other gastroenterologist, we would label this the small or narrow caliber esophagus or
an esophagus with congenital esophageal rings. There was also a lack of established diagnostic
criteria, so not only did we not know what it was, there were no criteria to actually diagnose it. The
prevalence is on the rise and that’s generally for two reasons. One, better education and better
recognition now by both primary caregivers, surgeons and gastroenterologists and truly and increased
incidence of allergic diseases.
So two studies have looked at this, one in the pediatric population, one in the adult population, there
was a study done in Cincinnati published in the New England Journal of Medicine that over 4 years
showed a 4-fold increase in the eosinophilic esophagitis. A study in adults, a prolonged study over
16 years showed increasing prevalence from 2 to 27 patients per 100,000 population, a pretty
impressive increase. And the authors of that study concluded that it was very likely the remarkable
trend reflected a real increase in eosinophilic esophagitis rather than just an artificial phenomenon
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due to enhanced awareness. And I think it’s a combination, we are seeing more and more of it, not
only just due to increased recognition.
What is the etiology? Truly unknown, but most believe that it is either an allergic response or
immune dysregulation driven by a food allergy or aeroallergen. It’s something in the environment or
in food products. It’s been shown to be associated with atopic conditions. A lesser school of
thought thinks it might somehow still be linked to reflux or an atypical presentation of reflux, and
there’s also a question as to whether we are dealing with two separate disease processes, adult versus
pediatric. Is there a de novo adult onset or the adults that we are seeing, are they just chronic disease
from childhood?
As I mentioned most of these patients will have an atopic predisposition, and IGE mediated food
allergies are seen in a significant proportion with up to 50% of adults testing positive to at least one
food type. And you can see some of the more common ones, peanut, egg and soy, milk is also very
common. Most patients you can also glean a history of either allergic rhinitis, asthma or eczema,
either as a child or currently; and most will recommend an evaluation formally by an immunologist
just given the high rates of concomitant allergic diseases.
The pathophysiology is such that it’s a chronic inflammatory condition and it’s defined by a dense
eosinophilic infiltrate that’s confined to the esophageal mucosa. Activation of eosinophils results in
degranulation, upregulated cytokine production, chronic inflammation and IGE production. And
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recruitment and activation of these eosinophils is regulated by cytokines, several of which I’ve listed
here.
What is the net result? Potential irreversible structural change to the esophagus, loss of mucosal
elasticity, fibrosis in the subepithelial layers, mostly the submucosal layer and loss of wall
compliance that gives you almost a lead pipe type of esophagus where you have a fixed lumen and if
you bite off more than you can chew so to say it’s not going to fit down the pipe.
The role of reflux is unclear. The etiologic evidence is lacking, there’s been failure to respond to PPI
therapy and that is one of the new evolving diagnostic criterion is that people do not respond to a
trial of PPIs. And patients with eosinophilic esophagitis by and large will have a negative pH study.
However we have to realize that reflux is very, very common, up to 35% of the US adult population
refluxes, so there can be overlay and we can see both exist at once. So GERD may play a secondary
role here.
There is also a subgroup that is being more publicized now, one that’s been labeled PPI responsive
esophageal eosinophilia. And this is a subset of patients with typical chronic solid dysphagia, they’ve
had GERD diagnostically excluded based on pH studies and they demonstrate a very impressive
clinical pathologic response to generally high dose PPI, meaning their symptoms of dysphagia
improve and upon rebiopsy we see the density of the eosinophil infiltration is much less.
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What do the PPIs do in these situations? No one really knows. The thoughts are that they may heal
disrupted epithelial barriers and prevent further immune regulation and activation, they may decrease
eosinophil longevity, they may have some type of strange inherent antiinflammatory properties or it
might just be unreliable diagnostic testing and we are really still dealing with reflux because the pH
studies were inaccurate.
As far as diagnosis, again clinical pathologic, we need the right story, we need the right biopsy
results. So we depend on the clinical presentation, endoscopic features are also key. We are tipped
off at endoscopy to take biopsies in the appropriate patients if we are anticipating this, and that’s
based on the clinical history. And there are set histologic criteria that are still somewhat debatable.
The typical presentation we see in adults are young adults in their upper teens, 20s, 30s, male
predominance, 3 to 1 ratio with an atopic predisposition, longstanding solid dysphagia. They may
have had recurrent food impactions and they generally do not respond to PPI therapy.
And you can see a table here comparing typical presenting symptoms in the adult and pediatric
population. Adults generally present with esophageal issues, dysphagia, food impactions, esophageal
strictures. The children on the other hand generally have abdominal pain, failure to thrive, won’t eat,
lose weight, nausea and vomiting, and so the pediatric gastroenterologists are very in tune to this and
we’ve learned a great deal from them. They were again the first to recognize this.
Signs. There are things we can check, although they are not very specific, peripheral bloody
eosinophilia can be seen in up to 50% of these patients. They will have increased serum IGE levels,
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some may have positive skin prick testing and some may have positive RAST testing to food
allergies. The issues though are that the food allergies in childhood may not persist into adulthood,
and we hear this all the time in the clinic, I was allergic to peanuts when I was a kid but now I can eat
them without difficulty. Did that lead to irreversible structural damage in their first years of life?
These are questions we don’t have answers to. Immediate hypersensitivity reactions are often not
apparent in the adult population and frequently eosinophilic esophagitis will occur as an isolated
condition in the absence of other allergic diseases. And I would say at least half of our patients don’t
seem to have any history of allergic rhinitis, asthma or eczema.
Endoscopic features tip us off and we need to anticipate this when we are scoping young patients
with a history of solid dysphagia. You have to look for this disease. Mucosal rings are very
common, they can be corrugated and fixed, which you see here; they can appear as what we call
felinization of the esophagus, an appearance like this and you can see a food bolus impacted down in
the lower right corner; linear furrows, if we look in the upper right corner we see these longitudinal
lines, this is a tip off that we are dealing with eosinophilic esophagitis; strictures; papules or
exudates, these little white dots, this is not candida, these are eosinophilic microabscesses if you
biopsy it and that’s one of the things we look for histopathologically. However you can also see
significant overlap with findings that support reflux, hiatal hernia, Schatzki’s rings, esophagitis, so
we have to always remember that reflux is very, very common in our adult population.
As far as radiographic features, barium swallows are much less sensitive in detecting a narrowed
esophagus and the subtle endoscopic findings that can tip us off. The gold standard for diagnosis is
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endoscopy with biopsy, it has a much higher yield and we can actually get histologic confirmation.
There are some astute radiologists out there, if you inform them that that’s what you are looking for,
you know they can detect subtle narrowings in the esophagus, generally this is proximal and
midesophagus that’s involved, and depending on the quality of the barium work you can see these
rings or indentations that are areas of fibrosis.
As far as histopathology is concerned, there is an eosinophilic infiltration of the mucosal layer, one
can see superficial layering of eosinophils. Eosinophilic microabscesses, extracellular eosinophilic
granules and lamina propria fibrosis; however the true consensus still lacks how many eosinophils
per high power field do you need to make a definitive diagnosis? You have to remember it’s a
clinicopathologic diagnosis, generally the bar is set at 15 eosinophils per high power field. If they
have 13, they have the right looking esophagus and the right history in my book they have it, so we
have to be a little bit open-minded when we interpret our biopsies.
There is also a consensus that is nonexistent on how many biopsies we need to take and the location.
I think most physicians if they are doing it properly will take 4 biopsies from the distal esophagus
and 4 biopsies from the proximal esophagus, and the important thing to do is to put them in separate
pathology jars, mark them distal and proximal and then we can compare. Generally in the setting of
reflux you are not going to see eosinophilic infiltration in the proximal esophagus, we see it all the
time due to reflux in the distal esophagus and that’s why it can be hard to differentiate these
conditions.
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This is an example here of an eosinophilic microabscess, superficial layers of eosinophils on the
upper left, on the lower – I’m sorry on the upper right, on the lower left we can see degranulation of
eosinophils. What’s also coming to light are there may be some genetic predispositions to
eosinophilic esophagitis, and there’s been a susceptibility locus definite on chromosome 5, this is
area that regulates thymic stromal lymphopoietin, which I had never heard of. But this is a cytokine
involved in T-helper cell determination and a genetic variant of this receptor gene that’s located on
the X chromosome has been linked to eosinophilic susceptibility in males. And we believe that
genetic markers will be available in the future that will help with diagnostics and potentially
prognostics. I can tell you I have several families that I follow now either parent offspring
combinations or sibling combinations, we are seeing this more and more also.
As far as treatment, I’ll break it down into 3 different categories. There is avoidance or removal of
the stimulation, there is immune modulation and structural disruption. As far as avoidance, that’s
generally dietary. Elimination diet it a pretty successful way to manage this more in children than in
adults. Personally I believe that this is an extension for childhood disease, we are almost dealing
with an end stage organ. There is significant fibrosis in the esophagus and it can be hard to reverse
that just by removing a stimulus, we try to do it but we are not always successful. So elimination
diets work very well in the pediatric population, the problem is compliance. There have been
modifications of it and one of the more commonly used one in pediatrics is a 6 food elimination diet,
you are essentially picking the 6 most common things that we see on allergy testing, milk proteins,
soy, wheat, egg, peanut and sea food. Probably the more palatable way to do this is food restriction
based on allergen testing results, however the results are very variable. We’ll find something
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abnormal and the patient will tell us I’ve never been allergic to that, I’ve been eating it all my life, or
I was and I’m no longer; so I think the results are very variable here.
This is a result of a fairly recent food allergy panel I ran on one of my patients last month. This was a
17 year old, I also care for his brother who is 26 who has known eosinophilic esophagitis, so it shows
you there is this familiar component. And you can see he tested extraordinarily high for the sea food
category.
Structural disruption is achieved through esophageal dilation and this has to be done very cautiously.
This was previously felt to be a very high risk procedure and I think it was just ignorance on our part,
we would go flying into the esophagus, our scopes are 9 or 10 millimeters in diameter, we don’t see
the fist centimeter or two of the esophagus very well because there’s a lot of secretions and it’s a
little bit more narrow, and this is frequently where there are strictures, so the next thing you see is red
out on your screen because of blood, and you pull back, clean up and there’s a huge mucosal tear or
rent that we’ve induced. I think since we’ve learned a lot more about this you have to think about this
disease going in and we are far more cautious, very gentle intubations and I only do these now with
anesthesia support, so under Propofol based sedation, I don’t want to fight with the patient during
these type of procedures. So we perform dilations very cautiously in this group of patients, we
estimate the diameter based on the size of our scope, as I mentioned we use 9 or 10 mm scopes and
we start with very small boogies, so the first one I’ll pass may be what I think the size of the liminal
diameter is, after each passage of the wire guided boogie we will reintubate the esophagus and we are
looking for a mucosal tear and we will keep slowly going up 1 mm at a time with the boogie until
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upon reintubation and reinspection we see a moderate mucosal tear, and you can see one in the lower
picture here, a nice rent in the mucosa and you can actually see it, that it’s fractured some of these
rings here. This is very effective in relieving dysphagia, the problem is it does not alter the ongoing
inflammatory process.
So we usually combine it with immune modulation, which is corticosteroid based, it improves both
the clinic – or the clinical and the pathologic features of eosinophilic esophagitis in most patients. If
you put someone on steroids go back 2, 3 months down the road and rebiopsy you won’t see as many
eosinophils there. The problem is, just like other diseases treated with steroids the recurrence rate is
very high upon discontinuation. And probably the most commonly used one is swallowed
Fluticasone, so we give people a Fluticasone inhaler but rather than inhaling it we instruct them to
spray it 4 times in succession into the back of their throat and swallow it. We have them rinse and
spit so they don’t get thrush, we have them avoid eating or drinking for 30 minutes. So it’s
essentially a topical steroid treatment to their esophageal mucosa. Generally this was done for 6
weeks and if there was a recurrence we would have them repeat it. Current trends are for longer
treatment. How long? No one knows. There are some patients now on this indefinitely to try to
maintain their ability to swallow. Budesonide has also been an option, a viscous suspension where
they swallow it once daily. The problem with this for reasons unbeknownst to me is it’s
extraordinarily expensive, it’s not a typical formulation and generally needs to be compounded.
For very severe refractory cases you can use systemic steroids, IV steroids if people can’t swallow at
all, or Prednisone tapers. Generally we see these extremes in the pediatric group that just aren’t
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thriving. I’ve used systemic steroids in a few of my patients that have been refractory and I’ve done it
immediately after dilation to try to prevent that esophageal split from healing right back down.
Montelukast is also another immune modulator, it’s a leukotriene receptor antagonist and there was a
small study done in Europe a number of years ago where they would titrate up the dose to quite high
doses, up to 100 milligrams a day and the problem is when you get up that high you get side effects
such as nausea and myalgias so that it’s usually dose limited. But it eliminated dysphagia in 7 of 8
patients, again a small study, 14 months median treatment and upon cessation six patients recurred
with dysphagia shortly after stopping the drug. This study got our attention and we’ve indoctrinated
Montelukast into our practice. There’s been a subsequent study that showed there is no benefit. In
the current guidelines published this July they do not support its use. I can tell you subjectively
from my practice and that of one of my partners, we’ve had very good success. It makes intuitive
sense that we’re negating inflammatory actions with use of this and I look at it as combination
therapy. So again, I’ve continued it, I don’t dose escalate, I keep my dose at 10 milligrams.
Biologics have actually been looked at, Mepolizumab is a humanized anti-IL-5 monoclonal
antibody. There are a couple of case reports and then two very small studies came out, very small,
four patients in eleven patients. The eleven patient trial believe it or not was a randomized controlled
double blind study. But the bottom line is, it decreased eosinophil infiltration so there was a
pathologic response but there really wasn’t a clinical response.
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In one patient they stated it improved their quality of life after one month and this was based on
visual analog scores so it’s hard to say what that really means. But this is an active area of research
that continues today.
What about prognosis. A long term study over 11 years looked at this and the only modality for
treatment in this study was periodic dilation. The authors concluded it was a chronic yet stable
disease, there is no morbidity, mortality or neoplastic change associated with this. However, the
patients have continued dysphagia and will need periodic dilation.
Getting back to our clinical case. This was the appearance of the esophagus, not a very classic
appearance but probably under insufflated. If we fill the esophagus with air we can bring out these
rings and on serial dilation we induce a fairly moderate mucosal tear and when we see that we stop.
We don’t want to push a bad position or end up with an esophageal perforation. It is not uncommon
for patients to awake with chest pain when we do this kind of work, I prep everyone for that, I don’t
sleep well that night. Frequently we both the radiologist with a barium swallow prior to them
leaving our unit. So this clinical case, the biopsy is taken. At the time of the dilation did confirm
eosinophilic esophagitis, the patient was treated with swallow Fluticasone for six weeks and
Montelukast 10 milligrams a day which is a maintenance medication he still continues and had no
recurrent dysphagia for the past 2 years.
So in conclusion the eosinophilic esophagitis is another example of eosinophil-associated
inflammation of the epithelia at the surface or interface between external and internal milieus. It’s
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similar in pathophysiology to bronchial asthma and atopic dermatitis or eczema. It’s a chronic
disease, it relapses with stopping treatment. The most common sign you’ll see on presentation is
chronic solid food dysphagia in a young adult, male predominant and personally I believe in
multimodality treatment. Removal of an offending stimulus is you can detect it. Immune
modulation, generally topical steroids and I still use combination Montelukast as a maintenance
medication and structural disruption through dilation. I tell patients my goal is to keep them out of
our endoscopy unit. Frequently we do their dilation on their index endoscopy where we also biopsy
to make the formal diagnosis but the goal is to try to keep them out of the endoscopy unit although
it’s been shown to be very effective in managing it with repeat or serial dilations.
As far as the future we need some larger scale randomized control trials that look at treatment. And
when we do that we need to define what our endpoints are. Are they clinical, are they going to be
histologic or are they going to be immunologic. Personally I believe in the clinical results, these
patients have trouble swallowing, they have food impactions, the last place you want to meet them is
in the emergency room at 2 am when they can’t handle their secretions. It can be a very dangerous
and risky situation. So I think clinical endpoints need to be first and foremost but it would be
certainly nice to have secondary endpoints of histologic improvement meaning we see a decrease in
the eosinophilic infiltrate and some immunologic improvement whether that’s IGE levels, whether
it’s interleukin levels or even potential genetic markers to come.
So I thank you for your attention and I’m happy to take a few questions.