Hello, people on Webinar vet. Welcome to this. Talk on protein losing enteropathy with myself, James McMorrow.
So over the next hour, it's gonna be my job to talk you through how we can, effectively diagnose, patients with protein losing enteropathy the kind of investigations that we need to do in these patients. To be sure of what's wrong with them and therefore be able to tailor the treatment as appropriately as possible to that individual. So quite a lot to get through.
We will start off with a bit of the introduction. So protein losing enteropathy is essentially a syndrome OK, which can be related to multiple different diseases. We'll go through the different causes a little bit later on.
Most patients just have one online cause, but some patients can have a combination as well. So we use this PLE as a sort of umbrella term for several different diseases. But fortunately, it's essentially a gastrointestinal loss of protein, from the body generally due to really quite severe gastrointestinal tract diseases.
As a result, patients present often with really quite significant clinical signs. Some patients can in fact be, almost moribund at initial presentation, and as a result of the severity of the protein loss, these patients can have really quite significant clinical pathological abnormalities as well. So it's very important in these individuals for a complete work up as early as possible, quite honestly and quite aggressive.
Therapy. As these patients you know are really at risk of succumbing to their disease and by delaying investigations and, sometimes with the use of inappropriate therapeutic trials, it can cause a seriously negative, you know, outcome for that individual patient. It's quite an interesting, sort of syndrome to deal with as well, because there are multiple complications as a result of protein losing enteropathy again.
We'll get to in into those, in a few more slides. And ultimately, we need to sort of know what we're doing with these patients from the outset, as even those patients that undergo complete diagnostic work up, get onto the appropriate treatment plan. They still have a guarded to poor prognosis, with approximately 50% of PLE patients not responding, to what we do.
And as a result of that, you know, whilst these patients can be managed in primary care practise. There should always be the option, You know of referral as well. And we'll get on to sort of what can be achieved in primary care practise a little bit later on versus at referral level.
As as we get stuck into it. So a little bit on pathophysiology particularly pertaining to protein loss. So protein loss can occur from the intestines because of generally one of three reasons.
Either we can have a physical or a functional lymphatic obstruction, and there'll be a bit more on that, in a little while, we can have release of cellular mediators in which can increase vascular permeability and fluid loss into the tissues. Or we can see mucosal inflammation. Which may be erosive, meaning there is a breakdown, in the mucosal layer or non erosive where the mucosal layer is intact.
And patients who've got protein losing enteropathy can actually have one or several of these things going on at any one time. Contributing to the build up of protein rich fluid, leaking from the interstitial of the gastrointestinal tract. Into the G I Lumen, So this can occur, as I say, without with or without, epithelial disruption, which we refer to as erosion or ulceration and that occurs through the tight junctions between cells.
So, with loss of protein from the body, the liver has to increase synthesis of proteins to try and compensate for that. However, the production of proteins from the liver is unable to keep pace with the loss of proteins from the body. And we have, a total loss of protein from the bloodstream.
And as a result of protein loss, we lose many of our important immunoglobulins. And that itself, can disrupt part of the immune system's defences. But also with the abnormalities we have in in lymphatic flow as well due to protein losing enteropathy, that itself can, reduce sort of the movement of white blood cells through the body and again impair host defences.
One of the interesting things as well that can happen in PLE patients, which you may not be aware of, is the increased risk of thromboembolism. Now, thromboembolism, typically in a PLE patient is most likely to be venous in low shear environments, but could be arterial in the higher shear environments as well. Thromboembolism is obviously a really serious complication of, other diseases.
And it can obviously form a thrombus in in one site that embolize elsewhere. And if that embolize to the brain, kidneys or lungs, it can be very serious indeed. So it's one of the things you want to try and screen patients for and treat for to reduce the likelihood of it happening.
It occurs in patients with protein loss because of loss of vitamin K. Loss of antithrombin three, inflammation. Which itself is prothrombotic, hyper fibrinogen, anaemia, vascular compromise and hyper aggregation of platelets.
So one of the things we're gonna consider in treatment of these patients is, prophylactic antithrombotic therapy to reduce the likelihood of an event So a little bit more about lymphatics. As the more we get into this talk, we'll sort of discuss that there is a huge amount of crossover between the two most common causes of protein losing enteropathy in dogs, inflammatory bowel disease or chronic inflammatory enteropathy, as we otherwise refer to it and lymphatic disease, including, lymph anet taia. So the lymphatic system is a unidirectional, vascular network.
That exists throughout, of course, the, intestinal tract. But the rest of the body, as well. And it's really important in the transport and absorption, particularly, of fat, from the gastrointestinal tract.
And if we have disruption of our lymphatic flow, we can struggle to absorb fat. And as a result of that as well, that will affect various other, sort of, absorption of substrates as well from the gastro test tracts, such as the fat soluble vitamins. OK, the lymphatics also are responsible for extracellular fluid homeostasis.
So when we have a build up of fluid in the interstitium in a patient, generally that excess fluid is carried away through the lymphatic system. And if that lymphatic system is is abnormal or is overwhelmed, then we can develop extra, sort of fluid build up within the interstitial of various different structures. But as I said a little bit earlier, the lymphatic system as well is really important.
For the immune system, as as primarily transports, you know, a large amount of white blood cells. Throughout the body. Lymphangiectasia itself is, something that we will talk about as a primary disease, which can be seen in certain breeds such as the soft coated Wheaton terrier, the Norwegian Lunder hund, Yorkshire Terriers, Maltese terriers and sharp Hays.
And but also, perhaps much more commonly, we now believe, exists as a secondary disease entity often seen in association with inflammatory bowel disease. Ultimately, lymphangiectasia is a disorder that causes the lacteals, within the gastrointestinal tract, to become dilated and filled with lymph fluid. This then can lead to lacteal rupture.
And the lacteal rupture causes leakage of protein rich fluid into the Lumen and Interstitium, which itself, obviously is a source of loss of protein for the body. But that limp that gets into the, interstitium of the small intestine actually sets off pretty significant tissue inflammation as well. Further propagating, the, cycle of inflammation abnormal lymphatic drainage.
That leads to the the sort of severe compromise of the intestinal wall. In some patients as well, the amount of fluid that leaks into the intest, can be so large that patients actually develop inflammatory, granulomas, sometimes referred to as, lipo granulomas. And these themselves, can cause such significant tissue reaction in that area that actually the region of small intestine starts to mimic that of an actual mass with it being so thickened and so irregular compared to surrounding regions of small intestine.
We've said secondary lymphangiectasia, occurs in association with, inflammatory bowel disease. And this is often, you know, noted on intestinal endoscopic biopsies, and has been reported to be as common as, occurring up to 53% of patients, undergoing endoscopic biopsy, for a chronic, diarrhoea. So just going through all the causes of PLE, then, we need to firstly, sort of I I'll get.
I'll get on to a little bit later on how we sort of decide that a patient most likely has a a protein enteropathy rather than other causes of protein loss. But once we're happy, the patient has, a primary intestinal problem. We then consider these differentials, So the majority of patients tend to have inflammatory bowel disease or chronic inflammatory enteropathy.
As it's otherwise known. And this, of course, is an idiopathic disorder of the small intestine. So we're really talking about small intestinal disease of protein is in enteropathy patients.
Not the large bowl. And this is a diagnosis essentially of ruling out, the other causes of inflammation in these patients with thorough diagnostic evaluation, including faecal analysis, blood work imaging, We once we ruled out other causes of inflammation and we've biopsied them and documented inflammation, which most commonly is lymphoplasmacytic. But could be, eosinophilic, neutrophilic or other.
These patients ultimately then achieve this diagnosis of inflammatory bowel disease, and we'll get on to a bit later on about how we treat those patients. But ultimately, you know, inflammatory bowel disease can really vary in severity from being incredibly mild at one end of the spectrum, that barely necessitates even dietary manipulation, really up to life threateningly severe at this end of the spectrum. When we're talking about protein losing enteropathy so intestinal lymphangiectasia again can be seen in around 50% of, PLE cases, and neoplasia as well sort of follows up after those two, as as the most common of the causes, of protein losing enteropathy.
And we're particularly talking about, lymphoma, being by far the most common neoplastic cause of a PLE. Don't get me wrong. There are plenty of other neoplastic diseases we can see within the small intestine.
However, it tends to be lymphoma that most commonly causes protein loss. For the gastrointestinal tract. So our top three causes of PL a are IBD lymphangiectasia and lymphoma.
Otherwise, there are other causes as well. That can, lead to protein losing enteropathy. So intestinal crypt disease, honestly, largely falls within inflammatory bowel disease.
So there are patients such as the Yorkies who have a high prevalence of, disease within the crypts of the small intestine. But often this is honestly, a sort of a feature of inflammatory bowel disease itself, so it can be largely lumped into, in with those patients. Otherwise, we have infectious diseases.
So parasitic bacterial, viral. You know, a good example would be something like canine parvovirus. You know, causing certainly, enough damage to the intestinal wall for patients to actively leak protein.
And these patients Honestly, we certainly will screen for when we're investigating the protein losing enteropathy. But these patients generally will present present much more acutely unwell, as an acute enteropathy patient, and we'll diagnose them as having protein loss. But they don't present really in the same way as your average sort of chronic protein losing enteropathy patient.
NSAIDs, of course, can cause protein loss because of various mechanisms, but mostly, erosion and ulceration of the gastrointestinal tract. And again, these patients, you know, might have quite significant G I blood loss as well, which we don't that frequently see with other protein losing enteropathy. So it can be quite easy to differentiate out from the other causes.
Be aware of our sort of breed specific disorders. So, you know, we have immunoproliferative enteropathy Ines. We have, sort of, a protein losing enteropathy slash nephropathy that we tend to see in soft coated wheat and terriers.
So just be very aware of, you know which breeds tend to be overrepresented for the various chronic, enteropathy, diet associated. So this is, quite an interesting group of patients in that most patients who have a dietary associated enteropathy IE, a chronic intestinal disease that responds to dietary manipulation, normally have relatively mild disease. However, it has been found in some studies that even patients with protein losing enteropathy can respond to simply dietary manipulation alone.
Now, traditionally, what we're talking about with dietary associated is a dietary allergy or intolerance, so they're largely interchangeable. Terms other than allergy has an immunological basis, whereas intolerance doesn't. But ultimately these are patients who res respond to, a change in diet and most commonly, that's moving them onto either a novel protein or a hydrolyzed prescription diet.
We have hypoadrenocorticism so Addison's disease as well as a possible cause. Again, these patients really don't present like most P LES and are quite easy to sort of, you know, weed out from your average PLE patient. So our Addisonian patients normally present either because of an Addisonian crisis, and whilst they may have some protein loss from their intestine, they're really abnormal.
Electrolyte arrangements of hyperkalemia and hyponatremia are often much more interesting, you know, and often push us towards hypoadrenocorticism before we consider other sort of causes of intestinal protein loss. Do be aware that with atypical hypoadrenocorticism, we have a lack of glucocorticoids but not minera corticoid. And therefore, we can have normal electrolyte levels in these patients.
But they can have chronic, gastrointestinal trap signs, because of a lack of glucocorticoid production from the adrenal glands. So, fortunately, this is something that we can quite easily screen for us to get to later on. And then lymphangitis which, you know, is associated with inflammatory disease of the lymphatic system and often associated with this rupture as well of lymphatics, and the formation of lipo granulomas in some of these patients.
So certainly if you're only gonna remember three of these protein losing enteropathy caused by IBD lymph inject taia and lymphoma would be the the ones to try and remember. When we think about the clinical presentation of these patients, often the clinical signs are very similar. Regardless of the cause of their PLE.
So things that we commonly see are ascites. And this is due to the formation of normally a pure transit date within the peritoneal space, which is due to them having such a decrease in their, blood. Total protein.
That that very low. Oncotic pressure allows fluid to move out of their vascular space, you know, and into, the cavities. So third spaces throughout the body and can lead to often, pretty significant ascites, which is normally something that, an owner can perceive when it's quite a large volume.
But this fluid as well may accumulate in the plural space, and occasionally you may have a PLE dog that actually presents with breathing difficulties as a result of a pretty significant, pleural effusion, which again would be, you know, a low protein, pure, pure transudate. We can sometimes see, patients developing, peripheral swelling of their limbs. So, subcutaneous edoema as well again as a result of the low oncotic, pressure within the, the vasculature.
Although this is nowhere near as common as as as CS and or pleural effusion. A lot of these patients have a reduced appetite. And as a result of that pretty significant caia.
So loss of their lean muscle mass and can be really quite under conditioned, at presentation. Now, the reduction in appetite is always something that's important to flag in in any patient that's got weight loss, because it helps us sort of refine our differentials for the cause of that weight loss. For instance, if we have a patient who has polyphagia and weight loss, we're actually gonna consider, maldigestion as well, as malabsorption and also mal utilisation of calories.
So patients who are, for instance, have diabetes melat or, cats with hyperthyroidism. Whereas when we've got a reduced appetite, normally, that's seen with more sort of degenerative painful inflammatory diseases. Such as, of course, lymph fantasia, IBD and, lymphoma.
Because this is a disorder of the small intestine, we often see gastrointestinal symptoms as well. Now, if you have inflammation of your small intestine as a cat or a dog, you could have vomiting or diarrhoea or both. And if you have diarrhoea, it normally is that typical small bowel diarrhoea where it's large volumes, you know, explosive, watery diarrhoea.
Typically, it's not lots of little poos. You know there may be musin, but not necessarily cos that's more large bowel. You know, there can be fresh blood, but again, that's more associated with with large bowel disease.
You know, But do bear in mind that actually, there's a small percentage of patients about 5 to 10% of PLE patients who actually don't present with any vomiting or diarrhoea. And these are the more tricky patients to investigate. And one of the reasons why we might see that is that we may simply have a patient with lower small intestinal tract inflammation that doesn't trigger, vomiting.
And whilst they might not have normally functioning small intestine, if the large intestine is functioning well enough, it can absorb enough water from the Lumen for you to actually pass pretty normally ST form stools. So don't ha use a lack of G. I signs to rule out PLE, when investigating patients with protein loss.
Something else that I just wanted to mention here as well is that when we're looking at clinical signs in our patients, we can actually use a scoring system. And there's a couple that have been published for use in small animals, with chronic inflammatory sort of anthropy signs. And these are the Syd and C SI scoring systems.
I'll show you, one of them in just a second. But essentially, these allow us to look at each individual patient and score the severity of their signs and then, sort of summ, their score to give them an overall, number, which we can use to sort of quantify the severity of their disease. Is it mild, moderate, Severe.
So that can help guide us from the outset with regards to prognosis and how aggressively we might investigate and manage their problem, but also allows us in the longer term as well to monitor response to therapy, so these can be quite useful. And it's something to sort of recommend. If you're not familiar with if you just google these two scoring systems, you can get access to the papers in which they were first, presented and and you know, start to to adopt them.
When managing these chronic enteropathy patients, we'll get a little bit onto blood work, a little bit later on, so this is an example of the CE SI scoring system. So essentially, if we just pull up my little laser pen. For each of these different, sort of features such as vomiting, appetite, attitude, we can score the patient from 0 to 3, depending on the sort of severity of that sign.
And then we S sum of, you know, add up the score together and give the patient an overall score. And that could be really quite useful, I think, in helping owners understand the severity of their patient's disease as well as helping us monitor their response to therapy, so purely can affect dogs and cats. Really?
Of any age, or sex. It is much more frequently seen in dogs than cats, however, and we sort of only lightly touch on cats throughout this talk, protein losing enteropathy themselves, most commonly affect. Well, the most overrepresented breed, I should probably say, is the Yorkshire terrier.
And that's certainly something, that that I guess most of you guys will perhaps be familiar with already. But otherwise, we do see border collies. Who, you know, also get other chronic enteropathy as well, including, congenital, hypercalm anaemia.
German shepherd dogs that we know really is the poster child for G. I disease with them being overrepresented for inflammatory bowel disease. Small intestinal dysp amongst others, Rott Villa as well and and various other breeds.
So, as I mentioned earlier, no G I signs in 5 to 10% of patients who don't let those catch you out. And other clinical findings that can be of interest. We sort of already mentioned the complications of thromboembolism.
But there can also be significant complications of some of the other metabolic arrangements that this causes as well. So as we'll get on to a little bit later on patients with protein losing anthropy can develop really quite significant hypocalcemia. Calcium, of course, is really important in lots of different sort of, systems within the body.
But in particular. And the, you know, the the neuromuscular system. And actually, patients can become so hypocalcemic with protein losing enteropathy that sometimes they will actually present with neuromuscular clinical signs.
And that can be weakness. Tremoring, collapse and certainly on occasion, myself. I've had, a couple of PLE patients over the year present primarily with neuromuscular disease and and no gastrointestinal tract signs.
And it's only through sort of documenting their hypocalcemia their hypoproteinemia that we then sort of figured out these patients actually had a a primary gastrointestinal cause of their neuromuscular signs. So again, quite quite an unusual presentation that you just sort of have to be aware of. So this is a nice bar chart that was taken from, a review study on protein losing enteropathy.
That I've actually got a reference here. But it is available Open access to the journal of Veteran Internal Medicine. If you search for pre losing enteropathy review, and basically, it looked at quite a large cohort of dogs with P LES, and essentially grouped them, based on several different things, but one of which was the actual, disease that they were diagnosed with.
And as you can see, the vast majority of dogs in the study were ultimately diagnosed with lymphoplasmacytic enteritis, which is very much interchangeable with IBD or chronic inflammatory enteropathy. A significant number, however, had, lymphangiectasia as well. And then as we'll get to a little bit in the hist.
Theathers can have a combination of vous blunting cryptopsy. Lipo granulomatous. Lymphangitis, primary lymphangitis, thromboembolism, you know, certainly seen in in quite a small number of patients, but nonetheless, seen in this this group, and hypocalcemia as well, as I alluded to earlier on, the prognosis is sort of guarded to poor.
Really? From the outset, with approximately 50% of patients being euthanized, you know, or dying as a result of their protein losing disease, And again, a little bar chart here with some of the most commonly affected, breeds. So when we look at the clinical pathology for these patients, this is where we can really help decide.
This patient has low protein, and I think it is because of gastrointestinal tract disease, Whether or not they've got G. I symptoms. Now when we're looking at the biochemistry, we're of course, going to be expecting you know, these patients to have a low total protein level, and normally it is a sort of moderate to severe, hypoproteinemia.
It tends to have to be that low for the patients to develop such sort of stark, clinical signs. But what we commonly see with a protein losing enteropathy is that the albumin level is low, but often the globulin level is reduced as well. Now, that's one of the things that helps differentiate protein losing enteropathy from other protein losing diseases like a protein losing nephropathy.
Because in PLN patients, even when they've got significant protein loss through their kidneys often, the the the globulin, molecules are just too big to leave through, the, glomerular basement membrane. And as a result of that, patients who have protein losing nephropathy exclusively have hypoalbuminemia without concurrent hypo glob anaemia, whereas in PL a, we can see both now a lack of a hypo globulin anaemia cannot be used to exclude a protein losing enteropathy. So don't don't sort of get caught out by that, once we get quite profoundly low total protein levels.
So, in albumin specifically of sort of 16 and below. That's the level at which we start to develop the spacing of fluid and these peritoneal and pleural effusions as well as, a peripheral subcutaneous edoema. Other things that we might see on routine clin path.
Lymphopenia is not uncommon. We quite often see leukocytosis as well, because of the inflammatory nature of of many of the causes of P LES, and a good sort of, telltale sign, of intestinal disease is hypocholesterolemia. So of course, cholesterol is absorbed through the gastrointestinal tract.
And when we've got a severe disruption of that, our patients will often become hypo cholesterol mic. OK, so this is a good one to be aware of, because again, when we're sort of trying to differentiate between protein losing nephropathy and enteropathy. Actually, with PLNS, we more commonly have hypercholesterolemia.
OK, decreased creatinine is really quite common as well in these individuals because of a loss of lean muscle mass. And, of course, your creatinine is proportional to the amount of, lean muscle mass. And then we can quite often see increased liver enzyme Acti, liver enzyme activities as well.
So a LT, a LP and and the others. And this, is most commonly due to a secondary hepatopathy. So any severe enough, particularly inflammatory disease of the gastrointestinal tract will cause a secondary increase in liver enzyme activities.
Now it's often quite mild and the increase in liver enzyme activities. And normally if we treat the underlying intestinal problem, those liver enzymes will normalise. Do bear in mind.
However, as we get on to in just one or two more slides. One of the other important differentials for a patient that presents with low dose of protein levels is, in fact, hepatic dysfunction. So we have to look at the liver enzymes.
We have to look at other markers of liver function in patients that present with low protein levels. Before we can, ascribe that abnormality to be due to a just a PLE hypocalcemia, we've mentioned earlier on, this is really quite common in in our patients. And it's primarily due to a lack, of absorption of, vitamin D through the gastrointestinal tract and as a result of that reduced, activated, vitamin D within the bloodstream so that we, you know, don't essentially have, release of calcium from bone stores, resorption of calcium from the kidneys and and absorption of calcium from the guts.
So this hypercalcemia is something that can be really quite severe. Now, one of the things that we have to bear in mind when measuring calcium is that on a standard in-house analyzer, What we're looking at is the total calcium OK, and that total calcium accounts for, essentially well, about 40% of that calcium is protein bound now. That means whenever we have a drop in our total proteins in a patient, we should always see a drop in the total calcium because about 40% of that total calcium is protein bound.
So if we have lower cal, protein levels, we're gonna have lower protein bound calcium levels. So it's really important in these individuals to also measure ionised calcium. OK, so ionised calcium makes up about 40% of all the calcium in the bloodstream.
It is the active part of calcium, and it is not protein bound. So whenever we have a patient who has low total calcium levels, almost irrespective of their protein levels, But certainly if the protein levels are low as well, we should check an ionised calcium. And if it is, you know, severely reduced, we'll have to consider how we're gonna manage that in that individual patient.
At the same time as well, it's sensible to check magnesium levels as if we have concurrent hypomagnesemia. We're going to struggle to actually, correct and treat that hypocalcemia and then a bit on Cabal Amin. So almost all patients with a chronic enteropathy would benefit from having their Kalam levels assessed.
And there's a few reasons why we do this. Firstly, cobalamin, which is absorbed in the ilium, can help tell us about perhaps where that patient's disease is. So if our cobalamin level is low, we can ascertain the patient probably has a degree of ileal involvement in their disease, and that might help guide us.
When we're thinking about biopsying this patient, we're gonna want to sample the ilium as well as the du duodenum and jennum. OK, also, when cobalamin level is reduced, we know it confers a poor outlook for that individual compared to when it is normal. Ok, now we already know patients with P LES have a very guarded prognosis.
So that doesn't really surprise us. But it is something to bear in mind. Cabal Amin being low reduces, worsens the prognosis.
But the other thing as well that's important about this is that we know we need to supplement Cabal Amin in patients who are Hypo Cam anaemic or they won't have as good an outcome. So we need to be checking Cabal Amin and all these patients. And it's really quite common, for patients, with P LES to be hypercalm anaemic.
Often Cabal Amin is run with folate as well, which, of course, is absorbed in the upper small intestinal tract. And low folate is an interesting one in that we've not found in studies that low folate confers a poorer outcome. And we've not consistently found that treatment of hypo folate actually improves outcome either.
But nonetheless, we're likely going to be running folite in these individuals. And again, quite often is low. For more information on caballa metabolism, I've just sort of referenced this paper here from the Journal of Veterinary Internal Medicine.
Again. It's an open access paper. It's a nice one to check out.
we may also see elevations of, pancreatic lipase, enzymes as well. Almost what we consider a secondary, pancreatitis in patients who have protein losing disease. So pancreatitis itself doesn't tend to cause a protein losing enteropathy.
But if we've got severe enough inflammatory bowel disease, for instance, we can often see elevations in our PL I and a degree of concurrent pancreatic inflammation in these patients. We mentioned earlier the risk of thrombosis, and we may do some, viscoelastic testing. So that's, looking at, platelet function to see whether they're sort of hypercoagulable or or hypocoagulable.
With, in vitro testing. One thing that we do know, though, is that, at least one study has looked at viscoelastic testing in PLE patients and found that whilst they certainly seem hypercoagulable on that testing the patients that have hypercoagulable viscoelastic testing, they don't necessarily correlate with the patients that then end up having thrombolic disease. So what, we're sort of sort of getting to is that Yes, we can test these PLE patients, to see, you know, if if the the analyzer can can confirm their, hypercoagulable.
However, the risk we know is there in all PLE patients. And perhaps it's just as sensible to treat all of them with antithrombotic as we'll get to a little bit later on. Then C reactive protein.
So this is an acute phase, marker of inflammation and is elevated in, particularly patients with inflammatory bowel disease. And we know from certain studies that having an elevated CRP, confers more likely the need for prednisolone as part of the therapy for IBD, which can be useful at diagnosis. But also we can actually use C reactive protein as well.
To monitor response to therapy in our patients. So that's been published, as well. OK, so what's the general rule of thumb for how we're going to approach the investigation of these patients?
Well, firstly, we need to think about the causes of low protein in our patient. And whilst of course, this talk is about protein loss from the gut and P LES, there are other reasons why you can have a low total protein. It's a relative short list of possible causes, but they include protein loss from the kidneys so PLN that we've already mentioned lack of protein production.
So advanced, liver disease. In fact, liver failure we should probably use as a more appropriate term in which there is a lack of production of protein levels. We can see it in patients who have burns where they're sort of exuding, plasma proteins from a burn.
Those patients are obviously quite easy, you know, to to to sort of separate from the other patients with low protein levels. And we can see it in various other disorders, including patients that have, undergone a period of of profound starvation. But ultimately the most common differentials for protein.
Hy the low protein levels other than a PLE is a PLN or hepatic dysfunction. So the standard sort of battery of tests that we're gonna use in these patients is a combination of biochemistry and haematology. And, of course, that's gonna include a bio acid stimulation test.
To help rule out liver dysfunction, we need to bear in mind that even if we have elevated liver enzymes, liver enzyme activities, don't tell us anything about liver function. OK, you can have markedly elevated liver enzymes but still have normal liver function. So we need to do that bio acid stimulation test in these patients to rule out a protein losing nephropathy is relatively straightforward.
We're gonna run a urinalysis and, of course, a urine protein creatinine ratio. And, in most patients who have protein using enteropathy, their U PC is normal or it may be mildly increased because of a secondary, glome orris. However, patients with primary protein losing nephropathy often have a really quite markedly increased U PC, often in the order of four and above.
And sometimes it can go as high as the thirties. In some unlucky individuals. As part of the routine work up of any chronic gastrointestinal tract disease, we're gonna do a full faecal analysis.
We've already mentioned the utility of folate Galin In these patients, that's gonna be pretty standard. And as I mentioned earlier, Addison's disease is on the differential list, so we can easily exclude that with a normal basal cortisol. Do bear in mind that, a low basal cortisol itself is not definitive for Addison's disease, and we need to follow that up with an AC TH stimulation test.
These patients then go on to have imaging of the abdomen, paying particular attention to the gastrointestinal tract. I'll show you some nice slides in a second of that. And then ultimately, biopsy is often indicated in these patients to get that definitive diagnosis as soon as possible to start targeted therapy as early as possible as well.
So once we've done our initial blood work, faecal work and urinalysis, we should be pretty confident that our patient has got a protein losing enteropathy. And then it's about deciding which one they've got. And one of the first steps, is to perform abdominal ultrasonography.
And this allows us to look at the small intestine of the stomach, large intestine, regional lymph nodes, the pancreas to look for changes consistent with primary gastrointestinal tract diseases, and to help us rule out any other diseases within the abdomen. Often these patients will be acidic, as we've mentioned, and we can sample that and be sure that the fluid that's in the abdomen is consistent with the PLE. So, a low protein effusion that's very a cellular, and what we're primarily looking for is sort of really, patients that at this stage have obvious evidence of neoplastic disease.
So on the ultrasound scan, if we see evidence of markedly enlarged lymph nodes, masses within the small intestine, then it's highly likely that patient has a neoplastic process and actually sending them for biopsy. An endoscopy might not be the best thing, but actually sampling them there and then with fine needle aspirates of their lymph nodes and intestinal masses is much more appropriate. And, of course, we've said small intestinal lymphoma is the most common cause of, neoplastic P LES.
And that's something that should be readily diagnosed on, aspirates from, lymph nodes and small intestinal masses really quite quickly avoiding the need for biopsy. Because certainly, you know, when we're thinking about, lymphoma of the gastrointestinal tract, it unfortunately, is one of the more aggressive forms of lymphoma. You know, whilst we have the option to treat it with multi drug chemotherapy, the outcome is really not as good as with many of the other forms, of lymphoma and therefore sort of identifying these patients as early on as possible.
It's really quite important to help decide. You know where we go from there with respect to treatment, but otherwise, let's say the ultrasound doesn't look like there's an obvious neoplastic process. What we would always caveat to that is that, even a normal abdominal ultrasound scan does not exclude lymphoma as it is an infiltrative, neoplastic disease.
But largely speaking, you know, if we can't see any evidence of neoplasia on the ultrasound, we're really left with essentially inflammatory bowel disease. Lymph ectasia being the most common, differentials. And we may see some certain, changes within the gastrointestinal tract that are suggestive of those two diseases.
So this is a patient here. This is the small intestine here in longitudinal section. So this is the Lumen in black, and then each side of that we've got the mucosa here, submucosa, muscularis and choza.
And essentially, this patient's mucosa is markedly hyper echoic much more white than it should be. Which is something we often see in patients with, IBD and lymphangiectasia. And as well, if you look closely, you can only start to appreciate these linear, hyperechoic striations of the mucosa, which is suggestive of dilated lacteals within the mucosa.
Ok, now, we previously may have said this is really synonymous with lymphangiectasia. But now we know that patients can have a combination of lymphangiectasia and IBD. Essentially, this sort of stuff is very interesting, but ultimately pushes us towards intestinal, biopsy with the use of an endoscope.
We cannot definitively diagnose lymphangitic, Tasia or IBD, on an ultrasound. Here is another patient as well, with sort of similar changes. So the mucosa should be really quite anarchic, as you can see in this region here, whereas actually, all of the rest of the mucosa is extremely hyper echoic in this individual.
This is, another patient again with a protein losing enteropathy. And this is the small intestinal transverse section. We've got a little bit of anechoic peritoneal effusion here.
And then again, you can really appreciate these hyper co linear striations here, almost forming a sort of wagon wheel like appearance on the small intestine, in transverse section. So once you've performed, ultrasonography, we're then gonna want to move on, to sampling of the small and testing. And there's a couple of ways that we can do this, of course, endoscopic a full thickness.
Now each of those has pros and cons. But currently, the accepted sort of most appropriate way of sampling these patients is with endoscopic, biopsies rather than full thickness biopsies. Laparotomy.
And there's various reasons for that. So endoscopic biopsy has the advantage of being able to see the mucosa itself really nicely, which we don't get with laparotomy. And as you can see on the screen, this is really important in patients that we do think have lymphatic disease.
So this is a dog with lymph and Tasia, and you can see these really obvious swollen, white, lacteals all over the lining of this mucosa. So that really helps us push us towards sort of more a lymphatic problem than other. When we can see the mucosa and other advantages of endoscopic biopsy are that it's much less invasive for the individual.
And there isn't the risk of wound deist or deists of an enterotomy incision. You know, which obviously can be quite catastrophic, catastrophic if that occurs. It also potentially is cheaper.
Certainly referral level. A gastro endoscopy is often cheaper than laparotomy with full thickness biopsies. And it allows us to start treatment immediately.
So a lot of these patients are going to undergo biopsy and we're gonna want to start them, probably on prednisolone at some stage. And if we're doing endoscopic biopsies, we can start prednisolone straight away. Whereas if we're doing full fitness biopsies, you know there is a risk that the PREDNISOLONE can increase the risk of wound deist, and we'd ideally want to delay the prednisolone therapy by 10 to 14 days.
Of course, the disadvantages with endoscopic biopsy is that we cannot sample the entire gastrointestinal tract. There's probably a large region of the jeden, for instance, that we can't get to. There's many of the scopes that we use in clinical practise go up to a length of only 1.5 metres, and we also can only biopsy the most superficial layers of the small intestine.
So we can't sample the deeper layers such as the muscularis, which can be affected by some transmural diseases. And therefore, if on the ultrasound we think, for instance, the muscularis layer is particularly abnormal compared to the mucosa, it may actually be more appropriate to do full thickness biopsies, in those individuals, other advantages as well. A full fitness biopsy are that it's, you know, generally, relatively straightforward to perform by anybody in primary care practise.
You know, so those are the sort of the pros and cons of of those two methods of biopsying once intestinal biopsy is performed, we'll have a look at the histopathology on these cases to try and help us achieve a definitive diagnosis. And we've talked earlier about the difference between endoscopic and full thickness biopsy. When we have patients diagnosed with inflammatory bowel disease, the pathologist will, normally refer to, the WS a VA scoring system, which was published a few years ago, for inflammatory bowel disease to help standardise the interpretation of these patients.
Ultimately, what we tend to see on, histopathology of the IBD patients, is inflammation, plus or minus crypt dilation, abscess and various other things like vous blunting, and fibrosis as well. A degree of lymphatic dilation is common even in IBD cases. And the most common type of inflammation that we see in these patients is lymphoplasmacytic enteritis.
Do be aware that the severity of changes on histopathology unfortunately, don't really correlate with the severity of disease in the individual. So ultimately, what we're really doing is simply getting that report back and saying, OK, this is not consistent with, lymphoma. This is consistent with IBD.
And then, regardless of really the severity of the changes, the the approach to treatment is more based on the clinical severity of the patient than histopathologic. In some patients, we may recommend, fish, so fluorescent in situ hybridization to look for the presence of organisms invading into the mucosa. This is something that's been looked at, particularly in cats, the gastrointestinal tract disease.
It might be something we consider more in patients who have significant neutrophilic components to that inflammation. We also have the availability of immuno chemistry and par, useful for differentiating some lymphocyte rich inflammatory, changes with patients who have emerging lymphoma. So if the histopathologist states on the report that there is the suspicion of lymphoma, then these are tests that could be requested to further clarify.
This is a bar chart that I pulled from the PLE review paper a few years ago. Just looking at the frequency of different, sort of changes that we'll see on Histopathology. And the severity score for each of them.
But as I say, bear in mind severity score doesn't really necessarily correlate with clinical severity. So a lot of patients, of course, here, having mucosal fibrosis, vous blunting epithelial injury. Lacteal dilation, Crip lesions and note as well.
Intraepithelial lymphocytes, the IELS. Intra epy the lymphs lymphocytes, can be one of the sort of indicators of a lymphoma. So if you do see evidence of that, you know, it might be worth contacting.
Sorry on the report. It might be worth contacting the pathologists and discussing that individual case over the phone. And their sort of index of suspicion that it could be an emerging lymphoma.
So finally onto treatment. How are we gonna manage these patients Long term? Well, one of the first things that we're gonna think about is diet and diet often really does form one of the cornerstones of treatment of PLE.
Ultimately, we fall into largely speaking one of two camps. Either we have primarily lymph ectasia. The disease of the lymphatic system in which an ultra low fat diet is recommended.
So when we talk about ultra low fat, we can talk about it in a few different ways. We can talk about it in grammes, per mega cal as I put on the slide here or in fat percentages. And really, what we're talking about is less than 2.5 per cent fat in wet diets and less than eight per cent fat in dry diets.
Otherwise, if we primarily think the patient actually has inflammatory bowel disease, then we're gonna be more likely leaning towards the use of hydrolysed or potentially novel protein diets, as standard for the treatment of IVD. Now, as I say in a lot of patients, there is some degree of crossover. And the decision will be made by the clinician on a case by case basis as to which of these diets is more appropriate.
Now, bear in mind that, we also will consider potentially multiple different diets in these individuals. Because we may consider starting an ultra low fat diet. And if that doesn't work, move to a hydrolyzed diet.
Or we may start one hydrolysed diet. And if that doesn't work, move to a different, hydrolysed diet. Because, of course, we have evidence that there are some animals who will respond to one hydrolysed diet, but not another, perhaps because of different protein sources, some coming from chicken feather protein, for instance.
Whereas others coming from soy based proteins. We also may as well move from ultra low fat, commercially available diets to ultra low fat, home prepared diets in some individuals as well. So what we want to be doing is reassessing the response in these individuals quite regularly in the initial stages of treatment with diet and sort of don't be afraid to change diet.
A few times, if we're not getting the response that we would we would like, bear in mind that whichever diet we do select, it should be highly digestible protein. It contains, it should contain long chain, fatty acids. We should consider supplementing these diets with fat-soluble vitamins.
And also, medium chain triglycerides as well can be supplemented safely, even in patients. With lymphangiectasia. But one of the big problems that we can sometimes see as well in these individuals is their lack of appetite.
So the significant hyper ria that they have means that they're just not that tolerant of these relatively, you know, low palatability, diets. Unfortunately, fatty foods taste good. And really, we want to be cutting out fat, as much as possible, certainly in the lymphatic Assia patients, but also in the IBD patients.
So, in the initial stages of treatment, it's often sensible to consider the use of esophagostomy feeding tubes, which can be placed during the time of endoscopic biopsy. And this will allow us to send the patient home, and be able to, you know, give the patient appropriate nutrition with a diet of our selection through the feeding tube. And sometimes this can make a really big difference.
Certainly, in the short term, in these individuals, when profound lack of appetite is a really, significant problem. As I say, if the protein levels aren't improving within three days of feeding, one of these new diets we can consider increasing the, the protein content of the diet. If the protein levels in the blood are not improving after seven days, perhaps consider an alternative protein source, altogether.
And when we consider PLE, we think about the severity of this disease and the fact that probably many of these patients need the most aggressive medical management. And often we think about obviously the use of prednisolone and second line immunosuppressives in those IVD patients. But do be aware that there are a significant number of PLE patients with really severe IBD They can simply respond to hydrolysed prescription diets.
Alone, and, therefore, you know, in patients, that even have the most severe forms of PL A. It is appropriate, in some instances, to initially start a hydrolysed prescription diet alone and monitor. You know, response, T to dietary manipulation before considering the use of immunosuppressive drugs onto immunosuppressives.
So along with, diet, these are generally pretty important, in our IBD patients, and the most frequently prescribed drug, of course, is prednisolone. So prednisolone is used at 1 to 2 megs per kig, daily. And, this is you.
You tapered every three weeks approximately, based on treatment response. With patients lowering the dose over a protracted period of time until we're able to either get them off of the drug altogether if they achieve clinical remission, which would be fantastic. Or, essentially keep them on the lowest effective dose long term, which is often the more common situation that you find yourself in.
Now, treatment with prednisolone is a little bit controversial because of the side effects of this drug. All of which can be a bit of an issue, really, in patients with protein losing enteropathy. So firstly, prednisolone is, prothrombotic.
So PLE patients are already prothrombotic within a prednisolone, risk of, thrombolic disease. So certainly, whilst we're on prednisolone therapy, we should certainly be using antithrombotic drugs. Prednisolone itself causes protein muscle metabolism, which is an issue in patients that already have significantly reduced, lean muscle mass.
And also prednisolone tends to lead to hyperlipemia, which again, is one of the things that we're trying to avoid in in patients, particularly, with, lymphangiectasia. So one of the alternatives we can consider is budesonide. So this is another glucocorticoid that has a high first pass effect and affinity, for intestinal steroid receptors, which essentially means it's not really absorbed into the bloodstream.
And therefore it doesn't cause the systemic, side effects that prednisolone does. It's a lot less studied than prednisolone, but certainly can be, you know, considered as an alternative based on, some of the evidence in the literature. Patients that fail to respond to prednisolone will often require, a second immunosuppressive agent.
And, it's not uncommon, you know, for these to be required in our PL EIB D patients. Ultimately, over the years, we've tended to use most frequently, cyclosporin, chlorambucil and previously as a thr each of these drugs certainly has its own pros and cons. And in each individual case, we need to sort of consider which of these would be most appropriate based on the cost of the drug.
The side effect profile of the drug, the availability of the drug, the clinician's experience using that drug, and the duration of onset of action as well in patients that are really profoundly unwell. More recently, there is evidence that certainly chlorambucil, is preferred as a thr, and as a result, most, most sort of evidence, really, at the moment points towards cyclosporin and chlorambucil being the two most appropriate drugs to use in our patients. So we'll start these drugs.
You know, in combination with prednisolone, and and monitor response. If we're responding to the combination of second line immunosuppressive and prednisolone, then we start to down titrate and discontinue the prednisolone before then decreasing the doses of the second line. Drugs.
And some patients as well may respond to one of these, second line drugs, but not another. So it's not uncommon. Certainly for me to see that I might start a patient on one of these drugs and prednisolone.
And if there's still a lack of response, then we may end up transitioning off of, prednisolone or the second line immunosuppressive and onto a different second line immunosuppressive as well. So there certainly, is a bit of trial and error. You know, with these patients, do note here as well that the cyclosporin dose, is, given twice daily, which is, off label.
So it's licenced for once. Daily use for at topic dermatitis, and we do use it twice daily for, immunosuppressive diseases. Probiotics can be considered for, dys biosis in our individuals.
And of course, as we mentioned earlier, there's the, importance of supplementing Cabal Amin in these patients as well. Long term, if they're hypoc anaemic, with regard with respect to when we stop the caballa supplementation. There was a a nice, Kalam review paper that was published a few years ago in the Journal of Veteran Internal Medicine.
And ultimately, what we can do is recheck Kabal Amin levels 8 to 12 weeks into therapy, and if they are super normal so above the reference interval, then that indicates that you know, the Kabal Amin stores are back up to, where they should be and that the intestinal disease, is being successfully treated. And therefore we can probably stop caballa supplementation. And, you know, recheck Kalin levels at a later date just to make sure they've not then dropped.
Whereas in an individual that is on cabal supplementation and we recheck, Kalam levels at a later date. If they're still within the reference interval, then that indicates that by stopping the Cabal Amin they'll likely drop low again in those patients. We need to continue caballa supplementation and, continue to aggressively treat the intestinal tract disease because we're still not on top of it in achieving appropriate cabal absorption.
If we do have a patient with profound hypocalcemia, we might need to, use calcium gluconate intravenously. In the short term to control neuromuscular signs, we might consider oral oral calcium carbonate. But do be aware that calcium carbonate or release is not very well absorbed and often is therefore needed to be given with, calcitriol, which is the active, vitamin D.
But also, calcium carbonate can cause gastrointestinal side effects, which you know, not ideal in this group of patients. As I said earlier, if the calcium levels are very, very low, and we're supplementing IV. We might want to check magnesium levels and supplement magnesium as well.
To help be able to correct some calcium more effectively. Because of the risk of thrombosis, we're gonna want to start anti thrombotic drugs. So, largely speaking, these fall into one of two categories antiplatelet drugs for patients at risk of arterial clots and anticoagulants patients at risk of venous clots.
Now, patients with protein losing enteropathy are most at risk of venous clots, and therefore the anticoagulants are more appropriate. So typically we'll be reaching for the factor. 10 A.
Inhibitors such as Apax ofan and Raban. However, these drugs are really quite expensive. And if, and also not not that readily available.
So if the client is unable to sort of commit to anticoagulant therapy, the next best thing would be to yeah, prescribe clopidogrel, as an antiplatelet drug. If we have a patient with effusions, we typically don't recommend draining them unless it's a a large pleural effusion that's compromising ventilation or a really large peritoneal effusion that's affecting the patient's ability to sort of sleep comfortably. Or, you know, eat or or even ventilate if it's pressing, on a diaphragm.
But generally we want to look at, medical management to treat the underlying enteropathy, thereby allowing the patient's protein levels to normalise, thereby allowing, the effusion to resolve by itself. We don't use diuretics in these patients, primarily because you know, they have not developed effusions because of, venous congestion as heart failure patients do in which relieving venous congestion can be beneficial. These patients have effusions because of low oncotic pressure, and all we're simply going to do by giving them diuretics is dehydrate them.
Which, of course, is not going to be ideal when we've got a patient that already has gastrointestinal tract signs and perhaps isn't eating and drinking as normally. So diuretics Honestly, often not necessary and and and largely contraindicated. Crystalloids as well, are often not beneficial in these patients.
These guys, will ause very quickly when we administer crystalloids to them. You know, as we're not improving their oncotic pressure but increasing circulating volume. So, instead, you know, yeah, Colloids may be, more appropriate in these, individuals.
Human albumin has been used, in some patients with the most severe protein losing diseases. To help control really severe effusions. You know, pleural effusion.
That's compromising ventilation. However, there are significant risks. Anaphylactic primarily being the one with associating.
Sorry with administering human albumin to dogs and therefore we generally recommend avoiding it. Neurotin might serve as a nice anti-nausea antiemetic, drug, to help, symptomatically treat these patients in the initial stages. Reat, has also been, discussed for the use of, intestinal lymph and taia as well.
And of course, if we do diagnose, lymphoma in a dog, as a cause of its PR E, we can consider the use, of chemotherapy. Do bear in mind that these patients are stage five, because the lymphoma is is existing in in the G I tract, which is outside of the lymphoreticular system. So they have the highest stage of disease.
They're almost always unwell, which is subtype B. So both these things confer. A poorer prognosis.
And also, they're quite frequently T cell lymphomas as well. So, response to chemotherapy with G I lymphoma in dogs, is is a lot poorer than the standard multi multicentric lymphoma. And you know, the survival times and even, sort of disease free intervals are are really quite short in in G I lymphoma patients, which is really quite a shame.
As I said earlier in the lecture, Overall, we have about a 50% non response rate. And of those responders, a significant number are on indefinite therapy, and may never achieve completely normal blood protein, levels. But some of them are, you know, are lucky enough to come off therapy at some point and can, you know, achieve complete clinical remission.
Without the use of any drugs, but often, you know, keeping them on a prescription diet. Long term, and certainly in my experience, it's impossible to predict which individuals are going to be responders and which aren't. I've certainly seen cases that seem, the most you know, terribly severe PLE patients with profound weight loss, profound, you know, lack of appetite and large plural and peritoneal effusions.
Really low blood protein levels. You know, and some of those individuals I've had achieved complete response to therapy, you know, and survive really protracted periods of time. But also vice versa.
And I think we have to, sort of remember to with these largely sort of difficult to treat patients, we have to remember, that we can use a lot of trial and error. Particularly with respect to diet, you know, before giving up on on these individuals, We have a lot of different diets. That can be that can be tried in these patients, based on what their primary gastrointestinal tract disease is.
And, you know, And if it is an IBD more than, say, a PLE. There are lots of different immunosuppressive agents that could be used in different combinations. So, that's pretty much the end of today's talk.
Thank you very much for listening. I hope, I've given you, a few top tips. Really?
To help you work your way through these, quite rewarding patients to diagnose, but ultimately, sometimes quite frustrating, patients to treat. All right. Well, you take care and I'll see you next time.