Hello everyone. My name is Nick Beckfield. I'm a small animal internal medicine specialist working at the University of Cambridge.

And welcome to this webinar vets, course. We've got 8 webinars. We're gonna be looking at a range of small animal internal medicine, conditions.

I'm gonna try and use case examples as I go through the different, conditions. We're gonna be studying. Different body systems, and we're starting with this first webinar looking at advances in the diagnosis and management of canine liver disease.

So I'll sort of provide an overview of the major liver diseases to affect dogs. We'll think about the latest developments in the aetiology and diagnosis of canine chronic hepatitis, which is the Biggest, most common liver disease that we see in dogs. We will explain how we diagnose, how we manage that, we'll touch on, copper associated liver disease, and then we'll finish by, covering a not that common condition, but can be difficult to diagnose and manage bacterial cholangitis and cholecystitis.

And in the second webinar we'll be covering cat liver diseases. So this is a study that we performed, a few years ago, and was looking at the sort of liver diseases that were out there in the dog population in the, in the UK. So this data.

Was collected from a large histopathology laboratory that received samples from predominantly primary care practises, but there will have also been some specialist referral practises sent samples to that laboratory. And we looked at the types of liver disease that those dogs had, so we could sort of get an indication about what liver diseases were out there in the UK and then we also looked at other data that we were able to generate, so whether there was any particular, you know, breeds that were predisposed to one type of disease, you know, the sort of settlement that we saw, and I'll present a little bit of that data, later on. So there was, you know, 45,000 liver biopsies that had been submitted.

And there's a number of disorders on here, and I'll sort of go into a little bit of detail on, on some of these, but I'm gonna focus on chronic hepatitis, which is by far the most common primary liver disease in dogs, and I'll explain to you in a moment what I mean by primary and secondary or reactive is the other name that sometimes puts instead of secondary, so reactive disorder. And, there's a number of those things on there which are actually, you know, reactive secondary disorders. Obviously, the first one is reactive hepatitis.

But what we're interested in is the primary liver diseases like chronic hepatitis. Another one on there would be cirrhosis, acute hepatitis, amyloidosis. And then you'll see that biliary tract diseases are also on there, so neutrophilic cholangitis, colo lymphocytic cholangitis as well, neoplasia.

Pace in neoplasia is the most common tumour in dogs, whereas we'll see in cats in the next webinar that they tend to develop, hemopoietic neoplasia, which is predominantly lymphoma, hepatic lymphoma. And then the final group, this disorders have impaired, vascular perfusion is animals with portosystemic shunts likely to be congenital port systemstemic shunts. So, big take home messages are that, parental disorders are more common in dogs and biliary disorders, and then chronic hepatitis is by far the most.

Common liver disease that we see in dogs. But also other take homes are that, you know, we as vets are biopsying dogs that have got secondary or reactive liver diseases and ideally what we want to be doing is identifying those from our clinical examination and our history and other tests rather than going and biopsying their liver. What we want to do is identify the underlying disease that's causing the liver to react and then to manage that disease, and I'll show you a few examples of those, in a moment.

So I wanna use a case example. This is Ellie, who's a 4 year old female English springer spaniel, and she came to us with a two-week history of relatively non-specific signs, so lethargy and appetence and there been some weight loss. She'd been vomiting intermittently, but also more recently there was jaundice and there's a picture of her of, hid her identity to try and retain her anonymity.

Physical examination. She was depressed. There was a very marked jaundice of the skin, the sclera, and the mucous membranes, so you can hopefully make out the significant jaundice there, yellowness of her skin.

Her abdomen was tense. There wasn't any particular sort of focus of pain, but we felt that her her abdomen was tense, but it was possible to find fluids, so she's got some ascites. Temperature was normal and yes, she's got a reduced body condition score.

So we moved on to do serum biochemistry. I think that's gonna be a very sensible thing along with, haematology, to try and determine the cause of her jaundice and her other non-specific clinical signs. And so you can see here, there's, mild to moderate, elevations in, liver enzymes, ALT.

Just to remind you, that's a marker of hepatic cellular damage. Whereas ALP is a marker of bile stasis, and you will remember that there are several isoenzymes in dogs of ALP, so there's the liver induced form, there's a steroid-induced form, so either endogenous or exogenous steroids, and then there's a bone isoenzyme, so that's really just relevant to growing animals with increased bone turnover. And you'll also see the albumin slightly decrease, so there's a number of reasons for that.

It could be reduced production in the liver, it could be lost from the kidneys or the guts. The urera is reduced as well, so that could be reduced production in the liver. So of course, the urea cycle converts ammonia to urea, which is then excreted.

So if there's decreased functioning liver mass, that can be reduced. And then the total bilirubin is significantly increased. We know that, of course, because she's clinically jaundiced.

So when I'm faced with a serum biochemistry panel, I always sort of look and think, well, yes, there's increased liver enzymes, could that be due to a primary or a secondary epatopathy? So one of these reactive liver diseases. And to try and sort of help me answer that question, you know, signalment and history and clinical examinations and pattern, pattern recognition are all very important, but I also look at the same time on the serum biochemistry, for, evidence of, liver, function.

And so the liver functional markers are things like. Albumin and urea. And if those liver functional markers are reduced, that tends to suggest more that an animal's got a primary liver disease, whereas we don't tend to see reduced function in animals with secondary liver disorders.

So I'm already thinking in this, in this dog that primary liver disease may be more, maybe more likely. So yeah, markers of reduced function, album in your ear and total bilirubin. What about, haematology?

Well, one of the critical things is, is to do haematology is to rule out a pre-hepatic cause of jaundice, as you'll be aware. So you're assessing red cell numbers which are well within the reference interval, . In her, so, you know, she doesn't have a pre-hepatic cause to her jaundice.

And there's an increase in white blood cells, which is predominantly due to a neutrophilia and also a, lymphoenia, reduced lymphocyte. So that could be a stress response. The neutrophilia is a non-specific change.

It could be related to inflammation infection, or again, yes, a stress, stress response, but the important thing is that we have ruled out a pre-hepatic cause to Ellie's jaundice. So this is the concept that I've, I've already alluded to, primary versus secondary or reactive disorders, and because the liver is central in many metabolic processes, it particularly philtres the blood coming from the, you know, gastrointestinal tract via the hepatic portal vein. It's very susceptible to secondary damage, so animals with gastrointestinal disease, be it IBD and, you know.

Infectious causes and tumour and other things often have mild to moderate to sometimes marked increases in liver enzymes just because there's lots of extra bacteria or bacterial cytokines being processed by the liver. We see animals with dental disease and skin disease that have got increased liver enzymes. Liver is very susceptible to drug and toxin injury as well.

So these are these sort of reactive or secondary causes as to why an animal might have an increase in liver enzymes, but again, these secondary things, and there's some more examples here, shouldn't cause a reduction in function. So function usually only reduces in animals with primary disease and over time. So yeah, this lists other causes of the secondary or reactive epitopathies and endocrine conditions are on there.

So of course in Cushing's you see significant increases in liver enzymes and in part that's due to the fact that glycogen becomes deposited in their livers and liver cells swell up. So you get bile stasis and And then you get damage to the hepatocytes. In diabetes mellitus, you've got hepatic lipidosis, you know, if there's hypoxic damage, of course, you can get death of hepatocytes, GI disease, pancreatitis we talked about, where drugs and toxins, and this, so this list is definitely not exhaustive.

So that's always for me trying to determine whether a patient's got a primary, like chronic hepatitis or, a hepatic lymphoma is two examples, or a secondary reactive to one of these things. And, you know, pattern recognition can help, you know, it's a pretty dramatic example, but this dog on the right, Bijon, that was, you know, 789 years of age that had a markedly increased ALP and ALT, but you know, it got a pot belly and was drinking more and developed alopeci it got Coumadin, you know, that dog doesn't need a liver biopsy to work out why his liver enzymes are elevated. You're going to, you know, test for hyperadrenal corticism.

So yeah, some important misconceptions about liver enzymes, they don't indicate liver function and that's one thing we're often interested in. And you don't necessarily see higher elevations in animals with primary disease versus secondary disease, and a good example is a dog with Cushing's disease that we've just discussed and have really high levels of liver enzymes. And very occasionally, the liver enzymes can be within the reference interval in a patient with very end stage liver disease, i.e.

Cirrhosis, but in reality it's not that common that that occurs. And the magnitude of elevation isn't necessarily prognostic, so you can have an animal that has really, severe, damage, say toxic damage following ingestion of a hepatotoxin, but they live, their liver function normal and they can, you know, return to normal health. So it, they sort of reflect the amount of damage, but they don't necessarily give any sort of prognostic benefits.

And then liver functional tests that we talked about. So again, liver function tends to decrease with chronicity and in animals with primary liver diseases. So albumin in your ear are probably the more usual markers we look for.

Glucose, very uncommonly reduces, tends to only reduce in sort of small breed dogs with little glycogen reserve that develop liver disease, particularly something like a portymic shunt. Bilirubin is, of course, a marker of . Liver function.

But of course bilirubin also increases if there is hemolysis, i.e. Pre-hepatic cause.

If the liver is not able to process that bilirubin, so that's the hepatic cause functional thing, and also with post-hepatic causes if there's an obstruction to biliary. Flow, that will also increase total bilirubin. And then bile acids, as you remember, are a useful indicator of a function, and we tend to do both resting and postprandial bile acids, and we'll sort of touch on those in the second webinar when we talk about port systememic shunts in, in cats.

So when we're investigating the patient with liver disease, you know, we were going to enter this sort of pathway at any one of a number of points. We may enter right at the start, so we have a, you know, a dog of a certain breed that we're suspicious might have liver disease based on clinical signs, historical findings, clinical examination findings, or we may enter this pathway because we take. A blood sample from a dog, say, you know, as a pre-anesthetic test or a, you know, screening test for another disease, or we may even enter this pathway when we're doing diagnostic imaging and we find abnormalities of the, of the liver.

So that's the sort of pathway from You know, history, clinical examination, signalment can be useful to clinical pathology, to diagnostic imaging, which is predominantly ultrasonography, to then maybe sampling the liver, be it fine lapirate or ideally ultrasonography, sorry, histopathology. So this was Elis, so remember Ellie is this young springer spaniel with relatively acute onset signs, lethargy, in appetence, intermittent vomiting, some weight loss, and then, of course, jaundiced and has got, you know, moderate to marked increases in liver enzymes. And, you can see that the liver is quite small, it's very irregular in outline, so it's got that undulating margin.

And that tends to suggest fibrosis is present in the fibrous tissue is sort of drawn in the capsule in places. It doesn't really show up very well on just a still image like this, but there was also some, heterogeneity of the, liver parenyma as well. So small liver, irregular outline, abnormal ecogenicity or irregular eogenicity.

Quite a lot of free fluid present. No signs of bilu tract dilation, so gallbladder normal size or in fact small. No evidence of common bile dilation, so that helps you rule out a post-hepatic cause, and then there were no other abnormalities in the rest of the abdomen like you may see in a, you know, an animal with pancreatitis causing post-hepatic obstruction.

So we remove some of the fluid and it's a modified transudate. There's an image of it there. Actually, other terminology nowadays tends to be, a protein-rich transudate, but we often still refer to a modified transudate.

And in dogs with liver disease, it's usually due to portal hypertension. It's uncommonly related to low blood albumin, it often doesn't drop low enough, it leads to as cites formation. So what happens in patients with portal hypertension is that when their liver becomes scarred with fibrous tissue, we get a lot of scarring around about the little portal veins as they pass into the liver or transverse through the liver.

And so if you get scarring of those vessels, you get contracture narrowing of the vessels, and so blood pressure increases in the portal system, the hepatic portal vein and tributaries from the guts, and the increased oncotic pressure in that portal system causes fluid to leak out to, within the, within the abdomen. It's also the reason why animals get, you know, GI signs and ulceration if they get portal hypertension because the blood supply to the guts is abnormal and they get, again, leakage of fluid into the lumen of their guts. And as the next and so the final step in, working out what was going on with Ellie, we took some liver biopsies and these were taken laparoscopically, as you can see at the top, but, taking them.

That exploratory laparotomy, celiotomy is another very good way of, probably a, you know, superior way in terms of number of samples and quality of samples and making sure that you can control postoperative bleeding, but it's obviously more invasive. We occasionally do sort of true-cut needle biopsies, but the yield you get is quite low on them, so we tend to go for the slightly larger samples. Fine needle aspiration, cytology of liver is of relatively limited utility, particularly in dogs and particularly in dogs when you're trying to diagnose inflammatory diseases.

It's OK if you think the dog's got hepatic lymphoma, or if there's a, you know, specific mass lesion and you stick a needle into that mass and get a sample of that mass, but otherwise it's not very good for inflammatory, inflammatory disease. So the changes, that the histopathologist saw were, inflammation. So there were lymphocytes and plasma cells, there was some fibrosis, which is bridging, which generally suggests it's quite advanced.

There was some regeneration going on, no obvious cause, and they use specific stains to look for copper. And a really critical thing as well, before you take liver biopsies on these patients that you think might have got reduced liver function is to check coagulation, so that's by way of prothrombin time, partial thromboplastin time. So checking secondary coagulation, because remember that the liver produces clotting factors and also activates 27, 9 and 10, which is the vitamin K dependent factors.

And so that's why animals with liver disease. Can bleed and they rarely bleed spontaneously. They generally bleed when you start to do things to them, like you stick needles into their, into their livers.

So yeah, importantly, check co coagulation pre-biopsy. If coagulation times are prolonged, obviously, don't continue with the biopsy. What you should do is give them vitamin K and usually 2 days' worth and see whether the coagulation times have normalised.

If they haven't normalised. You'll need to give that patient plasma or fresh frozen plasma to replenish clotting factors prior to doing liver liver biopsy. So these are just microscopically what the histopathologist would have seen.

So, inflammation, top left lymphocytes and fewer plasma cells. Top right is apoptosis, so cells that have undergone programmed cell death, plus or minus some necrotic cells, so the top, top right of that photograph. And then reticulum stain in the bottom images of a, you can see the fibrous tissue that's been outlined by that sort of darker material and you can sort of see the nodular appearance to the liver there.

So that's sort of quite classic of when it becomes more and more advanced and more fibrosis occurs that you'll see the sort of classical nodular cirrrotic changes. So all those things are . Suggestive of, of chronic hepatitis.

And it's a pretty common disease in the UK and this was based on quite old, quite an old study, a postmortem study but was done by a colleague of mine looking for animals, looking at animals that are actually having postmortems done at Glasgow vet school. And these weren't animals that necessarily had no liver disease. They presented from primary care practise with, you know, a variety of clinical signs or were euthanna for a variety of reasons.

And, you know, 12 out of every 100 of those dogs had histological evidence of chronic hepatitis. Now, you know, that study. Hasn't necessarily been replicated again or hasn't been performed, but it sort of does show, and I think clinically we see a lot of dogs with chronic hepatitis.

By no means will have those all been symptomatic by any means, but it's definitely out there in the UK like it is in the US and Scandinavia and and many and most countries. And we know that there's an increased risk in certain breeds, come on to that in seconds. And it's most frequently seen in sort of middle aged to older dogs and females more than males.

So these are some of the breeds that have an increased predisposition to developing this very common liver disease, chronic hepatitis. So you can see spaniels around there like Eli English springer spaniel, but also cocker spaniels as well. Labradors have quite high incidence, Doberman pinschers, Dalmatians as well.

But you can see chronic hepatitis in any breed. And again, looking at the ages, sort of middle aged to older dogs, maybe slightly younger in the spring of Spanish. But, and female dogs, generally more commonly than males.

So if I have a, you know, a nine year old Labrador retriever that comes into the practise, that's got, you know, non-specific clinical signs like, you know, weight loss and, some intermittent GI signs, vomiting, diarrhoea. And, you know, is, is maybe having periods when the appetite's a little bit reduced and things, and I happen to take a blood sample for, you know, screening for, disease, and I noticed that the liver enzymes are increased, you know, I'll already be thinking, right, well, I know that breed is a breed that's predisposed to, chronic hepatitis, so I'm gonna be going on and thinking about doing maybe functional testing, as we talked about looking at album in your ear. Maybe measuring bile acids and then maybe moving on to do imaging and then possibly, or probably, in fact, doing biopsy because signalments and things can be very helpful, but there's often no changes or signalments which are really patternmonic for a particular disease.

I suppose the exception might be an animal with a poor systemic shunt. You don't need to, of course, routinely biopsy those guys if you identify a shunting vessel. So yeah, what about the aetiology of this disease, which is very common.

So there's a lot of, postulated causes, but very many, very few of them have been, proved. So infectious agents, occasionally we see leptospirosis causing acute and then chronic hepatitis and very rarely with other infectious agents like adenavirus. Drugs and toxins are probably out there, particularly copper, we'll touch on that in a moment.

We think that some of these dogs have got an immune-mediated cause, like humans with, various liver diseases have got an immune-mediated cause. Metabolic conditions like things like alpha one antitrypsin deficiency, again, a human condition probably don't occur in dogs. And so in many cases seem to remain, seem to be idiopathic.

We don't currently with our diagnostic techniques, find the, find the cause. So yeah, we've, oh, I've spent a lot of time looking for, for viruses and using sort of candidate viruses and then looking for sort of known apatotrophic viruses, and there's no good evidence for a viral cause. I've mentioned a leptospira, and a few other sort of less common causes what you may occasionally see liver involvement in the sania or E canus that might lead to chronic hepatitis, but pretty uncommon, those things.

So drugs and toxins can definitely cause, liver injury, and some of the sort of drugs that we use like the anti-epileptic drugs are definitely known. Non-steroidals can do, particularly in Labradors. There's been association with carprafin toxicity.

But also importantly, sort of supplements, nutritional supplements, herbal and others, and they're quite a common cause of liver injury in humans. So, you know, in your history of these patients with evidence of, you know, liver disease or increased liver enzymes, just question very carefully about supplements that they may be on and if there's any doubt, get them to stop those supplements. And so the involvement of copper in liver disease in dogs is quite an important thing to, to touch on for a few slides because it's You know, it is a, a, a well-known toxic cause to why an animal develops chronic hepatitis.

So they basically have a buildup of copper, usually because of failure to excrete, and then that excess copper causes damage to hepatocys, secondary inflammation. And it may develop a sort of a copper associated hepatitis, and we've maybe moved a bit away from the sort of classical sort of copper storage disease, but copper associated chronic hepatitis occurs in a number of breeds. The most commonly recognised as the Bedminton Terrier, the top photograph, although nowadays because of Genetic testing, breeding programmes, we see far fewer of those dogs than, you know, a decade, 23 decades ago.

We do see increased amounts of copper in some Labrador retrievers and, and other breeds like Dobermans and West Highland white terriers. So, if you're collecting liver biopsies from dogs, and your histopathology laboratory don't sort of routinely stain for copper, you should ask them to do that, and you might have to pay a little bit more for that additional stain, but it is very important to do that in, most breeds of dogs, because It is one treatable cause of chronic hepatitis. People have maybe also moved away from taking samples and sending it off for copper quantification because it was quite challenging to do that, so we tend to maybe histologically grade it now.

So yeah, the sort of increase in copper accumulation is either due to increased copper intake or reduced excretion, and to be honest, probably, probably both of those things and that increased copper leads to oxidative stress and cell, cell damage. And we are aware of one or two of the mutations in the sort of copper transporting proteins that can lead to increased copper. So there's one on the screen there, COD1, that's the sort of Classical one in the Bedlington terrier that mines some Labradors that is mutated that leads to a failure to excrete copper and an increased amount of copper, so that one excretes copper from the, cytoplasm into the, into the bile to for, further excretion into the gut.

So we know there's mutations in that one and in a number of, in many, but not all Bedlington's and, some Labradors with with copper associated chronic hepatitis. But you know, before sort of genetic testings and things, we have an indication of increased copper from, again, histochemical staining that you can see in the top right, rhodinine or rubinic acid are generally tend to be used. And there's a scoring system, as I alluded to, so it's not necessarily required to take pieces of liver and send that off for specific quantification.

And it's, it's generally been not always accumulates in that, what's called that zone 3, and you can see that schematically now, which is sort of towards the central vein, where blood will, you know, comes in by the portal tri, the hepatic portal vein. Hepatic artery and then transverses the barrankima and it gets excreted into the systemic circulation by that central, central vein. So we tend to see copper accumulating in that zone in patients that have got copper associated hepatitis.

Some copper can be normal in dogs with just, you know, inflammatory liver disease because the liver is damaged and unable to excrete copper, but what we're looking for is significant amounts of copper that are accumulating that then we imply are the underlying cause of the inflammation, and those are the ones that we need to specifically identify and specifically manage their copper build up. By things that will come on to, slightly later on. What about immune-mediated chronic hepatitis?

Well, I alluded to the fact that in humans, there are, several immune-mediated liver diseases, and those are sort of diagnosed by, often by serum markers, but we don't sort of have those good serum markers at the moment in in dogs, so it's a sort of a a diagnosis of exclusion. Sometimes the histopathologists report that they see certain changes on there that might point to an immune mediated disease. We think we probably see certain breeds like the spaniels that seem to have a predisposition to immune-mediated diseases, that's why they develop IMHA and others.

And, you know, there's evidence for an immune-mediated aetiology, again based on breed predispositions, female predominance, and that's quite common amongst immune mediated diseases in general, you know, lymphocyte plasma cell rich, again, or antibodies, if we could measure them, some sort of generic, genetic associations. With the MHC, so the, antigen presenting cells, and then some of these dogs have concurrent immune-mediated conditions. But ultimately, we sort of make that diagnosis based on the response to immunomodulatory or immunosuppressive therapy.

And we're sort of doing some work at the moment to look for, serum. Markers of immune-mediated liver damage, i.e., autoimmune liver disease.

So what about how we treat this condition, canine chronic hepatitis? So this is super useful if you've, if you've got an interest in liver disease, you should be able to get this freely available. It's the ACAM consensus statement on the diagnosis and management of this condition in dogs.

It was published a few years ago now, but it's still, highly, highly relevant, and yeah, it, it goes through the sort of evidence. Go through the disease, the aetiology, the evidence for the potential causes, how we diagnose the disease, and yeah, quite a lot on a detailed description of, of treatments. So the aims of therapy are to try and treat the underlying cause where known.

In reality, we often don't know the underlying cause as we sort of just alluded to, but there may be increased copper, you can manage that if there's, you know, an infectious cause, uncommon, but you can manage that potentially, like chronic leptospirosis. If we think from the histopathology, there's an immune-mediated cause, you know, we could specifically try and manage that. But what we often try to do is slow progression, provide a great environment for the liver to regenerate, but particularly managing clinical signs and, complications.

And yeah, we can also make sure that we don't use drugs that could possibly do any, any harm. And so, you know, avoiding drugs that are metabolised by the liver, and You know, drugs that are potentially hepatotoxic if we have that patient with liver disease and we need to treat for a, you know, a concurrent disease, we wanna make sure that we, you know, avoid, avoid those drugs. Steroids are a are a drug that many people reach for if they diagnose a patient with liver disease or if they're suspected with chronic hepatitis, sorry, or that if they are suspicious, a dog might have chronic hepatitis.

And you know, they've got pros and they've got cons. You know, these patients sort of by definition have inflammation going on within their within their liver, and we know that these drugs are great anti-inflammatory drugs and inflammation makes animals feel unwell, so you can already see the sort of benefits potentially of reducing inflammation, . But the other reason to use anti-inflammatory drugs is that inflammation drives fibrosis, and fibrosis is the killer in dogs with liver disease, just like it's a killer in us with chronic liver diseases.

So, you know, we might use them as sort of anti-inflammatory, doses for their anti-inflammatory actions, particularly around reducing fibrosis. But also we may use them an immunosuppressive dose if we suspicious that animal has got immune-mediated cause to the liver disease. And fibro just as a side, if if you're interested why fibrosis occurs, well, it's to do with these cells called the hepatic state cells, which are also known as the Io cells which hang out in this area called the space of diss.

And in health, they're vitamin A storage cells, but when they become stimulated by inflammatory cytokines. They undergo a a phenotypical and morphological change and turn into these activated steellate cells. So there's a whole load of things which activate these steellate cells that can be, Inflammatory proteins, cytokines from white blood cells that can be from, hepatocytes, dead and dying hepatocytes themselves, for instance, but ultimately they undergo change and they then turn into cells that start to secrete fibrous tissue.

So yeah, they changed their shape, they further express receptors, they synthesise all this extracellular matrix. And you can see in these bottom images maybe make out that this sort of ghost-like looking cell, this quiescence state cell that's in the right hand image has become activated, as sort of spread out and start to secrete fibrous tissue. Which is then close these gaps, so these fenestrations that are normally there in the endothelial cells are closed, vascular endothelial cells are sort of closed up, so that's one reason why you can start to see this portal hypertension thing.

So the consequences of fibrosis are ultimately reduced liver function. And as I say, fibrosis is the, is the killer in, in dogs just like it is in us. So we need to try and do all we can to try and reduce the amount of fibrosis and reduce function.

You see things like, you know, melena due to gastric ulceration, jaundice, ascites, so these are all, bad sequela of reducing liver function and, and fibrosis. But the problem is, when we use steroids in animals with liver disease to try and reduce fibrosis, they do have side effects. Yes, got the, you know, standard side effects that you'll be aware of.

But they, they can cause even more side effects in patients with liver disease, so they cause. Breakdown, so that can push animals into an encephalopathic state or if they are currently encephalopathic can worsen that. They worsen fluid, they cause fluid retention, so they can worsen CITES or even precipitate ascites in some dogs with liver disease that are just on the verge of developing ascites.

They cause gastrointestinal ulceration, and these dogs are already on the verge of ulcerating if they've got portal hypertension, and yes, they may predispose to infection. And this image is a postmortem image, unfortunately, of a dog that had chronic hepatitis that had been managed symptomatically supportively for a period of time and then received some steroids. Unfortunately, quite a high dose of steroid that then caused gastrointestinal ulceration.

And perforation, full thickness, perforation, so this is, of course, you know, ultimately fatal in dogs. So yeah, what about, you know, dose and duration, well, if you think there could be an immune mediated aetiology, and this is predominantly from what, you know, your histopathology laboratory are gonna report. So, you know, if they're not mentioning anything about immune mediated aetiology, you know, give them a ring and just say, you know, could this, could this feature.

So there's certain changes that might point more towards an immune mediatiology and if there is, then you're gonna use a sort of a 2-ish milligrammes per kilogramme per day dose. If not, you might use an anti-inflammatory dose. So what's that?

0.5 to 1, probably milli milligramme per kilogramme per day. We don't know how long to treat them for.

Ideally, we'd re-biopsy, but we rarely do that. And so maybe some animals end up having lifelong treatment, but we aim to then reduce the dose onto an alternate day dose. And I tend to monitor liver enzymes, so drop the steroids down and You know, if the liver enzymes then start to increase, I might need to increase the dose again.

Caveat that of course steroids can induce that isoform of ALP. Although we did a study to show that in animals that have significant liver disease. The ALP will actually start to reduce on steroids, just because you're reducing the amount of liver damage and cholestasis and things.

So they can still be used as a, as a marker, particularly looking at progression over time. Other immunosuppressants, so again, if you're suspicious, and maybe, you know, over the next years, more data will come out that suggests certain breeds of dog and signalments and things have got an immune-mediated cause to this very common disease, chronic hepatitis. There are studies looking at other immunosuppressants, either on their own or combined with prednisolone, and probably the one that I would reach for nowadays is, cyclosporin.

And there is data on cyclosporin, as I'll show you in a second. I would avoid azathioprine, although there are studies to show it has been used successfully, but it, it in itself can be hepatotoxic and there's not lots of data on mycophenolates, so I'll probably currently avoid, avoid that one. So this was a nice study from a few years ago now looking at cyclosporin and the treatment of dogs with presumed idiopathic, and so the assumption was that actually a number of these dogs with so-called idiopathic cause they didn't have any way of at that time of identifying an immune-mediated cause.

A bunch of them actually will have, may have immune mediated cause the hepatitis. And they did actually, dogs did very well on cyclosporin and we've used cyclosporin in, in dogs with chronic hepatitis with some very good, good effects. So I think as we generate more data, that's definitely one to use.

So I'll also. I use it in animals that don't tolerate steroids, particularly if they have dramatic side effects of of steroids, or if we're not getting very good control on steroids, I'll use a supplementary drug or I have just used citrosporin, on its own. Well, the amount of copper associated hepatitis, so we said you should always ask the histopathology laboratory to look for copper if they're coming back with histopathology findings that are suggestive of chronic hepatitis, get them to stain for copper.

Use a, a, histochemical scoring system. So again, don't send biopsies off for qualitative analysis, sorry, quantitative analysis. So, how are you gonna manage these patients?

Well, one of the main things is trying to try and restrict copper intake. So you're gonna use a low copper diet and the best ones are probably a liver diet because they're quite limited in in copper. And then you're gonna try and probably chelate copper, so remove it, from the liver.

And you may also do something like give, zinc that's going to, reduce the amount of copper that's absorbed. So, top photograph, Bedlington. Terrier, bottom photograph, unfortunately, very end stage cirrhotic liver from a, Bedlington terrier with, significant copper associated with hepatitis.

And these animals develop progressive disease in the year, in the first few years of life, and then maybe develop cirrhosis, you know, in the, once they reach 3456 type of thing. So if you, you know, if you do have, significant amounts of copper elevation and that's causing damage and inflammation and high liver enzymes and the other things we've talked about, then you need to try and reduce the amount of copper in the liver and the penicillaine is a. And very good coppitulator.

It does take quite a long time for copper levels to reduce significantly, and it can have a number of side effects, particularly gastrointestinal side effects. So we tend to start on a lower dose and and build up. You know, ideally texts talk about quantifying the amount of copper, and that is the gold standard to try and determine whether your penicillin is working.

But in reality, again, we're not going to take those samples repeatedly and send them off for quantification. We're going to look clinically and then also look at something like ALP as a marker of reducing hepatocellular damage. And then, yeah, zinc, as I say, is, is, you know, relatively commonly used in patients with liver disease because it's a mild antioxidant, but in the context of copper associated copper associated liver disease, we're using it because it's Basically sort of binds to copper within the gastrointestinal tract, and reduces the amount that gets, gets absorbed.

So it's, it's not, you know, it's not something you use to try and reduce, remove large. Amounts of copper from the liver, it's something that you'll use, you know, going forward longer term to stop the copper building back up again. But it's useful to use at the same time as the penicillaine, of course, to stop further copper accumulation, but also as for its anti-inflammatory properties.

This is a super important drug, so sort of moving back now to general treatment of chronic hepatitis away from, from copper. Ursodeoxychoic acid or desolate or ursodiol, various trade names. It's a, hydrophilic, a water loving bile acid that displaces the hydrophobic, bad bile acids.

So it's, yeah, got colorectic, so it causes You know, movement of excretion and movement of biass through the liver. It's also got some, you know, immunomodulatory and antioxidants and anti-inflammatory and other properties within the liver and further afield. Used super commonly in dogs and cats and definitely very commonly in humans with a variety of liver diseases because it's generally thought to be safe with very few side effects, but there's very little data on it in dogs.

I mean there's really just a sort of a Single case report from a long, long time ago. So I would generally use it in every dog, like I would do in any, every cat will come on to that next webinar with, you know, a suspected primary liver disease. The exception would be a dog with a poor systemic shunt.

They don't need osodioxyoic acid, but, you know, beneficial in these patients with chronic hepatitis, and it's, as I say, very well tolerated and not an Expensive drug. The time to avoid it is if there's signs of complete biliary tract obstruction, which actually clinically don't occur very often. But if you had a patient that was producing very pale or anechoic faeces, and then on imaging had a very dilated gallbladder and common bile ducts and things suggesting obstruction, I would not use it then.

And what about the antioxidants? Well, these are, you know, there's a whole multitude of antioxidants available and Sami is one of the compounds that's in many of them, often combined with other things like silimarin, which is milk thistle, vitamin E, zinc, occasionally, and others. And SAI is an important molecule because it's involved in the production of glutathione.

And glutathione is a very important natural antioxidant, and we know that oxidative stress is really important in the, not only the initiation, but the perpetuation of liver disease. So we want to try and do all we can to maximise antioxidant properties within the liver. And we know that in liver disease, there is less SAI, so this cofactor coenzyme that's involved in the production of glutathione.

And then people have also measured the amount of glutathione, and that is decreased in certain types of liver disease. There's most evidence for the antioxidants in acute liver disease, particularly the drug or, you know, toxin, induced liver diseases like mushroom toxicity or, you know, lamotine, so anti-cancer chemotherapeutic drug, toxicity, but they're likely to be a benefit in other liver diseases and likely to be very safe. So you want to choose a product that's, you know, has got some research around it, and we are sure that it's got sufficient amounts of, SAI in, so ask, you know, manufacturers and reps to give you both of those indications before you choose their product.

So generally a very good drug, . But cost, you know, if you're treating this patient with multiple drugs, I would prioritise the steroids or the, you know, the penicillaine or the cyclosporin, and the desylate, before you do, before you use the antioxidants, so they'll come lower, lower down. What about, other drugs you might use?

Well, diuretics, Branolactone. So if the patient like Ellie has got ascitis, you may need to remove some of that fluid. You shouldn't do it by centesis because it's red.

Relatively high protein fluid and it will just reform again and you're reducing total body protein. So we use diuretics and the diuretic of choice for hepatogenic ascites is ranolactone, which is an aldosterone antagonist. So in patients with, ascites, it's secondary to this thing called portal hypertension, so they get fibrosis in their liver, reduction in portal flow through the liver, build up a portal pressure, fluid leaks out into.

The abdomen, and in fact those patients have got systemic hypotension, and so they get activation of of renin angiotensin aldosterone system and that's why we use an antagonist of that system, which is spranolactone. You might need gas protectors, but only if there's actual evidence of, you know, bleeding by way of melena or fresh blood. Occasionally these patients have got evidence of hepatic encephalopathy, so we might need to use antiencephalopathic drugs, and we'll, cover those in a bit more detail in the second webinar when we talk about systemic shunts in the context of a cat, but the.

Management is exactly the same for hepatic encephalopathy in both species. It's around diet, good quality protein, feeding several times a day, lactulose, plus or minus antibiotics. These dogs with chronic hepatitis, you know, it's very, very, very rarely a, an underlying bacterial geology, so they shouldn't have antibiotics.

And if you were to ever use an antibiotic, make sure it's one that's not patoxic or excreted by the, liver. Diet is really important. We don't know fully exactly what we should feed, but the take-homes are that you should not restrict protein intake.

You should use a diet that's got normal or possibly slightly increased protein. These guys need increased protein for hepatic repair and regeneration. They're often in a hypermetabolic state, they might have lost body weight, etc.

Etc. So. The only time when you do need to restrict the amount of protein is if there's actual overt hepatic encephalopathy, and even that's rare, it's more about just You know, giving good quality, highly digestible protein and feeding it several, several times per day.

The liver diets are great, you know, they're formulated with highly digestible, high quality protein, low in copper if that animal had an increase in copper and higher in, you know, B vitamins, fat soluble, vitamins and others and lots of other things, but they do come at a cost, and they do come at sometimes reduced palatability. So if you don't go from liver diet, just a good quality off the shelf commercial diet is sensible, and you should keep an eye on the animals' albumin over time, and if the albumin's dropping, then supplement them with high quality protein to try and maintain that albumin. So yeah, what happened to Ellie?

Well, she was, I saw her in the days when we weren't really, there was no data on other drugs by way of other immunosuppressants, so she was started on prednisolone at a sort of, you know, immunomodulatory dose. I would probably nowadays try cyclosporin in a dog like her and look for her response, because she did have quite a lot of side effects to prednisolone, at least at those initial high doses. She was treated with ursodeoxychoic acid, Dasylate.

She had some ascites, so she had sprung aactone. She was, you know, a little bit fluid deficient, so she had, intravenous fluid therapy, and her appetite was originally poor in the hospital and so she had the nasal esophageal tube and then once she started to eat along with some antiemetics, she was just fed a . Commercial, commercial diet.

And we gradually reduced the dose of prednisolone to about 0.5 mg per kilogramme over about 2 months and we kept her on that dose. In fact, we did drop the stop the dose completely, but then her liver enzymes started to increase again.

And yeah, she was alive significant amounts of time after, after diagnosis several, several years in the end. So these guys can do quite well. The more fibrosis that they've got, usually the, the worst, worst prognosis as you can imagine, because their liver function is compromised.

So we'll just finish on talking about bacterial cholangitis and, cholecystitis. Not that commonly identified in in dogs, but important conditions. Biliary tract diseases, particularly inflammatory biliary tract diseases, are much more commonly seen in cats.

So, I, keep a lookout for that second, webinar when we're talking about cat liver, liver diseases. So these are just some definitions here, cholangitis, which is inflammation of the biliary ducts, cholangio hepatitis, which is where that inflammation spreads to the surrounding hepatic parenchyma. And cholecystitis or occasionally variations on that name which refers to inflammation of the gallbladder and sometimes these things, these conditions occur together.

So, yeah, and there's not lots of data about these dogs with inflammatory biliary tract disease. We're seeing them more and more, and I think over the years we'll get more data generated, but this is a study of some years ago that, looked at 27 or 26 dogs with bacterial cholangitis, and, you know, just over half of them have got current. Inflammatory disease of the gallbladder, and there was one that just had inflammatory disease of the gallbladder and didn't have, inflammatory disease of those smaller biliary biliary tracts, which would be a bit, a bit unusual.

Dogs that develop biliary tract disease, so, inflammatory or infectious biliary tract disease, not uncommonly have a sort of predisposing disease, and we're not specifically talking about dogs with biliary tract mucous seals, or it's sort of associated with inflammatory biliary tract disease and so some animals with cholecystitis will go on and develop gallbladder mucoceles. Some animals with, Bacterial cholangitis may also go on and develop gallbladder, gallbladder mucoceles. So in in dogs with biliary tract disease, including mucoceles and the inflammatory diseases we're currently talking about, we know that there's a certain number of predisposing conditions.

Hyperadrenal corticism is definitely one, so we see quite an association. With lu tract disease and Cushing's disease, as well as diabetes mellitus and hyperthyroidism. So if you're diagnosing patients with bacterial cholangitis, cholecystitis, gallbladder mucoceles, have a look to see whether there is an underlying, disease, particularly one of the endocrine, endocrine conditions.

We also think that gut diseases like inflammatory bowel disease, definitely in cats and humans, is associated with an increased incidence of biliary tract disease. The same probably occurs in dogs. And sort of, you know, changes to the flora and inflammation affects motility, which again then is gonna cause further changes to the intestinal flora and then potentially bacteria that go .

Back up the biliary duct into the biliary system, and you can clearly see why then those patients might get a bacterial infection there biliary tract. So, yeah, underlying inflammatory gut disease, changes to the microbiome, microsurin things are probably all again important in predisposing these dogs to biliary tract disease. So if you see patients with cholangitis, so, remember that's inflammation of those intrahepatic biliary ducts just around about that portal area, so where the, hepatic portal vein and the hepatic artery and the bile ducts are, and There's no signs of obstruction, and those animals often have quite vague clinical signs.

It may well be pyrexic, as you might imagine, with a, you know, bacterial, what's most likely cause bacterial cause, to their cholangitis, lethargic anorexic vomiting. Whereas if they've got, inflammation, acute inflammation of their gallbladder, then of course you can suspect them to be, relatively ill with abdominal pain and fever and vomiting and, you know, maybe jaundice as well if there's any signs of obstruction. You're probably gonna be picking up signs of biliary tract disease from clinic pathology and then also particularly from from imaging.

And in those 27 dogs that I talked about before, which were dogs with bacterial cholangitis plus or minus concurrent inflammation of their gallbladder, cholecystitis. These are the increases in, these are the changes, clinical pathology changes that you can see. So, you know, practically them all had increased one or more liver enzymes, bilirubin was increased in a bunch and, you know, some other sort of relatively non-specific changes, I guess.

Very few of them had increased that were tested had increased, coagulation times, I guess, I guess it's not really a parentchimal, parentchimal disorder. So ultrasonography is probably the better thing. So you're gonna look for, you know, gallbladder wall, looking for material within the loommen as well as wall thickness, irregularity of, of the wall, and you're gonna follow the common bile duct from the gallbladder to where it enters into the duodenum.

And if there's dilation of the bili tract and that's not associated with an obstructive process, then you can see that with bacterial infections, so bacterial cholecystitis. Sludge is an important thing to look for. You'll all be familiar if you're looking for sludge in, in gallbladders, and in fact, some, some sludges are normal, normal finding, but it, it shouldn't be, dependents, and it shouldn't obscure the, the lumen.

So, you know, there's generally smaller amounts that, that move, move around within the gallbladder. You might see these sort of sludge balls, these roughly spherically acc accumulations of bile and mucus and things that move around depending where the, where the patient is and those definitely thought to predispose to gallbladder mucous seals and also predisposed to animals developing obstruction. So if there's changes in the gallbladder and it's more than just, you know, sediment or, or sludge.

Then, you know, Think about taking, taking a sample and I would probably, if you think suspicious patients got liver disease, biliary tract disease, I would probably check coagulation testing prior to sticking needles in the gallbladder. Definitely if you're sticking needles into the liver, even with fine need aspirate, it'd be good practise to check coagulation testing. Some people don't do it on .

And for, for gallbladder aspiration, but it's, you know, it's probably a sensible thing to do. And it's relatively straightforward to take samples from the gallbladder. You can do it under ultrasound guidance, you should never do it blind.

You can take it at, you know, exploratory laparotomy, or of course, at laparoscopy. And what you aim to do is to try and Remove as much of the bile as possible from the gallbladder to minimise the amount that then may leak from your needle, needle site. And then you send that off for bacterial culture and also cytology.

So these are what we got back from one dog that we were suspicious based on their imaging and their findings and their pyrexic dog with some abdominal pain that had high liver enzymes and bilirubin and a marked neutrophilia and increase in inflammatory proteins, serum amyloid A or CRP and abnormalities on the imaging to include irregularity of the gallbladder, gallbladder wall, and, you know, dependent. Material in their gallbladder and so you can see the image on the right, there's lots of neutrophils, so bile is normally relatively, you, you know, it should be pretty sterile, and there's relatively low cells, but, lots of neutrophils in there, you can probably make up bacteria as well. And then on the left, that's just a different, different image, and you can see lots and lots of bacteria in there as, you know, chains and single bacteria and, and others.

Those sort of orange things are sort of billy billy casts, so. Accumulations of of Billy material. Particularly Beubin.

And so, yeah, you send that sample off and your culture and most of the time you develop, you get E. Coli, but there are some animals that have bacteria apart from E. Coli, and there's a bunch of animals that have, multiple bacteria sometimes.

And of course what the issue, one of the issues is we're very bad, we're very, you know, it's very difficult to culture anaerobic bacteria, so we do tend to do tend to miss those, which is often why we use broad spectrum antibiotics, but we should be aiming them on our culture and sensitivity results. So aspirating the bile is really important for culture and sensitivity, but also doing, you know, a liver biopsy is the sort of ultimate diagnostic thing. We're gonna be looking for changes within the.

Liver, liver parenchyma and again, there's different ways to do that, and you should always check, check coagulation. We don't do it in every, in every dog that, has a, you know, suspected cholecystitis. But we, you know, cause I think probably getting bile from the gallbladder is the most, is the most important thing.

What about the therapy? Well, if it's bacterial cholangitis, so, inflammation of the, intrapatic biliary ducts, you know, predominantly in the portal area, we're gonna be using antibiotics, and we're gonna be using other liver supportive things, particularly sodium oxychoic acids. If it's cholecystitis, so inflammation in the gallbladder, you know, that's probably gonna be a surgical disease because the risks are that it ruptures, or that, you know, maybe it develops into something like a mucousy, which again can rupture, or you can get obstruction to the blurry, biry tract.

So yeah, you know, removing the removing the gallbladder is probably the way forward. These animals might then require long-term antibiotics because they are a bit prone to ascending and sending infections, and you're probably gonna use antibiotics around about the time of surgery cause a bunch of them, or probably all of them will have bacterial infection within the liver. It's not just gonna be restricted to that, gallbladder.

So yeah, medical therapy then is antibiotics based on cultural culture and sensitivity, broad spectrum, we're probably gonna use my first line would be to use A potentially amoxicillin because it's got kills E. Coli, that's the main bug. It concentrates very highly in the biliary system and has got effects of gains gramme positive, some anaerobes, and a few gramme negative.

So it's relatively, it's a relatively sensible first line and I'll probably use 66 weeks. If the animal doesn't respond very well or it relapses, as some of them do, on treatment, then you can use a second drug. Ideally, what you'd want to do is, reaspirate, and there's a nice study to show that in these dogs treated over time, a number of them.

Do develop resistant bacteria and so you might need to change your antibiotic, but, you know, as a first line, something like potential potentiate amoxicillin, unless your sensitivity results say otherwise is a, is a sensible thing. So this was one dog, Lucy, who was a Weimarana that had bacterial cholangitis, and those are the images actually that I showed you earlier and had moderate growth of E. Coli.

And, To, bladder, but as you can see, there's some, oops sorry, you can see there's some resistance and so we had to use, fluroquinolone, potentiate sulfonamides. I wouldn't, even though it's sensitive, they can be hepatotoxic, so I'd avoid, avoid those. But yeah, it's a bit unusual most of the time, the bacteria is gonna be sensitive to, amoxiclav.

And then other things also deoxychoic acid, we talked about that a little bit earlier in the context of chronic hepatitis or copper associated disease, generally pretty good drug, only contraindicated if there's complete biliary tract obstruction. So, use that and then the antioxidants are gonna be pretty good, like, SAMI-based drugs. Again, milk thistle and many of these drugs have got, combinations of these things, but there isn't lots of evidence, but they're unlikely to do any harm.

A prognosis is relatively favourable if you can identify the infection and you can treat it. If the, the lurex's ruptured, then of course, it's a guarded prognosis, and you can see the data from that study of, 27 dogs that, some of them, unfortunately succumbed to their disease with. Signs of probable gallbladder rupture.

And in fact, having multiple isolates didn't actually correlate with a poorer prognosis, and they can do well for significant amounts of time. So most of the presentation we've spent on, you know, the number one liver disease in dogs, which is chronic hepatitis and talked about. Etiologies and touched on copper and also a new mediated cause, but then we've just finished by talking about less common conditions, although we've seen them more frequently, so I guess there'll be more coming in the literature over the, over the years.

So, bacterial cholangitis and cholecystitis, and we talked about how to diagnose and manage those things and some of the changes on imaging and clinical signs and ultimately, aspirating. And trying to drain out as much bile as you can do to reduce the chances of leakage, plus or minus a liver biopsy, although you're probably not gonna do that in the, you know, acutely unwell, systemically unwell dog. So, yeah, I hope that's useful, and I look forward to seeing you for the second webinar which is gonna be on, feline liver diseases.

So we're gonna be, changing species and talking particularly about biliary tract diseases in cats.