Hello, it's Anthony Chadwick from the webinaret. Coming to you from a very, very sunny Manchester which those of you not from England won't believe what a strange statement that is, but I'm at the BSAVA conference which starts tomorrow. I decided to get here early because I'm very keener to hear what Amy Lamb has to say about liver under attack.

This is a webinar that's been kindly sponsored by ADM Protection and also SAS, which is this small animal specialist hospitals, which I think Amy is broadcasting from Sydney, but you have several clinics around Australia and it's obviously growing really well. Amy is a veterinary, surgeon who qualified from Australia, and she's followed in her father's footsteps to become a vet as well. She's been mentored and trained by colleagues across the globe, including Australia, spent some time in the UK and also in Hong Kong and the USA.

In 2008, she started her specialist training at SAS as a small animal medical resident and has published or been a co-author in over 10 publications and has trained multiple residents and received several awards from colleagues for her research and publications. Amy's particularly interested in the complexity and challenges of dealing with internal medicine cases, and she particularly enjoys infectious disease, endocrinology and immune mediated disease, as well as, of course, liver disease. She's going to be talking to us today all about the liver is under attack and what should we do about it.

So Amy, it's over to you. Thank you so much for your introduction and thank you for having me. It's exciting to be here, and exciting to have this online format where I can talk to you from Sydney in Australia, and, I know that this is getting out there to the UK and, wherever else, you may be.

So, the, I titled this talk as the Liver Under Attack, and I wanted to talk to you a bit about, liver disease in general today. So, I wanted to teach you a bit about why the liver is such an amazing organ, and what you can do for it in sickness and in health. I wanted to help you work out when you should worry about increases in liver enzyme activities, what the synthetic biomarkers of hepatic dysfunction are.

I wanted to help you learn if there's anything that you can do to help protect the liver from harm, how to approach cases with variable presentations of herpatobiliary dysfunction. I wanted you to be able to learn about some of the more common diseases of liver in the liver of dogs and cats, bearing in mind, we don't have all the time in the world for this presentation, and there's a lot of different diseases that can happen. So I wanted to give you some really, good methods for how to investigate liver disease.

I wanted you to, be able to answer the question more reliably of, is it too late? And I wanted to really get you understanding the nitty gritty of some liver pathophysiology, because I really believe that if you understand a bit of the pathophysiology of disease and we can make that a bit easier for you, then that's the best way to really learn about, liver disease and what you can do to help sick, pets. So why is the liver such an amazing organ?

Obviously, if you don't have a liver, you can't live, and the liver has a huge range of function. So one of the important things to know is that 80% of the liver's blood supply actually comes in from the portal vein, which comes in directly from the gastrointestinal tract. So everything from the gastrointestinal tract goes and gets processed by the liver, and then, only 20% of blood supply is actually from the central arterial circuit.

So with highly oxygenated blood. Through the hepatic artery. So that means that the liver really has an immediate role in detoxification of, different types of chemicals.

It is really involved in working out what to do with nutrients and toxins that are coming in, and so it's got a big role in digestive functions, in hormone regulation and production. It has a really large role in glucose homeostasis and glycogen storage. We have really big roles in synthesis and storage of fats, including triglycerides and proteins and vitamins and amino acids and trace minerals.

It's involved intricately in the metabolism of carbohydrates, lipids, proteins, and vitamins as well. And then it's got this massive detoxification, excretion of toxins and other substances, including bacteria. And the liver actually gets quite a high load of bacteria when you think it's not really that sterile an organ.

It has a big role in bile production and drainage and the enterohepado recirculation there. And as a result of all of these different things, it actually has obviously a big immune centre and immune regulation is one of the, key factors here for, for the liver as well. Another reason I think the liver is an absolutely amazing organ is it has this huge regenerative capacity.

So they suggest that if you have 1/3 or 2/3 of your liver removed, you can actually get regeneration of your liver function within 15 days if you're a human, 10 days if you're a rat. We expect dogs and cats to be somewhere in between there, and that's obviously without underlying major herbatic injury, but the type of regeneration that liver has may be by hypertrophy or hyperplasia. When we get more liver being removed or destroyed, we do get a different type of regenerative capacity, and there's a poor ability for the liver to differentiate and re-differentiate in these types of circumstances.

And we do rely on these cells called LPCs, to regenerate, and their ability to participate in liver regeneration at this point is actually much less clear in our understanding. And their expansion has been associated with the increased fibrosis and poorer prognosis in liver disease. So that's why we sort of say, if you have 80% of your liver function, 70 to 80% of your liver function, you may actually be able to, get some regeneration.

And one of the ways that that can happen is sort of documented in this nice diagram here, so. The central vein CV is there on the left-hand side, and portal vein is on the right-hand side, and, we've got, you know, different types of hepatocytes there, and then we've got these orange ductyer cells, which are those bile ducts, which are close to the portal vein. So initially, if there's just a mild acute injury, there's a little bit of reaction that can happen with those ductylar cells in particular and a little bit of toing and froing of those, hepatocytes.

As we get more significant and severe hepatic injury, those ductylar cells can have some ductyar reaction in particular. And that's where we start to get in a bit of trouble. That's when we can start to see some, a bit of haphazard environment being created, and sometimes that dactyla reaction and proliferation in particular can lead to marked proliferation of inflammation, fibrosis, and some, when that duct dealer plate that you may have read in your histopathology reports is damaged beyond repair, that's when we lead to cirrhosis, which is, which is your end stage liver, liver disease.

So given that the body and the liver in particular has such a good ability to regenerate, that's one of the reasons that we, that we find that when we're seeing advanced in injury, that's when we have those indications of hepatic dysfunction, such as jaundice, hepatic encephalopathy, coagulopathies, ascites, or hypoglycemia. And we'll talk a little bit about how that all sort of occurs, shortly. So really when we are, we want to be trying to identify these problems as quickly as possible so that then we can go and try and identify the cause, treat the cause, get on top of the cause and prevent any further harm, whilst we're managing obviously these other these problems.

So in order to understand more about liver dysfunction, we need to learn a bit a bit more about how the liver works. On this schematic representation, we've got the liver on the left, the gut on the right, and as I mentioned before, the majority of liver, blood flow is comes in through the portal vein from the gastrointestinal tract. And you can see here that the gastrointestinal tract has got a beautiful mixed bacterial slash viral protozoal, mix of microbiome.

We've got our epithelial cells, and our, we get that portal. Sort of draining, having a bit of trace microbial components and some nutrients that go to the liver, and the liver is ready and primed to react potentially to some of those components or downregulate its response to some of those components. And the liver then goes and, creates its bile that then is excreted back into the bowel, hence that recirculation or that in paddock recirculation that we see.

So we're actually getting a bit of, yeah, recirculation of contents from the gut to the liver to the gut to the liver to the gut to the liver. Once we do get those nutrients going into that portal vein, the portal circulation is a low pressure circuit, which means that there's lots of little branching sort of venues, that divide and join the oxygenated blood from the hepatic arterios, which then supply those hepatocytes. So we can see this on this schematic representation, the blood comes in through from the gut through the portal vein and then goes down through to that central vein.

We can also see here that that bile ductal, that where the hepatocyte, has created that bile and popped it back into those bile caniculi is very close to that portal vein. It's in the portal triad. So the portal triad, has the, the bile ductal and the the portal vein there, and that hepatic arterial.

OK, and then obviously once you've created that bile, goes into the bile ductiale, goes into the bile system, goes into the gallbladder, gets excreted from the gallbladder, it goes back into the gut. You can also see here that there's lots of sort of cells there ready to react. So we've got our, cook for cells, which are one of the macrophages that sort of sits in the liver, sort of sensing what's going on there.

We've got these leaky sinusoids, which is really important. Sinusoids are supposed to be a little bit leaky. We're supposed to get a little bit of those nutrients being transferred.

Got some steellate cells which sit on the inside of that membrane, also ready to react, but maybe not quite as pro-reactive as the cook for cells. So it's a beautiful little system here. Once the blood goes to the central vein, blood goes back to the right side of the heart.

So, at this point, let's have a little bit of a chat about some of the synthetic biomarkers of hepatic injury and I'm sure you're all aware of these biomarkers that we see on our biochemistry every day. So ALT is an intracellular enzyme within the hepatocyte. So this is a hepatocyte here.

We've got the red documenting the ALT. ALT is released into the blood in primary and secondary hepatic diseases. It can be associated with cell membrane permeability.

It comes from the cytoplasm and mitochondria of the hepatocytes, but it can also be released from muscle, kidney, and blood cells. So that's an important differentiator there. ALT has a really long half-life in a dog and a really short half-life in a cat, which is why we recommend investigations of increases in ALT in all cats.

The peak increase in ALT occurs about 48 hours after a cell is injured. After a blood sample is collected, it is relatively stable in the blood for about 3 days. There is some interference of ALT if you've got a really lipemic sample or a turbid sample or there's hyperbilirubinemia or homolysis, so we do need to be a bit a little bit careful there.

And please remember that if you do measure ALT, a number of greater than 1000 on an in-house blood test machine isn't actually a number. You do need to dilute it for your, protocols from the laboratory, or you do need to send it in to your reference lab to actually get a number. It's really important because you can monitor levels of ALT more accurately, and assess your patient response to treatment using ALT.

Drugs like phenobarbitone can increase the ALT numbers up to 4 times normal, but that can actually also be associated with cataccellar necrosis, so that's not a good thing. ALP is usually also increased when we use phenobarbitone. Steroids can induce ALT to 2 to 3 times normal in dogs, but ALP, should be, concurrently increased with it.

Frequently we see increases in ALT when we do have pettotoxicity, including from drugs, and we'll talk about that a little bit later on. ALT can still, can actually not be increased even when we have quite substantial liver injury, such as if we have a hepatocellular carcinoma, sometimes the ALT isn't increased, which always amazes me. Or in some cases, if you had insufficiency, we don't see increases in ALP ALT, and that's sometimes because the liver doesn't have enough cells to actually create enough ALT for us to be able to measure.

So that's always a little bit scary. So I always get worried when I see that the ALT is going down and a patient with paddock insufficiency. And insufficiency specifically in this situation.

In biliary disease we should see an increase in ALP, which we'll talk about in a minute, and, but sometimes you can get toxic injury to the hepatocytes from, bile salts and so your ALT goes up in that situation. One important thing to remember is to check your AST and your CK when there's a potential for muscle disease, because the ALT will be mildly increased in those situations, your CK and AST will be markedly elevated. So let's have a chat about ALP.

So ALP, as you can see here with these little green dots around this cannolicular membrane here, it's also found within the hepatocyte and within the cell membrane in particular, but it's more closely associated with the biliary tract and cannolicular membrane of the hepatocyte. We, can have some enzyme production being induced on the sinusoidal membranes here and then it can be liberated into the blood, and that's what can happen with steroids, for example, corticosteroids. Increased ALP is a sensitive indicator of cholestasis in the dog, but the specificity varies.

In cats, it's very specific to the cannulicular membrane. In dogs, it can be increased due to corticosteroids, whether it be endogenous or exogenous, Cats, not so much. We also have some isoforms of ALP in the bone, gastrointestinal tract, in leukocytes, and in late gestation in the placenta.

So there are some important differentiating factors there. When we do collect the blood sample, it is stable for 2 to 3 days, if refrigerated. There is again some interference with hemolysis, but not lipemia which is a relief given a lot of our endocrinopathies have increased in ALP and they are often lipemic.

So this does actually, you know, remind us that we do need to separate our blood samples. So if we do collect a blood sample that goes off to the laboratory in particular, it is really important that we separate that serum from the red blood cells so we don't get the homolysis increasing our ALP and ALT erroneously. So when we get cytotoxicity, due to hepatocyte damage from a parent compound or a locally generated metabolite, humans use this, R value, which helps them to differentiate whether there's cytotoxicity or cholestasis.

And so what they do is they look at the ALT and they look at the ALP. And they get the ALT number, they divide that by the upper reference range of their test. They divide that by the blood ALP divided by the upper limit of their normal reference range of the ALP.

And if they have an R number, which is greater than 5, that indicates you have a cellular injury, and R value of less than 2 indicates cholestasis. And a value of between 2 and 5 represents a mixed pattern. I think in dogs and cats, we can have a fairly similar type of description, but I feel that this system isn't quite as rigid for pets.

So for me, I normally look at sort of gross values of the ALT in comparison to the ALP and or if there's a mixed number. So for me, it's more like a, a very high ALT in comparison to ALP is called cytotoxic. ALP a lot bigger than the ALT is more likely cholestasis.

And if they're fairly similar, I think that there's more of a mixed biochemical cholangio hepatopathy there. So that sort of picture sort of describes that quite nicely as well. So if we have a look at a little diagram, and look at other numbers in our blood work to see if there's a toxic or cholestatic disease, we can also have a look at bilirubin, cholesterol PT, bile acids, and urea.

Unfortunately, bilirubin is likely to be increased in both situations. PT can also be increased in either situation, and bile acids can increase in either situation. But our cholesterol is actually a really interesting biomarker here.

And so it's one of the reasons why it actually is quite important that we ensure that our patients are fasted before their blood samples, because hypercholesterolemia, can occur more commonly in cholestatic disease due to decreased clearance of cholesterol in the bile. Or due to increased production of cholesterol-rich liver proteins, or to decrease liloin clearance. Whereas decreased cholesterol, I actually find it really helpful as an internal medic, because hypercholesterolemia really happens with severe hepatocellular injury and failure to synthesise the cholesterol.

But it can also be seen in gastrointestinal losses and protein losing enteropathies, for example. And sometimes B12 is a really important differentiation, factor here to help us differentiate between gut and liver disease as well. So liver failure is a syndrome.

You can have acute liver failure, where there's 75% of functional hepatocyte mass with insufficient functional hepatic parenchyma remaining to maintain a synthetic and excretary demands in the absence of pre-existing liver disease. It's a bit of a mouthful, but basically, acute means there's no pre-existing liver disease, and there's less, and there's more than 75% damage. Chronic means that there's progressive loss of more than 750 to 75% of the functional liver mass due to preexisting liver disease.

I think quite frequently we see acute on chronic disease. So we have a liver that's sort of rumbling and grumbling with irritation and disease, and then there's something that precipitates that liver failure. So a question for you guys is, do you know what some of the most common hepatotoxicities are in people?

I love this little awkward Yi, comment, you know, comic here, and I feel like this might be something that BSAVA might have a bit of an issue with over the the next couple of days. So, acute liver failure, the most common cause is paracetamol toxicity. And from some reading, I noticed that there's actually increases, increased levels of acute liver toxicity and failure over the last couple of years and since the COVID pandemic, which is a little bit scary.

And I think that's the, and there's quite a few take home messages here for us as, as clinicians. Because acute liver failure from parasoon toxicity isn't just from suicide, it is also because there's a lack of recognition that paracetamol is an active ingredient in generic and brand name medicines. That there's an uncertainty of what the maximum dose is for people, that there's a lack of knowledge about, taking two over the counter medicines, both containing paracetamol, that there's issues in the perceived safety of paracetamol because it's just available over the counter.

And that there's a lack of awareness that the misuse of paracetamol can lead to liver damage. And I also feel like this is quite a big take home message for us in that we are prescribing paracetamol more commonly for pets, for pain relief. A lot of clients often are surprised that their pets can have paracetamol.

A lot of them have the message that it's not safe to give. Dogs. Unfortunately, you know, obviously not allowed to give it to cats, but I do worry that people are going to start to think, oh, I can give it to my cat, I can give it to my dog.

So we really need to work as a profession to make sure that this doesn't start happening. Alcohol-induced liver failure is the most common cause of chronic liver failure in people. Both acute and chronic liver failures numbers have increased since the pandemic, as I said.

It's interesting that, most of the time when they have a patient with acute liver failure, they do go to an intensive care facility where they have got potentially the ability to do a liver transplant if needed. When it is really in failure, they try and treat the cause of the liver failure first, but, and trial and trial, sorry, try and treat some of the complications. And obviously, it does liver transplants are very, very, very challenging things to be doing.

And that's certainly not something that we can do for veterinary patients at all. So let's think about some of the synthetic biomarkers of hepatic failure. When the liver is in real failure, what you notice is that there's a decreased uptake and excretion of bilirubin and bile acids that lead to increased levels in the blood, that we get decreased uptake and conversion of ammonia to urea, leading to increased ammonia and decreased urea concentrations.

That we see decreased synthetic capacity of the liver. We can see alterations in lipid metabolism that can lead to hypocholesterolemia. We can see concurrent defects in red blood cell membranes leading to pole cytosis, acanthocytes and target cells in our blood.

We can have alterations in glucose homeostasis with hypoglycemia being the most common situation. We can see decreases in protein synthesis leading to decreases in albumin and transferrin, which is obviously a binding protein, which can lead to very variable drug, concentrations. We get a mixed coagulopathy that I'll talk about a little bit more, and we can see obviously reduced immunological function, resulting in systemic antigenic stimulation with increased immunoglobulins, but we can also get low levels of bacteremia in these situations as well.

I love Big Bird. I'm a girl of the 80s. So for me, like Big Bird's like the big thing.

But, jaundice, like whenever you see a patient with jaundice, you know, that's a late indicator of liver damage. But it can occur for many, many reasons, and it's really important you put down three differentials, where each case you see with jaundice, including pre-hepatic, which is mostly hemolysis, hepatic and post-hepatic. And we do get mixed situations as well, but if you see a patient with jaundice, hepatic, pre-hepatic, post-hepatic, boom.

It's really important to remember that 2 + bilirubinemia bilirubin urea, sorry, is normal in a dog, but only boys, not girls, not cats. If you're concerned about the level of bilirubin, because I know it can sometimes be difficult to tell the difference between a 1 and a 3 plus and a urine dipstick, for example, just check your serum bilirubin, because your bilirubin in your blood should not be elevated, just your bilirubin in urine. So that gives us a gateway to have a bit of a discussion about how we produce bilirubin.

I love this diagram that came from nature. It made things seem so much more simple for board exams. So it just describes that how we produce bilirubin, so red blood cells retire or broken down.

The hema proteins had been broken down from haemoglobin to bilirubin in the macrophages of the liver and the spleen, as documented up here in, step number 2. And then the bilirubin is transported to the liver and taken up with glucuronic acid, or other types of acids depending on the species of, the patient. The bilirubin is secreted into the bile and then into the intestines.

The acid is then removed from the gastrointestinal bacteria, and the bilirubin is converted into urobilinnogen and enters the portal blood supply to be recycled by the liver. And some of this is then transported to the kidney and excreting excreted. Making the urine yellow, and the rest of the bilirubin is oxidised by the intestinal bacteria to brown stercobilin, making your bit brown.

So it's this is a really nice diagram, that's available online. Bleeding disorders are relatively common in end-staged liver failure as well. So we, the liver synthesises all types of clotting factors apart from factor 8.

This includes pro and anticoagulants, including antithrombin 3, protein C, protein S, and plasminogen. Platelets or decrease and become less functional, but we can get, real mixed hypercoagulability as well. And this diagram coming up here, which is a bit busy, lots, lots of things happening here, gives us a bit of an, an understanding as to how complex coagulopathies are in patients with liver failure.

So, for many years we thought that it was just a bleeding disorder, but the, the dogma has really become under challenge with the discovery of some of our more, sensitive coagulation tests in particular. And we've worked out that some patients actually are more likely to develop thrombosis when they have liver disease. And so things to notice here, we have increased fibrinolysis, we have dys fibrinogenemia here, like low grade DIC or high grade DRC, to be honest.

We get thrombocytopenas and patheas, and we get decreased anti-M procoagulants. So it's a really mixed bag that we get. And homeostasis is reset when we have a patient with liver failure.

It's our homeostasis is really fragile and easily disturbed, that can either lead to bleeding or thrombosis depending on the initial stimulus. And increasing levels of endotoxins from that gut in particular, can be primers for hypercoagulability and, and blood clots there. And we're really trying to work out what, what the best way to manage these patients are.

I'm sure that, many of you will be measuring your coagulation times, eu mucosal bleeding times, those types of things which are really helpful in trying to understand if your patient's got a bleeding disorder, and giving obviously vitamin K, as needed as well. So the liver is pretty, it, it can be easily damaged. And, as I said before, I can't talk about every liver disease, unfortunately tonight, and I'm but, you know, there's great reference textbooks and and articles that you can read, but I wanted to give you a couple of, take homes about, and I wanted to just help you just work out how to approach a case with liver disease.

So, obviously, the first starting point is the full full medical history, examination. And then you can make a basic assessment. So, in my consultation, obviously, I'm looking at the age, breed, signalment, neuter status of the patient.

I try and get a little bit of history, whether the signs are acute, chronic, and or a bit of a feel for acute non-chronic disease, whether there's exposure to toxins, including drugs, or what the environment the patient's exposed to. Are they near waterways or agriculture or rats, or other, other dogs, or, have they been travelling outside of, their normal area, or did they come from a different area initially and I guess for those of you in the UK, obviously some of the questions I'm sure you're asking are, have you travelled around the Mediterranean? Has your dog been a rescue dog?

Where's your dog from? For those of you around Australia, obviously, we're seeing on the eastern seaboard, we're seeing some increased cases of leptospirosis. So maybe we, ask a little bit more about our, what our pets are doing.

So whether they're going to the park, whether they are, you know, whether they're rats in the environment, for example. But all of those things sort of, need to come out in these initial questions, if you can. We need to have a bit of an understanding for what our previous or concurrent medical problems are.

We need to ask all the questions about what the current medications are, what previous medication exposure is, all the supplements, all the herbs that that that patient might be on, we need to have a bit of an understanding as to what the patient's vaccine status is, what prophylactic healthcare the owners are using, including the types and frequency and of and of administration. Need to have a bit more understanding about the diet, whether it's cooked, whether it's raw, whether it's commercial, whether it's something weird and wacky, whether it's something really nice and, baseline, whether there's a mix, whether someone's giving. Some Xylitol in there or some artificial sweeteners, not realising what they're doing.

We don't need a really detailed history here. We also need to know, where the patient has come from, how it was obtained, where from, was it from a breeder, was it from a rescue agency, and where that agency is? And sometimes we need to do, we do need to follow those, those leads up a little bit more.

When we examine the patient, I think it's, you know, we, we do a very thorough exam if we, if we can. For me, the big things are sclera, oral exam, abdomen pain, nausea, mentation. Like, I often just put the patient on the floor and just watch them walking around the consult room whilst I'm obtaining all of that other history.

I'm looking to see if they're looking into space, looking into the walls, head pressing, doing anything a bit weird. Then I'll examine them obviously, we want to feel whether there's bilateral pulses, if the heart rate matches the heart rate matches that pulse rate, whether we have 30 pulses, what our respiratory rate and if it is. Ideally, we take the patient's temperature.

If we don't take it in the consultation room, we need to remember to take it away, take it when we go to our examination area with our nurses. Do appreciate that it's not the most enjoyable task, taking a patient's temperature, but it's important for us. And we obviously need to try and get a bit of an understanding as to what the patient's hydration status is.

And then the big question here is, are the signs acute or chronic, or are they acute or chronic? And then, in an examination, I still write a damn it be list, like, I, I love this. It's a good way of not, not.

Missing big areas of disease that we could potentially have. So if we think about some of the degenerative types of causes or congenital deformations, we can think about like portosystemic shunts, for example, we can think about toxicities and what type of exposure. We can think about what type of infectious agents we might potentially have.

If there's any indication of an increase in body temperature, on our exam, if there's any other indications of sepsis, like that little red line and like the slightly hypovolemic thready palsy kind of dog, we can have a look for different types of inflammatory foci. Sometimes there's more than one inflammatory foci, or there might be pain, in particular in the abdomen. We can look for masses, we can look for indications of cancer, like histiocytic disease or big masses in the liver, or, indications of, neuroendocrine tumours, for example, which might have multiple things in their physical exam.

Hopefully, trauma would be relatively obvious, but it's not always. Sometimes, a patient has had trauma that we're not aware of, but we can look for little scuff marks on the nails as to whether a patient's gripped onto the ground, for example. We can obviously get more information about metabolic problems from our medical history, but thinking about drugs or steroids, or hepatic lipiddosis, or endocrinopathies or B12 deficiencies and those types of things, breed signalment for amyloidosis or, copper toxicity that we'll talk about shortly, .

We can think about whether the patient has any indications of parasitic infections and cholestatic types of diseases or mucoceles and like mild grumbling, grumbling pain. I think like one of the big things that I try and look for in a patient's exam are whether they're just lip smacking a little bit, which might be an indication of nausea or pain, or whether they're just suddenly turning around to me when I touch particular parts of the cranial quadrant. If I'm looking at liver disease.

Obviously, I want to do a little ballotment to see if there's any indication of ascites. And I guess if I'm in doubt about a patient having ascites, because let's face it, like it's not always that simple, just quickly prop on an ultrasound probe and have a look and see if there's free fluid. This diagram from Ettinger is something which I have, in my, like I had this in my study books and I used it religiously.

I found it really, really helpful. So, I, it sort of gives you a really good indication as to how to manage a patient with, with, jaundice. So the first steps is to do some blood work, have a look and see what the hematocrit is and see if you need to do any further investigations there.

If the patient's pyorexic, look for indications of sepsis. If it's not pyorexic, add on your biochem, you'd add on your biochem, even if you thought the patient had sepsis. So, yeah, it's, it's just a step.

If you add on your biochem, the indication there to try and work out whether it's paddock or poster paddock, which is what we were talking about before with that cholesterol in particular, remembering there is a bit of overlap, with our test results. The next step is really to do an abdominal ultrasound and see whether we've got indications of a mucouscele or biliary disease, or dilation of the common bile duct or a pancreatopathy or gallbladder changes, whether there is a scites of which you need to take your your fluid sample, whether there's any focal hepatic lesions, in which case, then you can do some fine needle aspirates, or if there's a hypoechoic or a hypoechoic, or whether it has a normal appearance. And then wherever you can, I guess, like, it's important to think about taking some samples.

Remembering that finding aspirates, I always tell clients, like, we've got a 60 to 70% chance of finding the answer, but we have a 30 to 40% chance that that might be wrong or inconclusive. And so you really have to put that information from your aspirates back to your patient and your exam findings and what your thought process is for that patient. To decide as to whether you think that that is appropriate for your patient.

Biopsies obviously give us a lot more detail. They give us some architecture as to what's going on. And so that's actually sometimes a really, really helpful next step to take.

But obviously, it's a big next step to take. Taking a biopsy from a patient's liver is, is tricky, and we'll talk about that soon. My hot tip on this type of diagnostic workup is to have the best ultrasonographer you can to do your diagnostic workup, because it really does pay dividends.

Yes, my husband's a radiologist, and I'm very lucky to have him, but, I just, I just find that the best person that you can have to do your ultrasound is the one that you want to pick to do your liver diagnostics here. So, as I said, sometimes we really do need to get liver biopsies that can be done true-cu biopsy, so ultrasound guided, true cut biopsy, and there's all sorts of different types of methods of doing that. There's laparoscopic biopsies, there's surgical biopsies.

What you need to remember is that you need 5 biopsies from at least 2 different lobes. And you really need to, to consider checking your coagulation times before biopsies. Before aspirates coagulation times are not as important, And I guess like whenever I have a patient with liver disease, I remember that they are at increased risk of bleeding, potentially.

And so these are the factors from the American College of Internal Medicine. These are the factors that we need to think of, that we've got higher risk of bleeding from a liver biopsy. So if you've got a patient with a hematocrit of less than 30%, platelet count less than 50,000, prolonged coagulation time.

And I guess, like, we don't routinely measure fibrinogen or von Willebrand factor activity, but these are factors that can increase risk of bleeding. So, for, say, a Doberman, you do want to try and measure von Willebrand factor activity. Fibrinogen is something that I can't necessarily easily measure in Australia, but I might do something like a rotum or a tech to try and have a look and see what my coagulation status is, before I did a liver biopsy in a patient that I was concerned about.

Or we could, also do, or, and we should say, we can do a mucosal bleeding time, and if it's more than 5 minutes, then that's a high risk as well. And I guess like then you need to have that conversation with the owner as to whether it's appropriate to take liver biopsies or whether you have to take some risks. And for us, sometimes we have to take those risks, but we always have blood available, plasma available, and I, and critical care available to us.

So we're very fortunate in a referral setting on that basis. But if you're in a general practise and you don't have access to those things, I think it's just really important that you make sure you've communicated these risks. Certainly, I would not be doing a liver biopsy in a patient of a, with a platelet count of less than 50,000.

That is not appropriate. And I would be doing everything I could to increase our ability for blood to clot before I did a liver biopsy. If, if I had a patient with prolonged PT or APTT and a dog, So, and obviously like some patients, yes, they have a lower red blood cell count here, and maybe they need to have a preoperative blood transfusion if that's the case.

We do need to avoid our necrotic centres. We need to consider culturing the liver. I know one of my first cases of when I saw a case of mycobacteria a couple of years ago, I had to send my surgeon back in to get me cultures, because we saw something that we were concerned about in histopathology, but I didn't have cultures, and that was a bit silly.

But I learned, I've never done it again. You need to remember to do an aerobic and an anaerobic culture. And we also need to save a sample for metal quantification for copper.

You do need, 20 to 40 milligrammes of liver, which means like if you do true cut biopsies, you're not going to get good liver, hepatic quantification here. I am aware that there are some digital liver quantification, Available in both the UK and US and hopefully Australia as well, but, just you need to check with your laboratory as to how they're going to measure copper, and if it's not digital copper, you do need to get decent samples of liver for medical quantification. All right, so dogs, one of the most common reasons that, we see with liver disease is hepatitis.

Usually it's chronic active hepatitis. And we usually identify that in a liver biopsy. And we're very, very lucky that the ACAM has a consensus statement available for this, on how we can manage a biopsy of a patient that has chronic hepatitis.

So in these situations, this algorithm helps us differentiate between lobular dissecting hepatitis. There are some very specific historic pathological features here and more common clinical scenario is in young adult societies, multiple acquired shunts, hypoalbunemia, and increased bile acids. With chronic, hepatitis, this is also where we do need to obviously make sure we've checked our copper quantification, and we can see the difference between chronic hepatitis and cirrhosis.

Cirrhosis is defined by this portal to portal or portal to central fibrosis with lobular architectural distortion. That's a histological diagnosis of cirrhosis. Really, really important.

Non-specific reactive hepatopathies, they don't have fibrosis or architectural remodelling or necrosis. They have mild inflammatory change. And this is really where we need to be starting to think about the potential for non-specific reactive hepatopathies and look for extraopathic causes.

So there are plenty of patients with gastrointestinal disease that have chronic, hepatitis as a result of the gastrointestinal disease. For example, but there's all sorts of different scenarios here. Heart disease can do it, pancreatitis, etc.

Etc. So, this, flow diagram really helps with differentiating those. When we see chronic active hepatitis, they can have multiple origins, including immune, copper storage, Leishmania, in particular, if you're in the UK and a patient's coming from the Mediterranean, or even Australia, we are seeing dogs that are imported from the Mediterranean, so it's important for us to have that information when we're getting our medical history.

And there are other potential infectious agents, as you can see here, mycobacteria from my little patient, but, there's, there's numerous different types of infectious agents that can cause chronic hepatitis. You can see here also the evidence, for chronic hepatitis. One thing that's really notable is, here is the viral triggers.

We know that we do get adenavirus that can cause chronic active hepatitis, and there's just not a lot of evidence, behind it at the moment. And certainly not the active trigger of it, it might be that it's causing injury previously, but there's also obviously other problems here to be considering. Things that also support chronic active hepatitis, from immune disease include if there's lots of lympho lymphocytic infiltrates or if there's an MHC class 2 haplotype, if there's positive autoantibodies, on our, immuno histopathology, if there's a history of familial disease, if there's a female predisposition, if there's a favourable response to immunosuppression, or if there's another autoimmune disease that you can currently find.

Copper, can be easily visualised on hepatic biopsies, using some very special stains, and it can be quantified as long as there's enough liver provided to the pathologist. Copper is often due to inherited disorders, and in that type of situation, we see that around that central, central lobular area here on our hepato asinine. But when we have it due to cholestasis, it's typically more here around this peri-portal area, which you can understand now from our pathology.

With predisposed breeds, we have Labradors, Dobermans, West Highland whites, and Bentlington terriers. They have Bedlingtons have cleared genetic predisposition of comedy one. We can also get light onset, in those, even in a breed that's predisposed to associated hepatitis.

With copper, it can actually vary in its distribution, so it is why we need to biopsy more than one lobe, and regenerative nodules should be avoided when you're taking your, when you're doing your copper biopsies, because later diseases it can be quite hard to differentiate. So, when we treat copper associated hepatitis, copper accumulation can actually be quite difficult to treat. The penicillamine is a drug that I'm very familiar with using for copper associated hepatitis.

It combines with copper and other heavy metals, allowing it to be mobilised from the liver and excreted into the urine. It can also be used, as an antifibrotic agent, and it can help to reduce collagen. It can cause some mild gastrointestinal signs, and prolongulation of copper can lead to copper deficiency, which can include anaemia, anorexia, vomiting, and weight loss.

It's important to note that this can be teratogenic, so it's very important that you pick your that you make sure that patients that clients are aware of that and do handle it very carefully. I haven't had experience with using trientine. It can be used.

It's usually a secondary agent to the penicillamine. It can remove more copper, and it can be a really aggressive treatment, and it can, be a good choice if you're getting hemolysis from, high copper loads. There's less side effects, but there's also less data on the use of this in dogs.

Typically we do reach for the penicillamine. After you've used a course of the penicillamine, you can repeat the biopsy and see if your copper levels have decreased. Alternatively, you can switch to using zinc, that would decrease the absorption of copper from the gut binding to the enterocy that's shed every 5 days.

And zinc may not be more effective than, dietary management because we do have commercial liver diets that are available that are supplemented with zinc, as, as you can see here. So NRC minimum of copper is 6, AFO minimum is 7.3.

The average dog food has 15 to 25 milligramme per kilogramme dry matter. And hepatic diets have a much lower concentration of, of copper there. So the hepatic diets that, have been studied include Royal Canon Hepatic, Hills LB and Purina, hepatic, which is available in Europe only, sorry, Aussies, and they have been documented to have lower than the AFCO and NRC requirements.

So we often know what the cause of hepatotoxicity is, but sometimes some dogs don't tell us what they've eaten. I wish sometimes we had dog cams on all of them. But this, there's two main ways as to how you can get drug-induced toxicity, .

We can have dose dependent or idiosyncratic. So dose dependents include things like paracetamol, obviously cats are much more toxic, cat dogs, the toxic toxic dose is 90 milligrammes per kilogramme per day in a healthy liver. Toxicity may be due to the parent compound or the metabolite, just so you're aware, These dose dependent hadrotoxicity are pretty pretty predictable.

So you pretty much know that they, you know that they can do it and you can, You sometimes use therapeutic drug levels to have a look and see whether they're actually going to be toxic. So, we've got paracetamol phenobarb, the azoles like ketoconazole, a nice little surprise one would be sort of azathioprine, we can also amiodarone, Lamisine, and tetracyclines. Old tetracyclines can cause microvesicular steatos, steatosis due to lipid accumulation, that can cause, toxicity as well.

Idiosyncratic hepatotoxicity are much more difficult to, predict. They occur in a very small proportion of patients, they're not dose dependent. They often can cause oxidative stress, such as when you use methimazole, although they can cause mitochondrial damage, which is what we see with, diazepam.

The, the drug itself or the metabolite can cause hapton triggering, which can create an immune response. But idiosyncratic hepatotoxicity requires a discontinuation of the drug, and structurally related drugs can also cause a similar reaction. A couple of drugs to just note in here, would be things like midotaine, methimazole, TMS, zinnizamide, and cyclosporin.

Zinnizamide, there's a nice new paper that suggests that there's very low risks of hepatic injury, but it's something that's, which we always mention to clients when we start sinnizamide. So let's just have a chat about a case. So this is cute little Monty, who's a very cute little boy, 3 year old mal neutered Maltese that presented to us with hyperexia, lethargy, and icy sclera.

So our first thing that we're doing is we're writing our, we've got jaundice, so we're going to think about pre-hepatic, hepatic and post-hepatic disease. So, Monty had a CBC biochem. His CBC showed that he had a mild non-regenerative anaemia, he had a little bit of hyperprotemia.

He had an inflammatory leukogram, he had some schistocytes, he had some thrombocytopenia that was moderate. There was some regeneration of his red blood cells. His saline agglutination test was negative.

He is ALT in comparison to ALP. I'm sorry that that slide didn't come out quite right. So his ALT was 5,248, his ALP was 1,232.

So at that point, I'd be pretty happy to say that that's a hepatocia or cytotoxic injury there. And No prizes for knowing, well, actually, well, I could give a prize. I can just give it electronically about what these seeds are.

So in, in Sydney in particular, we have, these beautiful palms. So these seeds that we see here were on a rectal exam, which needs to be done on all patients that are sick, unfortunately. The palm, all parts of this palm are sago cyca are toxic to pets.

And this Saocycad, is really, really toxic. Sago cycads are not palms, but they're sort of called palms erroneously. But they can cause gastrointestinal, hepatic, and central nervous system toxicity.

And signs develop within 12 hours ingestion, so usually the seeds are still there at the same time, and they can cause vomiting, diarrhoea, weakness, seizures, and sadly, liver failure. If there were no seeds in rectal exam, we have a, a, different, we need to write a differential list, so we need to consider whether there's access to things like a mania and magic mushrooms or Xylitol, one of the artificial sweeteners, where the dog's eating a cake that the owner made, for example, or gotten into some chewing gum. Whether there's any access to any drugs, we also need to consider this dog might not have a toxicity, it might have a primary hepatopathy, whether it be infectious, inflammatory, cancerous, hypoxic, or potentially endocrine, whether there's a secondary hepatic injury, whether there's, changes in blood supply, for example, to the liver.

So just need to make sure that we always write our differential list. Because this patient did have Segacycad seeds in its rectum, we could more clearly say that the most likely thing is that this patient had a toxicity from the Sega Cyca. This patient didn't have any indication of encephalopathy, which is a real relief.

It still does make a guarded prognosis, but it's not grave. When there is encephalopathic damage or disease from Segacycads, unfortunately, the prognosis is more grave, but with, the Segacycad here, we had the ability to offer further care. So first thing was, let's decontaminate this patient as much as possible.

Let's do some enemas, get rid of those seeds, let's give it some charcoal and see if we can make sure it's not absorbing any more of the, the seeds. We then need to do everything we can to protect the liver, which we'll talk about in a minute. And obviously, we also need to think about all the supportive care options like hydration, electrolytes, nausea, pain, and nutrition, which are beyond the ability for this talk tonight.

So, let's talk about how treatment, what our treatment options are and how they can actually work. So, full disclaimer, unfortunately, there is limited evidence in pets. There's much more evidence in people, but we do have some really nice, supporting pathophysiological rationale and evidence inferred from people, and really there's also a lack of adverse effects of a lot of these different treatments.

Yes, it would be wonderful to have more clinical trials, And one really big take home from my point of view is if you can identify a trigger, do everything you can to treat that trigger as well. So let's have a chat about hepado protectants. Hepato protectants are available and need to be used because there's depletion of antioxidant defence mechanisms, which justify the use of cytoprotective agents or hepato protectants with antioxidant, properties.

And that's primary. Primarily because of this big gun called glutathione. So glutathione is one of our really important detoxification systems in the liver.

Glutathione is produced from glutamics glutamate, cysteine and glycine, and then it's essential antioxidant found within the parasite. Reduced concentrations can be found in a wide range of both dog and cat hepatobiliary diseases, and as a result, a lot of our hepatorotectants are revolving around the replacement of this and support of this system. So, a lot of you have you heard about an acetylcysteine or used it yourself.

These are some lovely complex diagrams about how it works. But basically, an acetylcysteine is a thyro donor, and by doing so, it replenishes cysteine and glutathione concentrations in the liver, protecting it from further injury. It does need to be given injected, as an injection, because there is limited oral bioavailability in dogs and cats, and it can cause vomiting in dogs and cats as well.

So we do give it intravenously, it rapidly increases our glutathione levels, and it's our standard of care for paracetamol toxicity. It's cytot protective and antioxidant. We administer it as a 10% solution intravenously, diluted 1 to 2, with saline.

Our initial dose is usually 140 milligrammes per kilogramme, followed by 70 milligrammes per kilogramme intravenously 3 times a day. We usually give 9 to 10 doses if, if we can. If the patient is, needing intravenous treatments, longer duration of treatment, does impair our ammonia metabolism.

So longer treatment is not indicated for this particular drug. Eccidenal methionine is what we often switch to after we've used an an acetylcysteine. So eidonome methionine is an intermediate metabolite, which is really essential for a lot of these types of hepatic reactions of detoxification and antioxidant changes.

Severe liver injury can down regulate the production of aidan methionine. You may need to provide, synthetic, table synthetic salts with an enteric component, coating of your adeno methionine supplement. Not all of our supplements are the same.

Different salts have got different bioavailability. There's a really nice ACBM consensus statement from back in 2013, old but still good, that really recommends using methionine products from reputable manufacturers, of which, the bioavailability and fiberkinetics are rapid readily available and have actually been reported. And we're really lucky that tonight we've been sponsored by one of those manufacturers that had done done the work that is required to determine the bioavailability and pharmacokinetics of their product.

Esoanno methionine is a glutathione precursor. It's an antioxidant. It helps the cell membrane function, bile conjugation and flow, anti apoptotic, so, decreases that programmed cell death, and it's also potentially an anti-ancerous.

There's some good pre-clinical evidence that esidan on methionine has had a protective actions in vitro and in in animal models of liver disease. And unfortunately, the clinical benefit isn't thoroughly investigated in all of our liver diseases, but we have used it in And studied it in acetaminophen or paracetamol toxicity, and it does increase hepatic GSH concentrations, or glutathione concentrations. It also helps with corticosteroid-induced vacuola hepatopathy, reducing oxidative stress.

It doesn't necessarily change your ALP, but it does help with the oxidative stress and biopsies. In addition, eidal methionine combined with ilamarin, which we'll talk about soon, has also helped protect patients which have been treated with CCNU or Lommainein, associated hepatic toxicosis. And we noticed that patients have a decreased ALT and LP and bilirubin when it's used with Lomasteine.

Yes, we need more studies to work out how good these drugs are, but, we are pretty comfortable with using it. There is a lack of, negative side effects. We use 20 milligrammes per kilogramme, once daily on an empty tummy, you really can't crush it or split it, because of that protective barrier that they've created to try and help with the bioavailability of the product.

Acidoxycholic acid is one of the treatments, which I find really interesting. So this is actually a medication that has been synthetically created. It used to be used in Chinese medicine from Sun Bears and, from China, in particular, that they, we, they, the Chinese doctors noticed that that, bile, salts that they had would actually help to reduce jaundice and hepatic injury in, in those patients.

Since then, they've identified the chemical that's, involved in that, and they've created this product, it's, ursodeoxycholic acid. Sourydeoxycholic acid is a relatively hydrophilic, secondary bile acid with colorectic, so it helps to flush the bile system, immunomodulatory by helping reduce your cook for cell activation, antioxidant, anti-inflammatory, cytoprotective, anti-apoptotic properties. So it's got lots and lots of different arms as to how it can potentially work.

And it's used for a wide range of liver diseases in people. It hasn't been widely studied in dogs, but it is safe to use. There is some relative evidence to suggest, very, very, very high caution in a patient with cholestasis, and inflammation, .

Sorry, with cholestasis or bile duct obstruction, when you do have an obstructive bile duct, that's usually a surgically, managed disease. There are some patients where, it's not an option under any circumstances, and that's where you may need to discuss with a specialist as to whether this may be an appropriate medication to use or not. But, the, this, medication can help.

With displacing some of the more toxic bile acids from the circulating pool, it can help as a cytoprotective agent in reducing that programmes cell death. It's used in people for biary cirrhosis. The only main side effect that you can see is from the diarrhoea.

We use it quite commonly in our patients with chronic active hepatitis, and it is immunomodulatory. So, one caution from my perspective here is, although we've used this, suspension for a long period of time without noticing in particular side effects in most patients, this, current formulation does control contain Xylitol, which obviously is a toxin to the liver. So, I would have extreme caution when using this particular product.

The capsules obviously are not a big problem, We use 15 to 10 to 15 milligrammes per kilogramme per day, ideally if not obstructed, we give it with food, and if used early, it can also help to reduce biliary cirrhosis and primary sclerosium cholangitis as well. Silly Marin or milk thistle. So, despite the historical use of milk thistle derivatives for liver disease in humans, there has been a recent, increase in popularity of using, in this in dogs with suspected liver disease, and document, we are needing a little bit more evidence for the documentation of beneficial effects for dogs, but there is some really good evidence, in particular circumstances.

There again, is some, challenges with the bioavailability of different milk thistle compounds, and so that's something to be very, very careful of. A a client going and getting this medication from the chemist, or, from the shelf, from their, bioceuticals may not be appropriate. We do have good pharmacodemic studies, from, our, our, our sponsor tonight.

Because Cillaerin can inhibit certain cytochrome P450 systems, we do need a little bit, be a little bit careful when we're using polypharmacy. So just be careful when you're using something that's, associated with something which is, being metabolised by the P450 system. A combination of esiddenny methionine syllabin product has also been used as we talked about before, for CCNU toxicity.

Cilliarin is an antioxidant free radical scaminger, and it can help to reduce lipid peroxidation. There's lots of other potential effects. The typical dose is somewhere between 5 and 10 milligrammes per kilogramme per day.

We typically combine that with the eidin and methionine cause they work nicely synergistically together. And it has been documented to reduce death by, magic mushroom or in mante toxicity. So there is some nice and documentation of, of, of benefits for dogs, in particular with this treatment, and a lack of side effects as well, which is really important when we're prescribing these medications.

Just a quick note on vitamin E. It's an antioxidant, for the cell membranes. It has been used in the diet for 3 months and can, really improve GSA concentrations and redox, regeneration, etc.

It's usually very well tolerated, typically use 10 to 15 international units per kilo, once daily, and it can be used in a wide range of liver diseases. Bonus treatments would be things like omega 3s, vitamin B. Obviously, vitamin K, if you've got a coagulopathy.

We don't recommend just empirical treatment with antibiotics for patients with liver disease. We need cultures and evidence for use of antimicrobials, wherever possible. When we have Amy, just 2 minutes, just 2 more minutes, please.

2 minutes. OK, alrighty. So when we've got inflammatory disease, prednisolone, cyclosporin, azathioprine can be used, colchicine, not as much evidence.

So really quick mention about portal hypertension. I think it's really important that you document that a patient has ascites and document the type of fluid that it is. So please do abdominal fluid analysis, so that you know what, whether it's high protein, low protein, high protein fluids, usually pre-sinusoidal, so, sorry, low protein fluids are usually pre-sinusoidal post, So it's very important that we measure that total protein.

When we're looking at patients with hepatic encephalopathy, I think it's really important that, we document that they have, high ammonia levels, for example. Hepatic encephalopathy is multifactorial. There are lots of different things that can cause a patient to get hepatic encephalopathy, not just ammonia, there are other endogenous benzodiazepines and things as well.

When we're diagnosing hepatic encephalopathy, ammonia tolerance tests are very helpful, remembering that Australian Maltese terriers have abnormal bile acids. Ammonia tolerance tests are very, very labile, but really high bile acids can often help you with the diagnosis of padic encephalopathy. When we manage ammonia, it's really important to use lactulose as your primary agent, not antibiotics wherever possible, as part of our antimicrobial stewardship, but we also need to remember to avoid cattabolism of muscles in particular, so making sure they're on anti-nausea drugs, for example.

Really quick mention about changi hepatopathy in cats, there's a really wide range of cholangi hepatopathies in cats, neutrophilic, lymphocytic, destructive and chronic. Biopsies really help you to work out what type of disease it is. Cats don't always read the rule book, so we keep on finding out.

So this is where it's really important that we find out, what the underlying disease is, and biopsies are really helpful. Neutrophilic cholangitis typically needs antibiotics, lymphocytic cholangitis typically more steroids, and other diseases need to be treated as appropriately. Hepatolipiddosis is very uncommon for us to see as a primary agent in Australia and the UK.

Try and find the underlying cause for for hepatic lipiddosis in those types of situations. Sometimes it is hepatobiliary disease, and biopsies are important, but really big take home message from me is treat the underlying disease if you get hepato lipiddosis, or at least find the underlying disease and provide nutrition, nutrition, nutrition. So as always, the prevention of liver disease is always best, but if you have a sick patient, hopefully these tricks will help you to manage your patient.

Liver disease can be really hard, and if you need the help of a specialist or somebody, then early referral is best for the patient wherever possible. So that brings us to a close of, one hour, very rapid rundown of pathophysiology and diagnostic and treatment algorithms for common liver disease. I hope this talk has inspired you to think a little bit more broadly and also have some tools to narrow down your diagnosis and be aware of the challenges.

And I hope you've been able to understand how our treatment works, and we're very fortunate tonight to have been sponsored by ADM, which does supply one of the most bioavailable products of esidone and methionine and silamarin, and I am really, really relieved to have this back on our shores in Australia. So, thanks, Benji. Thanks so much Amy, that was a brilliant session.

I've made loads of notes. I think it is one of those benefits of doing webinars that we'll be able to go back over some of the really great charts as well, so that was fantastic. Thank you so much.

As you said, we've been so fortunate to have so many people coming on from all over the world. To listen to this, and it's all down to obviously yourself, Amy, but also to Benji at ADM. And I know, Benji has some slides for us.

Benji's the sales and technical manager for Australia, so Benji, over to you while Benji's getting his slides ready, do tell us where you're from because once Benji's finished. Those of you who want to stay, we're gonna do some questions. Those of you who need to go off to clinics or whatever, and the good thing about a webinar is you can slink out and we will never know.

So over to you, Benji. Cheers. Thanks for that, Anthony.

Just want to say, a big thank you to, to Amy for, for the webinar. I think I learned a lot. I'm sure everyone else learned a lot.

I don't know how you fit it in one hour. There's just so much to talk when there's, when we talk about liver disease. So, good on you for doing that.

I'm glad I didn't have to do it. . Yeah.

Well, yeah, exactly. Also, I'd like to say thank you to SAS for sponsoring the event. Thank you to the webinar vets, and also thank you to everyone who tuned in.

Whether it's in the morning or evening, I don't know, there's people. From everywhere. I said, thank you all for tuning in.

I'm just gonna take 2 minutes of your time just to, give you, let you know who ADM Protein are and the products that we supply to vet clinics. We're one of the largest vet nutraceutical companies. We've been in the UK for about, 25 years now, and we recently launched in Australia with our flagship product called Procol and, and we have a, a big range of products across over 40 countries.

Now it's in Australia, New Zealand, it's in the UK, and again, it's in a lot of Asian countries and like that, and countries like that. If you're not sure if our products are available, feel free to contact us and we'll be more than happy to, to let you know. But talking about, liver, liver disease today, we've just relaunched Danne Marin in Australia.

It's continued to be available in the UK and US, and this is a high-level support for the liver with market leading bioavailability and excellent stability. So as Amy briefly mentioned, it's got two antioxidants support in the form of semi andyabin to help increase your, your glutathione levels, which help to detoxify. And the most important thing with Denimarin is that it has published studies supporting its Efficacy, by availability, and stability.

And when you talk about semi-products, that is the most important thing because the stability and bioavailability vary greatly between products. So it's important to have published evidence behind it. So the, as, as Amy mentioned, the ACVIM, they recommend to, to use SAMMI products, from reputable manufacturers with proven bioavailability and pharmacokinetic data, which is what Denimarin, which is what Denimarin has, and it's one of few products which actually has that data.

So, Amy did briefly mention a study. It was published in the Journal of Internal Medicine in 2011. She mentioned that CCNU Lomastein chemotherapy is, is hepatotoxic.

And in this study, there were 50 dogs with, with, tumours receiving this hepatotoxic chemotherapy. 25 of the dogs received Denimarin, and 25 didn't receive Denimarin. And what they found was there was significantly lower ALT.

AST ALP, and bilirubin levels in the, Denamarin group compared to the control group. So the, the average ALT activity in the Denamarin group was 173 versus the control group of 692. And essentially the, the results support the use of concurrent Deimmain to help minimise increased liver enzyme activity activity in these dogs receiving the chemotherapy.

So Denimarin's back in stock in Australia. It's still available in many other countries. And then for those that don't know, we've got pro colon, which we see on most of the shelves in, in the UK and in Australia.

That's for your acute gastrointestinal disturbance. So it's got your pro and prebiotics to restore normal gut microbiome, and it also has kin, which helps bind the poo and pectin, which is a mucoprotective agent, just to relieve the symptoms. Then you've got your symbiotic DC, which is a daily preventative and support.

That's got the same pro and prebiotics as procolo, but it doesn't have the, the, the kin, so it's more as just a daily prevention. As well as that, it is supported by the largest study ever published with dogs and probiotics. And that was published in the Journal of Internal Medicine, where symbiotic reduced the incidence of diarrhoea by 33% in shelter dogs.

We've got cabelazorb, which is an oral B12 supplement. It contains a hyper-supplemented level of B12, and it contains folic acid and or B9, as well as prebiotic. So it's good for animals with B12 deficiency.

And then to round out the GI products, you've got, procol and enterogenic, which is For chronic gastrointestinal disturbance. That's got your pro and prebiotics. It's got a mucoprotective agent in MPS Protect, got vitamin B12, it's got mucosal nutrition in the form of alpha glucan beyogenic, which is the main food source for Eterocytes, and then it's got immune support through beta glucans.

Then we got two urinary products, Cytophan, which is a dual action support for feline urinary health, which has glucosamine and hyaluronic acid, to which are both key components of the glycose and the glycan layer to support the bladder lining, and it's got L tryptophan as well, which converts into serotonin and has been shown to reduce stress and anxiety in these cats. And then lastly we've got Sister Pro which helps to support canine and feline urinary health. And this has type A proanthanidines, which is a type of cranberry extract which has been shown to have anti-adhesion effects.

It's got an acetyl D glucosamine, which is the building block for the glyco glycan layer, again to help support the lining. And then it's got probiotics and targeted prebiotics to help reduce the growth of, important pathogens like E. Coli.

We've got, reps all over Australia, and now we've also got a rep in New Zealand, So if you are in Australia, feel free to reach out to us. If you want a lunch and learn for your team, an appointment, we're more than happy to have a chat. If you're from the UK or elsewhere in the world, we have, again, we have reps all over the world.

So reach out to us and we can, put you in touch with someone. And then I'll pass it back to Anthony for some, for some questions. Benji, that was fantastic, .

Amy, I, I don't know if you agree that you always have a favourite company or favourite companies, and ATM is certainly one of mine. I love the fact that all of these products they produced, and I know you were talking about it as well, it's, it's so important for us to think about antibiotic stewardship, and I know, sometimes you do see vets giving antibiotics for a diarrhoea and I know it's slightly off topic, but it's . Usually not indicated, is it, and I, I do love the procoin products as well as obviously the liver products that we're talking about today.

So a tiny plug, but only from a, a clinical perspective in that I've enjoyed using the products so much. Also we like to make our webinars authentic, Amy, and I did hear the dog barking in the background as well, which, which always adds authenticity to all veterinary webinars, so that was great. But, do let us know where you're listening in from.

You, we've had a few brave people, some people being a little bit shy. We've got the Isle of Wight, which is just off the coast of the south of England, and we've had somebody listening in from Ghana, somebody from Belgium. Ireland as well.

We would like to see a few Aussies, so hopefully there's a few Aussies listening in, do let us know. Er Cintra in Portugal, Tamworth. New South Wales, Australia, there you go, another Australia in Melbourne, from northern New South Wales, Canberra.

Toronto, New South Wales. I thought there was just Toronto and Canada, but that would be very early in the morning, Amy to have people up at that time. Sydney, Brisbane, South Africa, Darwin, Northern Territories, Nottingham, UK, Sydney again, Adelaide.

I've got some family in Adelaide, so it's great to hear people listening in from Adelaide as well, and Melbourne and the Philippines. Geelong, Cheltenham, I presume it's Cheltenham, UK, but there may be a, I suppose there's a Cheltenham Australia somewhere as well, and Tasmania, I think we've got pretty much all the, the states there and safety Bay in Western Australia as well, so, right, that's fantastic. So some questions.

There was an interesting one. Why do we see this bilirubin bilirubinuria. In, in male dogs and not female dogs, Amy.

Yeah, it's a really good question. I think, I, I don't actually know the answer to be 100% sure right off the top of my head, but I believe that's something about the prostate and the urinary system and a dog, a male dog, because it can happen in an entire or castrated dog, that, that does excrete bilirubin, but it's only up to 2+. 3+ is not, not seen.

This is the lovely thing, you know, as a lifelong learner, I'm now 30 years a vet and I've been making notes and, and that's the first time I can remember seeing that. So again, we do our dipsticks and we see a bilirubin in your ear, and I think I remember saying, oh, it's not that specific, but it, it's great to hear that, that reason behind it. So then.

Yeah, even last week I saw a dog for the that, came in for bilirubinuria, and it was a male dog, and I was like, Ah, it'll be nothing. But actually, the dog ended up having really severe forminent liver failure. So, I was really appreciative that they're referring that sent it straight away.

Like, they were like, no, not OK, off it goes. Yeah, no, it's really important. I think for me, if you learn one thing from a webinar, it's been worth going on, so certainly learned that as well as other things.

So it's been great. Another person's asking, how long should an animal be fasted before blood tests to ensure cholesterol is not affected by food intake? Yeah, I'm really glad this person asked this because this is something which I really feel quite passionate about.

So, really want, we want all of our patients fasted for 12 hours before a blood samples collected. I can fully appreciate in a diabetic patient, you may not want to fast your patient, but really 12 hours for cholesterol. If you're measuring triglycerides, which is a little bit off topic, but still a fat, that's an 18 hour fast, ideally.

Brilliant, OK. And Greg's asking, when do you decide to give vitamin K in liver disease? Yeah, that's another really good question.

I certainly would strongly recommend doing a coagulation panel if you're thinking about doing a liver biopsy, if you've got a patient with, like, with liver disease, to give you the recommendation to whether you use vitamin K or not. I certainly use it for 48 hours before doing a liver biopsy, . So that, and or if I've got bleeding tendencies and I've got my coagulation panel pending, then I'll use vitamin K in that situation as well.

That's fantastic. Is there an alternative to desolate? Given that there's a current shortage in the UK.

I might have to ask if there's someone in the audience who can answer that, because I don't have a current, desolate, deficiency. There, I'm, I'm sure. So, yeah, so Benji is one of your counterparts there that can answer that question?

Not with me. I'll, I'll keep an eye to see if anybody answers it for us. Thank you.

I guess compounding is always an option. So contacting a company such as Boba or a big compounding chemist might be able to give some solutions in that situation. I know that like with any of these types of medications and supplements and things, there's often, and in particular, I think since the pandemic, like, variability and drug supply.

And sometimes we do have to go with the flow of that. Anytime I get a deficiency of a drug being available, I do reach out to the compounding chemists as one of my first points of, of, because they usually have a little bit of access to more of the international, supply of, of medications. No, it's a really good call.

. The problem with webinars is you don't hear the tumultuous applause at the end, Amy, but Robert is saying thank you awesome. So and there's quite a few people also commenting on how much they've enjoyed it, so, yeah, that's been really good. .

G Garner has said about immune-mediated chronic hepatitis, there is a paper comparing human and dogs, and there is some info that with people they test for autoantibodies and IGA. Does veterinary medicine know this is useful to the dog? And she said, thank you for the lecture.

Oh, that's very nice. That's a really nice, interesting study. I'm going to go and find that, and have a read of that for tomorrow.

I don't unders I don't believe that measuring IGA in particular is something that's routinely done in our veterinary patients. But I do think that's a really exciting area to research, because obviously, chronic hepatitis is such a common disease for us to be seeing, in older dogs in particular. Mm.

Denist is saying any tips on paracetamol toxicity in cats that are given it by accident. Yeah, I guess, obviously it's a very sad situation when you get to that, Sort of situations, so an acetylcysteine, esidyl methionine, treat aggressively and as quickly as you can. If you can decontaminate the cat using like charcoal, etc.

Or enemas, unfortunately, you have to do it. And Zoe's got a question, she said, Amy, great webinar. Thank you.

What he hepatorotectants could I consider in dogs with leptospirosis? It's a really good question, and I don't think we necessarily know the answer to that in terms of the, any evidence, but I certainly would be very comfortable to use Denimarin, or esodenal methionine, silarin, and ursodeoxycholic acid, given the type of injury that they can get in their liver from lepto. And they certainly wouldn't be contraindicated.

I thought Benji, that was a lovely study that you'd that you did with . The Lemustine just showing what a huge effect, supporting the delivered or that sort of treatment, obviously Lapirosis is. You know, it's an infectious disease, but as we become more and more progressive with our treatment and of oncology and things then that, that really did have a massive effect, didn't it?

Yeah. Yeah. I think as Amy said, you know, there's, there's a tonne of lack of evidence in, in dogs and cats.

I mean, not, not just with, you know, these sorts of products, but with, with so many things, you know, human medicine is so far and advanced. And, and having studies like that, you know, supporting, you know, how to protect and so I think it's a step in the right direction and it gives us some evidence-based products to use, you know. That's brilliant.

Palmer is saying thank you, thank you, I learned a lot. And then Susan is saying, sorry, have to go, great lecture, looking forward to being able to rewatch, to just go over all the information again. So this is, this is the benefit of recording, webinars, which we really didn't do sort of 13 years ago, so it's really good to, be able to go back over that.

Should be up within the next 24 to 48 hours and we will give you a, An email to let you know when it's up on the site as well. I think that's probably about all the questions. Thank you so much, Amy, that's been a brilliant talk.

As I say, I've got quite a few notes here to, to go over and I think particularly looking at ALP and ALT, the half life of them, how they can predominate in some conditions more than others, we probably look at blood results every day of our lives, and it's so important to be able to interpret those and with our values and so on. Benji, obviously thank you so much for making it possible for so many people to, benefit from Amy's training and, yeah, hopefully see everybody else on a webinar very soon, but thanks again and good evening, good afternoon, good morning, wherever you are in the world. I hope you have a great rest of the day.

Take care, bye bye.