Hello, my name is David Tweed. I'm on the faculty at Colorado State University, and what I would like to do is talk about 3 liver conditions that perhaps you didn't learn about in veterinary school. And first off, do you guys remember embryology?
I think about the only thing I ever remembered about embryology was my textbook was blue. But I'm gonna take you back to 101, embryology. And just to remind you that the liver forms from an out pouching from the GI tract and you've got these primordial liver cells that then go on to make the liver.
And develop into normal hepatocytes. Within that liver bud are portal veins and these portal veins grow into the liver and around these portal veins is what's referred to as a ductal plate. And this ductal plate then divides and then goes on to make bile ducts.
So the portal vein and the bile ducts grow into the liver together. And there are some congenital development. Developmental abnormalities associated with bile ducts and portal veins.
And these congenital abnormalities, we're starting to see more and more cases with this type of a problem. And these can be associated with portal systemic shunts, portal vein hypoplasia, but also bile duct disorders as well. And there is some overlap, and sometimes it's hard to tell the difference if it's coming from portal vein or if it's coming from bile ducts.
So this is Gucci, Gucci is an eight month old intact female little shih-tzu that was presented to her veterinarian for routine ovaral hysterectomy. The physical exam was completely normal. The veterinarian did a pre-anesthetic blood profile and identified that the ALT was 201, which was twice the normal reference range for this laboratory.
The dog's history, he was completely healthy. He was on some heartworm preventative vaccinations were current, the dog had been deworms. Well, the owner asked the veterinarian, why is the ALT abnormal?
And the veterinarian said, you know, I really have no idea. Maybe you should go to Colorado State University and see what they suggest. And so, it was about 4 weeks later, I happened to be on clinics.
I saw Gucci. And at that time, the owner comes in and I says, I'm here because my dog's ALT is abnormal. Physical on this dog was completely normal.
I repeated the laboratory profile and the only abnormality was an ALT of 246. This owner was a very good client. She wanted to determine exactly what was going on with her dog.
And so I'm trying to think of logical reasons why the ALT would be abnormal in this dog. Do you think it would be associated with just being a young dog? Well, probably unlikely because we do see a hos elevated in young dogs, but not ALTs.
Medication associated ALT increases, well, any medication could potentially do that, but heartworm preventative, I've never seen that being a problem. This dog could very possibly have a congenital vascular anomaly. How about copper associated hepatopathies, and that's unlikely.
I usually see these in dogs over a year of age, as well as chronic hepatitis in older dogs, middle aged to older dogs as well. This dog, however, could have some sort of secondary reactive hepatopathy from some other underlying disease. So we went ahead and tried to further figure out exactly what might be going on with Gucci.
We did some bile acids. The pre-bile acid was 45, the post was 34. Both of these are significantly abnormal, which would suggest either hepatocellular dysfunction or portal systemic shunting.
We did abdominal radiographs. The abdominal radiographs were unremarkable for little Gucci. So we further pursued these abnormal bile acids and we did an ultrasound and shown on the left is the ultrasound and our radiologist confirmed to me that the portal vein was going into the liver and there was no evidence.
Of a portal systemic shunt. We then did go ahead and do a CT angiogram of this dog, and we were able to identify the portal vein as seen here going into the liver, and our radiologist said this dog does not have a portal systemic shunt. So what do we recommend for Gucci?
Do we prescribe liver support medications and recheck the dog in 6 to 8 weeks? Do we do nothing and tell the owner it's not a serious problem, or should we obtain a liver biopsy? Well, what we decided to do was to recommend getting a liver biopsy.
The owner won her dog spayed and so we felt that would be an opportune time to go ahead and perform the ovarian hysterectomy and also take a liver bi. The referring veterinarian looked very carefully for any evidence of portal systemic shunts, did not find any, did do a liver biopsy, submitted it to our laboratory and shown here is a close up of the liver biopsy. And our pathologist said there is evidence of arterial hyperplasia, smaller absent portal veins, dilated per portal lymphatics, and this liver was not normal.
And their comment was that these changes are consistent with a portal systemic shunt. But with all our testing, we did not see any evidence of a portal systemic shunt. Well, what this dog has, or what we believe this dog has is portal vein hypoplasia.
It has been previously called microvascular dysplasia, but we believe that probably the best terminology is portal vein hypoplasia. And this was one type of congenital portal vascular anomaly that we can see with abnormal portal vein development. We can also see portal vein abnormal development with in and extra padic shunts, which we were unable to identify with little Gucci.
And this is kind of a a confusing terminology and a years ago the WS AVA established a group of pathologists and they did have a couple of internal medicine clinicians which was, I was fortunate to be one of those, to look at liver biopsies of animals. So if you do a liver biopsy in Europe, and I do a liver biopsy in North America and it's the same disease, we call it the same thing. And what they felt is that portal vein hypoplasia is a much better terminology describing what's going on than microvascular dysplasia.
And they also explained to me exactly what was going on. And in the normal animal, The portal vein goes into the liver, and then it branches off and goes into the various liver lobules. And in the liver lobule, there is a portal triad.
Can you remember all that from vet school, portal triad. And in that portal triad is a bile duct, a hepatic artery, and a portal vein. And about 80% of the blood flow is coming from the portal vein, about 20% from the hepatic artery, and then that blood mixes together, perfuses the hepatic sinusoids, and then is removed from the liver through the central vein.
Well, a consequence of decreased portal blood flow can be the result of either one, an extra padic portal systemic shunt or maybe even an intrapatic portal systemic shunt, decreasing. Hepatic blood flow, or the other possibility which we think is going on with Gucci is a very poorly developed hepatic portal veins. So these hepatic portal veins are very, very small or maybe even absent, although the portal.
Vein does go into the liver, but these little branches are very, very small. So when you look at the portal triad, the portal vein may be very small or very absent. Well, the liver cells say, I need oxygen, I need blood.
And so what happens is the arteries start to proliferate and so you get this arterial proliferation that is then going to supply most of the nutrients and blood flow to the liver. So the consequence of this with this high pressure system is one, it is a very high pressure system and to try to keep those pressures down, small little shunts will develop that will go around the sinusoids to keep the pressure down, and these small little shunts are what are responsible for elevations in bile acid concentrations. And so, with this condition, this is what we usually see histologically, and this is a view of little Gucci's liver biopsy.
And this is a portal triad area here, and this is a bile duct and the bile duct looks very normal. We see these big dilated lymphatics, and that's usually an indication of increased pressure in that portal area. And then we see a lot of busy work in here, all this stuff in here which is abnormal, and these are all arteries.
So we see this arterial proliferation in this Portal triad, we don't even see a portal vein, and we see dilated lymphatics, and portal vein hypoplasia, we believe is very common, much more common than the congenital portal systemic shunts. However, it's a relatively new disease and going through med looking at publications over . Almost a 20 year period of time, there were very few cases in the literature talking about this condition.
Most of these animals have no clinical signs, and one of the most common things I usually see is maybe an increase in ALT concentrations, and that may Be a reflection of maybe just not getting the right amount of nutrients or blood flow to those hepatocytes. These bile acids are generally abnormal, although they are usually less than 100 milligrammes per deciliter. They're not sky high as you would expect with an extra paddock shunt.
And typically we often see this in small breed dogs. I usually think of the small little fluffy white dogs having this portal vein hypoplasia, and we believe that there is a genetic basis to this, and the genes may be very closely related to the genes associated with the extra padic portal systemic shunts that we often will see. The diagnosis is finding no evidence of portal extraathic portal systemic shunting and a liver biopsy showing these typical changes.
One of the things to keep in mind if you are doing liver biopsies, you would like to, you would always want to take multiple liver lobes because one liver lobe could be normal and a second liver lobe could be abnormal, and these lesions can be quite patchy. There was a recent study, . Well, maybe not all that recent.
It was in 2014, 10 years ago, a Japanese study looking at 463 cases that had liver biopsies, and what they found is the most common histologic diagnosis was portal vein hypoplasia. And in that study, what they found is 48 of these dogs that had this portal vein hypoplasia, most all of them were asymptomatic. Their mean age was 3.7 years, but 40% of them were under a year of age, and that's typically what we often see as well.
And what they also found is the most common breed in Japan with this condition was the little toy poodle. It was overrepresented. You have to realise though in Japan, most of the dogs are usually small breed dogs.
And those dogs that had complete blood work, 28, 46% had increased ALT concentrations. However, 75% had increases in their alkaline phosphatase. I don't typically see that, and maybe it was because these dogs were so young and they had alkaline phosphatase that was coming from bone and osteoblastic activity and not.
Reflecting hepatic damage. Bile acids were abnormal in most of those dogs, and the other thing that they found is 71% had decreased fibrinogen levels as well associated with this primary portal vein hypoplasia. They also showed that survival was greater than 5 years, so most of these animals did very, very well.
In that study, 2 dogs died secondary to acquired portal systemic shunts. There was also a paper, in the United States looking at protein C and protein C is produced by the liver. It, is involved in coagulation.
It helps prevent or control clotting. And what they found is looking at protein C often will differentiate between dogs that have the extra padic or inopadic portal systemic vascular anomalies versus the dogs that have portal vein hypoplasia. And they found that dogs that had greater than 70% protein C activity.
On the test, were dogs that did not have portal systemic shunts that may require surgery. And we looked at little Gucci, and what we found is Gucci's protein C was 92%, which would go along with a dog having portal vein hypoplasia. So, kind of in summary with this portal vein hypoplasia, there's really no specific therapy that can be done.
Some people will recommend antioxidants, and we believe that most dogs with this condition will have a long-term survival. However, there is a small percentage of dogs that may go on, maybe in later life developing oral hypertension where they could develop ascites and hepatic encephalopathy and even GI ulceration associated with this disease. I got an email once from a veterinarian this last year and she said, hi, I'm reaching out to you because my six year old dog, Cookie was diagnosed with idiopathic and chronic hepatitis.
She's currently on Prednisolone, Usodiol, Danaerin, which is a SAI preparation. She's not tolerating the medication, she's losing weight, and she wanted to know if I could give her a professional opinion as to what is going on based on the records. So she sent those to me.
I looked at it. The ALTs ran from 150 to 250 range for over 2 years. The APOs, however, remained normal and usually dogs with chronic hepatitis, I will see increases in alkaline phosphatase.
This dog have bile acids at one point and the bile acids were quite high and the post bile acid actually was up in the range of 148, and that's usually a range where I usually will see acquired shunts starting to develop. An ultrasound on this dog showed a small liver. And some sort of hepatopathy and abdominal effusion.
And they also went ahead and did a laparoscopic liver biopsy, and this is the liver biopsy and you can see a lot of blue in here, so there's something going on in this liver, and they also did a serious red stain and this dark red is usually representing fibrosis, so there was a lot of fibrosis in this liver biopsy. And some changes going on on an H&E stain. And they said, the report said there's mild chronic lymphoplasma city hepatitis with bridging fibrosis and bile ductalar reaction and mild copper accumulation.
Copper was 509, normal is 400 or less, and they called this idiopathic chronic hepatitis. Well, we looked at this biopsy and we actually did some additional staining, and this is a trichome stain of the liver and all this dark blue is fibrosis and you can see a lot of holes in here. And all these holes are bile ducts.
We did a special stain. It's called the cytokar 19 stain that stains bile ducts, and we see all these unusual shaped, multiple bile ducts in all this area of fibrosis. And this is compatible with the ductal plate malformation.
And it's often referred to as congenital hepatic fibrosis. And what happens is with all this fibrosis and this bile duct proliferation, these dogs often will develop portal hypertension, they get acquired extrahepatic shunts. And they can develop ascites and a ppatic encephalopathy.
This dog does not have chronic hepatitis. We recommended stopping the steroids and we also recommended other therapy and management for this dog. This is Bishop, an 11 month old, female Rottweiler that was presented to me that had polydipsy and polyurea.
I had a cites that was noted for over a week, had very high liver enzymes, ALT and alkaline phosphatase in particular, had very high bile acids. The bile acids went from 245 to 313. Bile acids that high in a non-ectic animal has to have portal systemic shunting.
We did ultrasound on this dog. The dog had a small liver, had ascites, had a bunch of apparent, abnormal veins in the caudal abdomen. The radiologist, diagnosed that this dog had a congenital portal systemic shunt and recommended to the clinician that this dog needs surgery for correction of the shunt.
I'm not sure that I would have taken this dog to surgery, and I'll tell you why in just a few minutes, but it was taken to surgery. And at surgery, this dog had a very small liver and in fact, the left liver lobe was atrophied, and I don't know if you can see this here, but this is a very unusual, atrophied liver lobe. There are a lot of large tortuous veins.
There was congestion, in the mesenteric vessels, portal veins. They did measure portal pressures with a manometer, and this dog had marked portal hypertension and had, acquired portal systemic shunts. And we can see the acquired portal systemic shunt secondary to portal hypertension.
And the best example that we usually see clinically is maybe the dog with cirrhosis where portal blood flow draining the GI tract can't get through the liver, the pressure builds up, ascites can develop and as that pressure builds up in the portal. System, acquired shunts will develop, and these acquired shunts generally are very torturous. They're usually found around the left kidney, and they drain into the posterior vena cava, trying to decrease that portal pressure.
Well, congenital macroscopic portal systemic shunts do not develop ascites because they don't have portal hypertension. So if you see a dog that you suspect maybe has a congenital portal systemic shunt and has ascites, it probably is one of these conditions. With Bishop, we also did biopsies.
We did see with this trichrome stain all this fibrosis. We also did a special cytokeratin stain looking for bile ducts. This, stain, stained purple for bile ducts.
So you can see in this portal triad area, there's all this fibrosis and many, many, many bile ducts. And this is referred to as a ductal plate malformation. It's it's also been referred to with this particular phenotype, congenital hepatic fibrosis.
At one time, it was often called a non-cirrhotic portal hypertension, but we believe that's probably a poor terminology. And on the pathology, what we found was there was no significant inflammation. There was all this fibrosis, abnormal bile ducts, abnormal number of portal veins.
There was no evidence of nodular hyperplasia, necrosis, or inflammation. And this is something that is extremely common when we're seeing more and more cases with this ductal plate malformation. So going back to embryology, remember I told you that the portal vein grows into that liver bud and around that portal vein is a ductal plate.
That ductal plate then divides, and those two layers of that ductal plate go on to make the normal bile ducts. So around the portal vein are bile. Ducts.
But this malformation, what can happen is that you can get this ductal plates that become very cystic, and so you're seeing cystic changes. Or the other thing that you can see is that these ductal plates start to proliferate and you get many, many abnormal bile ducts with lots and lots of fibrosis. And this is thought to be a genetic defect, maybe in cilia formation associated with this ductal plate.
Irregardless of how these form, there are different types of ductal plate malformations that we see both in human medicine as well as in veterinary medicine. And there are ductal plate malformations associated with the small little ducts in the periphery. Medium sized ducts where we can see cystic changes and then even in the big, larger extrapatic ducts and even the common bile duct, we can see malformations.
One of the most common we see is the congenital hepatic fibrosis. And this is again where you have all this fibrous connective tissue and many, many little small abnormal bile ducts. There is another type of complex in human medicine, they call it the non-Mynberg complex or also hamartomas, which are little aggregates of small bile ducts and fibrosis usually around in the periphery of the liver.
We can also see the medium sized ducts often becoming very dilated and very cystic in formation, and it's these can be single cysts or polycystic type of bile duct disease. So, with these, ductal plate malformations, there are a number of other things that we often see that might clue you in. You may not see a gallbladder.
We often can see gallbladder agenesis. We can see that left liver lobe atrophy. Sometimes.
In cats, we can see a biliary cyst adenomas that was once thought to be a neoplastic process, but now we believe that it's part of a ductal plate malformation. Polydocal cysts, which were out pouching in the major bile. Common bile duct, polycystic disease, we see that in cats.
And also, if you ever get a case that has a peritoneal pericardial diaphragmatic hernia with the liver herniating into the pericardial sac, that has also been associated with a ductal plate malformation. One type of the ductal plate malformations, the Coroli disease where you have big cystic ducts and on ultrasound, you may be seeing big cystic areas in the liver histology. You can see these big cystic areas as well.
And oftentimes these cause no clinical signs at all. However, in some cases, these cysts may become secondarily infected and 1 may need to use antibiotic therapy in some of these cases. There is hepatic cysts that occur in cats as well, and in particular, one type, an autosomal dominant type defect in Persian cats where they get renal cysts as well as hepatic cysts.
So if you do see cysts in the kidney and or the liver, you want to look at the other organ to see if there are cystic changes in there, and that may be a manifestation of a ductal plate anomaly. And this is a relatively newly recognised disease, and going back and looking in PubMed, looking at publications over a period of over 15 or approximately 15 years, there were very few cases that were ever published talking about this. It is identified usually in younger dogs.
It has been previously diagnosed as chronic hepatitis, cirrhosis, cholangitis, liver cysts, and, we now know that many of these cases were associated with ductal plate malformations. Classically, well, I generally see are maybe more commonly larger breed dogs, but again, we can see mixed breed dogs, we can see small breed dogs with congenital hepatic fibrosis as well. Breeds that seem to be maybe a little bit overrepresented might be the Doberman, the cockers, boxers, Rottweilers, goldens.
In other breeds. We can also see it in cats. Most of these animals often present under 3 years of age.
They often present with signs that might be associated with either one abnormal liver enzymes, with increases in ALT. In my experience, oftentimes they're a hos. Tends to be normal, because they don't have a lot of cholestasis, but, alas can be abnormal as well.
Sometimes they will have ascites because of their portal hypertension, they can develop hepatic encephalopathy, GI bleeding, and classically, these dogs will develop extra hepatic acquired shunts and their bile acids are usually very, very high. Bishop, the dog that I just told you about lived until approximately 6 years of age with medical management and then was eventually euthanized because of its disease. With this, condition, we often will see, with the congenital hepatic fibrosis condition, we often see hepatic encephalopathy.
These, this is A golden retriever that has ascites and a ppatic encephalopathy. Those dogs, again, it's not a surgical disease. They're treated with liver diets, lactulose, GI antibiotics for their, hepatic encephalopathy.
They also can develop ascites. Our experience is furosemide or Lasix is not a very good diuretic. And your anti-aldosterone, diuretics such as spironolactone is often, what we would use in a case like this.
What we're also finding is the angiotensin receptor blockers such as telmisartan is also very effective in helping control some of the ascites. And what telmisartan does, as well as having some diuretic effects, it reduces portal hypertension. And may also have some antifibrotic effects as well.
We also will see GI bleeding and probably the GI bleeding is spontaneous and associated with portal hypertension, and we can see, either just erosions in the GI tract, sometimes we can see, ulcers or just diffuse bleeding, from portal hypertension. In those cases, we usually will treat with a proton pump inhibitor such as omeprazole or sucrofate. And then the less common form is the cystic form, and again, there's no specific treatment for that.
Most animals are asymptomatic and it might be an incidental finding on ultrasound finding cysts in the liver. Some of those, however, may become infected. There is some suggestion that maybe yoursodiol may help increase bile flow through those cysts, but that has not been very well, documented.
As far as prognosis, it's kind of unknown at Colorado State University, we're now doing ongoing lifelong study of cases, so we're enrolling cases and trying to follow them throughout their life. Again, cysts may be incidental, hepatic fibrosis. Some cases, we think will progress over time.
And there was one study looking at 30 boxer dogs with, congenital hepatic fibrosis, and some of those dogs had acquired portal systemic shunts. Some dogs did not, and they tried to develop a survival curve, and this is a statistical probability, and it appears that the dogs that had acquired evidence of acquired shunts, had a, a shorter survival time as compared to those without acquired shunts, but, it appears that some of these dogs may get up to the age of 8 or 10 years of age with this condition, maybe with medical management. So those are two congenital abnormalities.
The last thing I wanted to talk about was abnormal alkaline phosphatase in normal dogs. And there was a study a number of years ago looking at a big diagnostic lab. Looking at alkaline phosphatase, and they found that 51% of the dogs over eight years of age had elevated alkaline phosphatase samples.
Now, again, they didn't identify what the underlying cause was, but it's a common thing that we see in older dogs. Alk phosa is not specific for the liver, however, and that's because there are a lot of isoenzymes of alkaline phosphatase. And, the major isoenzymes that we can measure in the blood are alkaline phosphatase isoenzymes associated with bone, liver, and steroid.
Now, bone is pretty easy to rule out because bone alkaline. Phosphatase is generally associated with osteoblastic activity, and that's generally associated in young growing dogs before their pial plates close. Occasionally we can see osteogenic sarcomas that will have an elevated alkaline phosphatase, but bone from arthritis or fractures, that's not gonna cause a bone a isoenzyme increase.
So the two other major causes are liver and steroids. And in the liver, This is a liver cell here, and this is a bileannulicui, and anytime there's decreased flow of bile, or we call it cholestasis, and increased pressure in these little bioannulicui, that singles signals a gene to produce liver alkaline phosphatates. So cholestasis.
Bile duct disease will cause increased liver alkaline phosphatase. But unique to the dog, there are also steroid receptors in the liver. And so if you have, for example, prednisolone percolating through the liver, it can bind in a steroid receptor and it will stimulate a different gene to produce steroid alkaline phosphatase.
So steroids can cause increase in alkhos, and cholestasis can cause increase of alkhos, and these isoenzymes are both produced in the liver, and this is unique to the dog and not the cat, the steroid isoenzyme. So this is Joe, and this is a dog I saw a number of years ago, 10 year old mixed breed dog that had a very high alkaline phosphatase, and this alkaline phosphatase had been increasing over 2.5.
Years, this dog had no clinic signs on no medication, getting the same diet, and the physical exam is completely normal. And this actually belonged to one of our veterinary students, and she came to me after one lecture and said, I think my dog has what you're talking about. So I said, well, tell me about your dog, and she said, he's just had this increased out costs over 2.5 years and we can't figure out exactly what's going on.
And what she said is, before I got into veterinary school, I was working for a veterinarian. We did some lab work on my dog, and, and we identified that the alky phosphatase was 452, normal being usually less than 100 or thereabouts. Then I got into vet school, I went to community practise and the alkaline phosphatase was 495.
And the clinician at that time did an ACTH stimulation test, which was completely normal. They told me to come back in about 3 months to reassess my dog. I did.
The alkaline phosphatase was 777. And a second ACTH stimulation test was also normal, suggesting my dog doesn't have Cushing's disease. Then 9 months before before I saw the dog, the class had gone up to 972.
So I said, well, bring your dog in. Let me look at your dog and so, she did. She told me that, you know, I've read about Cushing's disease.
I've monitored my dog's water intake. My dog's not drinking excessive amounts of water. There's no evidence of my dog getting any type of exogenous cortical steroids.
And on my physical exam, the dog was completely normal. So I did another biochemical profile and the alkaline phosphatase was 1088. Everything else on the profile, the urine analysis, the CBC, everything else was completely normal.
I don't know if you see cases like this, but I see a number of cases with the very same type of scenario. So with Joey, what would you do? What would be your next step in this case?
Would you do a low dose dexamethasone suppression test? Would you measure urine cortisol to creatinine ratios? Would you look at the percent a phos isoenzymes?
Is it all steroid or where is it coming from? Would you do an ultrasound, needle aspirate, and cytology of the liver? Would you do a liver biopsy?
What would you do in this particular case? Well, with Joey, we did all that. And we one of the things that we looked at was the steroid alkaline phosphatase isoenzyme, and what we found is it was 95% steroid isoenzyme.
And one can, and there are laboratories that can do an electrophoresis of the alkaline phosphatase to show the various isoenzymes with Joey. It was predominantly the steroid fraction, but You can also determine what's coming from the bone and what's coming from the liver. And what we know is that the steroid alkaline phosphatase isoenzyme has a high sensitivity for hyperadrenal cortices.
And so the cushionoid dogs, predominantly most of their isoenzyme is steroid induction. However, it has a very low specificity. So meaning that other conditions can also have increases in that steroid isoenzyme in addition to other isoenzymes as well.
And it's really not a very good test for diagnosing hyperadrenal corticism, and I don't normally recommend doing it, but I decided to do it in this case just to see what was going on. We also did some bile acids and those were completely normal. We did a urine cortisol to creatinine ratio, and one of the things that you can do is if you see a high cortisol in the urine compared to the creatinine, that usually suggests hyperadrenal corticism or increased stress with cortisol release.
And it was completely normal. Now, if you ever do this test, one, it should not be done in a sick animal, it shouldn't be done in the hospital, it should be done at home in a non-sick, non-stressed animal. And if that ratio comes back normal, it's highly unlikely that the animal has hyperadreinal corticism.
If it comes back abnormal, it could be Cushing's disease or it could be just stress associated with steroid release. We also went ahead and did a third ACTH stimulation. We looked at ACTH levels and we did a low dose dexamethasone suppression test, and we also did a thyroid evaluation and found that the thyroid function was completely normal in this dog as well.
So we went ahead and did an ultrasound evaluation and the liver looked normal. I had our radiologist look at the adrenal glands. They look completely normal.
We did a fine needle as part of the liver, and what we found was lots of vaculated hepatocytes. Well, what we know about fine needle aspirts of the liver is that they aren't always diagnostic of, hepatic disease. And in fact, in a study we did, we found that a third of the fine needle aspirs did not correlate with histology at all.
A third did correlate with histology, probably best being carcinoma or diffuse vacuolar disease, and a third, there was some partial correlation. So fine needle aspirate doesn't always give you the diagnosis. So what we decided to do is go ahead and get a liver biopsy.
We did a laparoscopic liver biopsy on Gucci and, or pardon me on Joey, and you can see that the liver is a little bit pale in colour. The edges of the liver are somewhat rounded and we took 4 different liver lobes, biopsies from 4 different liver lobes. And we submitted that for histology.
We also measured hepatic copper concentrations in the liver as well. And after we examined the liver very well, we went ahead and looked at the adrenal glands, and this is looking at the right adrenal gland here. This is the caudate lobe of the liver, the right kidney, this is the right adrenal gland.
This is the vena cava right here. Now, I didn't biopsy the adrenal gland because I knew the name of this blood vessel here, the vena cava, . And, but it looked normal size and normal shape.
So we submitted our tissue for histopath evaluation and the pathologist diagnosed that Joey had hepatocellular hydropic degeneration, also, often referred to as a vacuo hepatopathy. And you can see the biopsy here with all these sort of hepatocytes that are kind of swollen and have you know, they're just sort of look very vaculated. Well, the comments from the pathologists were that these changes are similar to a steroid hepatopathy, and they suggest that I evaluate the dog for Cushing's disease, and I know exactly what happened.
My student probably Said in the histology request, elevated alkaline phosphatase, liver biopsy, and that's probably all they said and they didn't give a complete history. And if you're ever doing a liver biopsy, it's extremely important to give a complete history. We also went ahead and did a PAS stain and PAS stains for glycogen.
And glycogen, and so this is the liver biopsy and all this dark purple stuff is glycogen in these big vaculated hepatocytes. And so this dog had excess glycogen. The causes of excess glycogen that I can think of would either be one, a dog that is getting steroids or having steroid effects, or second, a glycogen storage disease, and glycogen storage diseases are extremely uncommon.
We usually see it in young dogs with great big livers full of glycogen, and they have a genetic defect where they can't get the glycogen converted to glucose, and they come in with hypoglycemia and usually they don't live more than 3 or 4 months with the disease. So extremely rare. So what is a vacuolar hepatopathy?
Well, This may be somewhat nitpicking a little bit, but a vacuole hepatopathy, true vacular hepatopathy has mem is a membrane-bound vacuoles or inclusions, and that's usually lipid. And so we can see lipid vacuoles associated in dogs with diabetes mellitus, hypothyroidism, hyperlipidemias such as the schnauzers with their congenital hyperlipidemia and so forth. What we see more commonly are, which has also been referred to as vacuolar hepatopathies, although they're not vacuoles, and it's probably the better terminology is cytoplasmic rarefaction where cytoplasm becomes, very rarefied, also referred to as hydropic degeneration, and this can represent cell injury and so any cell, liver cell that becomes injury, the membranes become Damage, fluid fluxes change and the cells often can become swollen.
So that can be just a non-specific injury problem. But we can also see a syndrome where we see this, these sort of vacuolar type changes associated with glycogen accumulation that can be associated with Indigenous or exogenous steroids, other adrenal steroids. Some drugs can do it.
I can see penicillaine doing this sometimes, and then chronic stressful episodes, illness, neoplasia and so forth. Sometimes you can see these secondary type glycogen type accumulation. And there's one paper looking at this a number of years ago where they looked at 336 cases and what they found is going back into the, history that 55% were getting glucocorticoids.
Some of those dogs had Cushing's disease, some of them were getting exogenous steroids, but 45% were not getting glucocorticoids based on their history, and the authors felt that oftentimes these changes might be associated with chronic stress or an illness, where they were getting some sort of exogenous, steroid, release, and, but some of them were also idiopathic, where there was no evidence of illness at all that had these type of changes. I think that what we see now quite frequently is this idiopathic glycogen hepatopathy. It's also been referred to as idiopathic vacuolar hepatopathy.
We see it in usually older asymptomatic dogs. They have unexplained. Elevations in their alkaline phosphatase, the ALT and the GGT are often very normal.
they have no evidence of, Cushing's disease, with. Ender adrenal testing, they have a hypochoic liver, due to all this glycogen accumulation, and if a biopsy is taken, you often get this cytoplasmic rarefaction or hydropic degeneration with glycogen accumulation. And some people suspect that this may be secondary to abnormal adrenal, sex types hormones, so other hormones, not cortisol causing these type of changes.
So, what should we do as the next step? And you have to realise that we spent a lot of money looking at trying to figure out what was going on with Joey. I should tell you, however, that I probably paid for most of this through a research study, but, Should we stop and perform no more diagnostics?
Should we treat the dog for Cushing's disease? Do we retest the dog in 6 months, or do we just put the dog on Sammy or some other antioxidant? Or should I have the owners take out a second mortgage and continue testing?
Well, we decided to continue testing the dog. And so one of the things that I think is important to understand, and I hate to show this next slide because it's pretty daunting, but this is a giant adrenal gland. And in that giant adrenal gland, cholesterol goes in, goes through a whole bunch of different steps and makes.
Cortisol, and that's what we measure. But there are all these other adrenal steroids and much more that's been shown in this little, diagram that may be abnormal in, concentrations and productions that could be causing this vacuolar type hepatopathy in some of the dogs that we're seeing. So we actually did an adrenal panel which looks at an Number of different adrenal steroids.
And what we found with Joey is doing a an ACTH stimulation test again that the cortisols were in the normal reference range, but we saw elevations and progesterone, 17 hydroxy, progesterone as well, and they thought this was supportive of a very hyperactive adrenal function. I normally don't run this test. It's quite expensive.
I'm not sure we're actually measuring what's causing this condition, which hormones, there are a lot of others that we're not measuring, so I'm really not quite sure of, the accuracy of this type of test. So what should I do with Joey? No therapy, put the dog on liver support stuff, melatonin or flaxseed oil, that's been suggested sometimes in cases where they may, melatonin in particular, may decrease the adrenal steroid production.
Use Lysedrin, which kills adrenal glands. Trilata, something other, you know, I have tried Lysatron in some of these cases. It's, I think it's very dangerous.
The therapy is probably worse than the disease, and I've shown that their alkaline phosphatase goes back into the normal reference range, but it's very difficult to monitor these animals. I'm not sure exactly how you would do that successfully. Well, follow up with Joey.
Joey died at 16 years of age with no therapy, actually died from a ruptured hemangiosarcoma, and had a high outclass his entire life. We do see potential complications, however, and those complications include protonuria, hypertension, and that's those are steroid effects we see that in Cushinoid dogs. There is some evidence of liver tumours, mucocele production and, and, often, progression to, possible progression to more advanced type liver disease.
So that is a complication that we sometimes will see. . This idiopathic vacuolar type hepatopathy has been reported in the Scottish terriers.
And they have a high alho, they have a steroid type hepatopathy, and it has been associated with increased adrenal steroids such as progesterone and 17 hydroxyprogesterone. Some of these, Scottish terriers, their disease will progress where they can develop portal hypertension, ascites, and so forth, and we do believe that these, Dogs also have a much higher risk for developing liver tumours. So I think any dog that has this idiopathic vacular type hepatopathy, you probably wanna do a repeat blood work yearly, maybe an ultrasound yearly, and also definitely check them for protonuria and hypertension and treat those if that is present.
So, as kind of a final summary of dogs with only high alkaline phosphatase, I always wanna check drug history. Certainly the animals that have Cushing's disease or signs of Cushing's disease, you're gonna work them up for Cushing's disease. And treat their Cushing's disease.
Dogs with only a high alphos, with no drug history, not showing signs of Cushing's disease. Some of the things I think about would be this idiopathic glycogen hepatopathy, maybe hepatic neoplasia or nodular hyperplasia of the liver, and then certainly cholestatic liver disease like mucoceles or other types of cholestatic conditions. And so those would be the things I would be thinking about.
My next step in a dog with only a high alkaline phosphatase would be to do an abdominal ultrasound looking at the liver. Are there nodules? Is there a tumour?
Is there a mucouscele? Or does the bile duct and the common bile duct look abnormal? Seeing none of that, then very likely it might be that idiopathic glycogen hepatopathy.
Maybe a fine needle aspirin in cytology might help support that suspicion. So those are 3 conditions that I think you ought to be aware of associated in dogs that maybe you weren't taught in vet school. And again, if you have specific questions about what I talked about, certainly you can give me an email.
This is my email address, tweet at Carlostate.edu and I hope I've enlightened you with 3. Common conditions we're seeing associated with the liver.
Thank you very much.