Thank you, Anthony. It's a big pleasure to have this opportunity to talk here. Actually, I'm not the president of the European Society of Endocrinology, I'm the past president, but I'm very proud of this society, of course.
And thank you to give me the opportunity to talk about what I love, which is veterinary endocrinology. And this evening, the idea is to talk about hypercortisolism. Most of you probably, you know, this disease more as hyperadrenal corticism.
Today endocrinologists prefer to talk about hypercortisolis because it's an excess of cortisol. And not a hyper function of all the cortex of the adrenal gland. This is the reason why we use mainly hypercortisolis instead of hyperadrenal cortices, but this is just a detail.
And when we talk about Predatory dependent hypercortisolism. We know that it's the most common form, roughly 80% of our dogs with Cushing's syndrome, they have a PDH and let's see which is the best approach or let's discuss which could be the best approach. An adrenal target treatment option or a.
Target treat option and I hope this lecture will be useful to understand which are the potential options. Probably there is not a perfect one, but we will discuss the different potential options. So when we think about a predatory target, do we have something?
Yes, we have. In humans, the best treatment option and what they do usually for PDH is a pituitary surgery. They, they do an adenomectomy, to remove the tumour.
This is possible and feasible also in dogs and I'll discuss this briefly. Then we can irradiate the tumour, the pituitary tumour, especially if it's a big one, we want to reduce the volume of the tumour, but today we have also some medication that potentially could be useful and act at the level of the purgatory gland. We will discuss about cabergoline and pasturide a bit.
But most commonly we are used to treat the PDH, so pendent hypercortisolism with an adrenal target medication and the classical one, the, the one, the medication that is registered in every country is Trilostine. Varil is the, the, the medication that we more commonly use. And now, but we potentially we could have other options like midotane, the laserdrine, ketoconazole, ketoconazole, I was just to mention is not a very good option.
And I will discuss this potential treatment option and we will see which are the, the positive and negative aspect of all these procedures. So, of course, . I would start with an adrenal target because this is what routinely we do in the most of the cases.
When we diagnose the PDH, I would say in the vast majority of cases we give trial things. In sometimes we could use and I'll tell you when I use miotaine, ketoconazole I wrote. Very small because we use very rarely.
What is Trilosan? Trilosan is a very nice medication because it's an inhibitor of an enzyme, the 3 be hydroxy steroid Derogenase, that is an enzyme that is necessary to, to obtain the production of cortisol and therefore, if we are Able to block the tributed drugs the steroid derogenase, we are able to reduce the production of of cortisol. Of course, I have to find the right dosage not to have an excess of suppression and so we have an adionian crisis, but also a dose that is not enough and So I am still a hyperco Islamic state.
About trials, I could talk for hours, we know that it's the most commonly treatment, the treatment the most commonly used. We know that as a peak of action after 1.5 to 4 hours after administration.
And the duration of the effect is about 18 hours. Of course, there is a difference from dog to dog, but usually is, this is the duration of effect and it is known that if I, we administer the medication with a meal, there is a better absorption. I told you that I could talk for hours.
For several years there was a big discussion if Trilosan it works better if administered once a day or twice daily. I tell you, I don't want to show you all the literature, but today more and more we are using Trilostine twice daily, and I think that if you look at this graph from this paper, it is. Clear why probably it's better twice daily.
Look, when I give a time 0 the trial stain, you see that the maximum effect is after 23 hours, 4 hours, but then after 12 hours, 18 hours, we have almost no effect. This is a study that was looking at the cortisol in several hours after trials and administration. Looking at this graph, to me it looks.
That this medication works better when we administer it twice daily. And so I tell you what I, I'm doing at the moment. This is what I do with my patient.
Usually I, I start when I diagnose Cushing's syndrome. I start 0.5 to 1 unit milligramme per kilogramme twice daily and .
Even if I have a dog that is, I would say 80 90 kg, my maximum starting dose is roughly 30 milligrammes twice daily. In the past we were using much higher dosages. But we had problems with Adizonian crisis and in my impression, but not only my impression, several endocrinologists impression that now that we are using lower dosages, it works better.
We are able to control the disease much, much better. We have to avoid the Adizonian Adizonian crisis and remember that To monitor the, our patient when we start a trialling those, we have to look at the clinical signs and the laboratory findings. Sometimes we have dogs where the clinical signs are totally in agreement with our laboratory findings.
I will tell you which other method that we are using to monitor our patients. Sometimes there is a disagreement between, between clinical signs and laboratory. Finding, for example, the dog is clinically very well, but the lab is not perfect, or the, the, the, the dog is still with clinical signs and the lab tells, no, everything is OK.
So remember that if we want to be a good clinician, we have to trust more the clinical sign. I personally give much importance to the clinical signs. But, what can we do to monitor our dogs, that we are treating with Trilosan?
Historically, the most commonly, most common method that was used to monitor ridostan was to do an ACTH stimulation test, so tetracosattide a measure before and one hour after ACTH tetrachoacide injection and . Not in every study was done at the same time point, but in most, most of the endocrinologists were in agreement that an ACTH 2 to 3 hours after administration of Triostan, so the moment of maximum effect of Triosan was a good moment to do the ACTH stimulation test. And in several textbook or or papers we can find this cut off between 1.4 and 5 mcg per deciliter.
You have also the value in nanomo per litre. This is a quite low value of post ACTH cortisol that was considered appropriate. The problem is, .
These results should be always analysed together with the clinical science because it has been demonstrated from several studies that we have, could have a discrepancy. So the ACTA stimulation test tells the, that the value is OK, but the dog is not doing fine or the opposite. So, There was a long discussion about is this matter a good one?
We don't know, we don't know. There it's, it's a weak method to monitor our patients. I can tell you that in the literature, several papers were published evaluating several different methods.
In monitoring, trials and most of them, they, and the, the, the conclusion was that this new method was not very appropriate. They measure urinary cortisol to prein ratio, acute phase proteins, ACTH to cortisol ratio. It's interesting this paper that was published by the group of Ian Ramsey from the Glasgow University, probably you are aware about the, the, this study because in this study, this group decided to measure cortisol pretrista, the so-called pre-pill, and they did also the ACTH stimulation test after 3 hours.
So in this study, they were measuring the basal cortisol, the serum cortisol before. For Trilosan administration and then after giving Trilosan after 3 and 4 hours, they do the, they did the ACTH stimulation test. It's interesting if you look at the statistic of this study that the best performance of these 3 parameters, the best correlation with the clinical parameters was not the post ACTH was not the Pre-SCTH but was the pre-pill cortisol concentration.
Therefore, today we know that we have also a range of the pre-pill cortisol concentration and today this is also a method that we use to monitor our patient looking very. Very well, the clinical signs and as laboratory finding the pre-pill. Unfortunately, also this method is not perfect.
We don't have, I tell you, we don't have a perfect laboratory method to monitor our patient and I show you two papers. This, this study was done by Carolia Reyna together with, together with several other authors and last author is Edward Feldman, and they tried to, to evaluate several methods to, to, to define which is the best one to, to assess or define if the dog is well controlled with or not well controlled with Cushing's syndrome and that they did also a certain cortisol curve and I tell you only the, the conclusion. Of this study, they evaluated several laboratory methods to decide if the dog was well controlled or not, and they, they conclude that no single variable of, or groups of variable was good to discriminate dogs that were well controlled from dogs that were not well controlled in in dogs treated with rilostein for PDH.
And I show you also a, a similar study that we did in Bologna together with other colleagues, where we evaluated. In 44 client owner dogs with PDH and 94 reevaluation, 12 different potential monitoring methods. So in every dog, every dog received a clinical score to the look at the by a specialist to define if the dog was well controlled or not well controlled, and we evaluate a lot of parameters.
Use urinary cortisol operating ratio, ALT alkaline phosphatase, opttolobin. Prepe cortisol, prepure cortisol correlated with ACTH post ACTH, a lot of parameters, and I tell you that the results, we were comparing, trying to find a better parameter and something that tells us, yes, this dog is well controlled or not. I tell you that in 3 parameters, we had a, a bit better performance.
So dogs well controlled, they have A lower ALT, lower GGT, and lower optoglobin concentration, but the overlap between well-controlled and not well controlled dogs were pretty big. So at the moment, I tell you, we don't have a perfect method to monitor our dogs with Cushing's syndrome. So usually, we give a big importance to the clinical signs or if the, so if the dog is not eating well, has vomiting, gastrointestinal signs problem.
Is an overdose. If the dog has still polyure and polydipsia, weakness, and clinical signs of Cushing's syndrome, pro probably it's not well controlled. Of course, we can look at the poster CTH cortisol or the pre-prito cortisol just to have an idea, but remember that the clinical signs are the most important.
And we have to be aware that even if today we are using lower dosages of Tris then so we have less probability to induce an Adizonian crisis. Sometimes you can have an Addisonian crisis. So, as soon as it happens, we have to discontinue the treatment to check the electrolyte.
It's very useful to do an ACTA stimulation test to be sure that it's an Adizonian crisis, so the dog is vomiting. We have to be sure that this vomiting is related to an Adizonian crisis and not something else. And in severe cases, we can give fluid therapy to to treat this Adizonian rogenic adizonian crisis and supplementation of glucocorticoids, sometimes also mineral or corticoids.
And what about Trilos and Trilozan is a very effective medication. Look at this dog. This was a dog with all the clinical signs of Cushing's syndrome, so POPD bad hair coat, and also this dog had a severe calcinosis cooties at this level, and the response to the treatment after 4 months was really great and this is the dog 8 months, after 8 months.
Of treatment. Fortunately, in the majority of cases, this is what we observe. So a good response, this is a medication that works really well, especially if you are using it twice daily and using the low dosages that today we recommend it's very, very good.
Unfortunately, it doesn't work in every animal and there are some Dogs where you start with Trilotan, you increase the dose, you increase the dose, and the, the medication is not working. And this is an example of the in this dog, this was a classical example of a dog that we were increasing, increasing, increasing the dog of ridostan administered twice daily, but it was not a good response. We see that hair coat, but this dog had PUPD had Polyphagia.
In this case, usually what I like to do is to not to increase and continue to increase the dose but change. In these cases, I use the mitotane. So in these cases where I have 1010 to 10, 15% with a better response, I use miota and this was the response to the dog.
The dog was responding very, very well to the mitota. And so what about Migoten? Today we talk much less about igotten because we have a medication that is just the for Cushing's syndrome.
But still, this is a very, I think it's a very useful medication, especially in my opinion, and this doctor that are not. Responding well to trials. It's a, a more aggressive medication because this produces a, a necrosis of a zona fasciulata and reticular arteries of the adrenals.
So it's also a medication that works at an adrenal with an adrenal target. It's needs to be used very carefully because it's more possible to produce probable to produce an electrogenicadisonian crisis. So we have to carefully instruct the owner.
Usually the most commonly used protocol, it's, has an initial phase, it's a so-called induction phase where we give the medication 50 milligrammes per kilo. Per day in administration, given the meal and every day we check that we don't have clinical signs of Aizone. So we have to check that the dog is eating well, it's not vomiting, has no depression, the water intake is high, and as soon as the dog is showing any clinical signs potentially consistent with Edison, usually this occurs in most of the cases after 8 to 10 days.
Sometimes it's less, sometimes it's much more. Probably this induction phase is completed. In this case, usually we perform an SCTH stimulation test and if the cortisol is low, so a post ACTH below between 1 and 4 mcg per litre, usually we go on with the maintenance phase that consists in giving the dose, the amount of Medication that we, we're giving every day we give during a week.
So for example, Monday, Wednesday, and Friday, 150 milligrammes per kilo in total in the week. This allowed to maintain the normal Islamic state. In my opinion, if you, we, we use well this medication, it works very well and personally I use only in these cases where Trilostan is not working properly.
But now I want to show you this case because I want to talk about which is the bad aspect in treating in, in concentrating our attention only on cortisol concentration. I show you Sophia. Sophia is a Labrador retriever female spade and 9 years old.
With the diagnosis of Cushing's syndrome in October 2018, the doc was showing polyure polydipsia, polyphagia, all the clinical signs of Cushing's syndrome. I don't show you the blood work and endocrine test, but trust me, they were all positive and this owner was very motivated, did also a CT to look at the predatory gland and this It was a pituitary gland that you can see with the the two green arrows that was not huge but also not very, very small. OK.
Here the the decision was to start with trilostan and and the trilostan was administered twice daily. The dog was doing very well. PUPD was gone.
The, all the clinical signs were the Polyphagia was reduced and the dog was doing fine in the initially. But in September 2019, so a few months later, the dog was showing depression. The, the veterinarian that was managed was managing this dog was reducing the trials in dose because the dog also started having vomiting, asthmia, tremors, and weight loss.
So if you have a dog that is receiving a medication that is reducing the cortisol concentrations, the risk is to induce an Adisonian crisis. So the first suspicion is that the triosine dose it's too much. So immediately we did an ACTH stimulation test and the basal cortisol was 13 and the post ACTH was 15.
So, if you remember, I gave you the range that the post ACTH should be between 1 and 5 roughly micrograms per deciliter. So, look, this was not a cortisol that was too low. So what does it mean?
It means that That these clinical signs are not due to low cortisol, they are due to something else. And you know what is the something else? This was the CT of this dog in October 2018 and now I show you the CT of the dog.
Yeah, in 2019, you see that the, the, the adenoma now is huge. The, the structure is very irregular. So the, the problem of this dog was the growth of the tumour and this is a problem when we decide just to consider an adrenal target treatment.
We don't know if, the treatment with Trilostan is inducing the growth of the tumour. We have no evidence of it. But in healthy dogs, so this is a Japanese dog where in healthy dog they were giving very high dosages of Trilotan.
In, in healthy dogs, the, the trilotan was able to increase the volume of Of the, of the predatory gland and also increase the concentration of ACTH. These are some MRI where there can be a growth. We don't know if it's the case in dog with predatory tumour, we don't know, but what is important, this is probably the most important slide of my lecture.
Look. These are 6 CT images of 6 dogs with PDH. This you can understand that this is a completely different condition.
So, here you have a, a dog with a very small nodule, not visible at all. Here a medium size here. Also here a bit large.
Here it's a huge till the very enlarged pigatory tumour. So the most common mistake that I see in practitioner that are managing Cushing's syndrome is this. Consider Cushing's syndrome as a disease connected with hypercortisolism.
It's the problem of cortisol. It's not appropriate to define Cushing's syndrome as a problem of cortisol. It's a problem of cortisol excess due to a predatory tumour in the predatory form or an adrenal tumour in an adrenal form.
We know, for example, that for an adrenal form, it's much better to remove surgically the adrenal tumour instead of blocking the production of cortisol. And so more. And more, we should think about what is happening in the pituary gland and, and try to focus our attention on the pituitary level also.
So I tell you, in every patient, when I diagnose PDH, I strongly recommend a CT or MRI because we have to understand and know what happened in the pituary gland. I'll give you an example. In a dog like this, like this finger here, I, the, the tumour is very small.
I concentrate, I put all the effort to regulate, to decrease the corticosol concentration. In this case, I try to do my best in decreasing cortisol concentration. And this could be the case also in this case.
But I will show you that for some cases like this and this, we can have also the other treatment options. For example, hypophysectomy. It's not available everywhere, but some, in some places today, it's possible.
And if I have a huge tumour like this or like this, I would propose radiotherapy when feasible. Surgery maybe is not. Yeah, but if an owner has a low budget and the tumour is like this, probably I would say we don't treat the animal, we leave the animal, we don't try to understand why this dog is so sick, and but at least we know what it is.
So I am a strong supporter of CT or MRI for every dog with predatory form. But let's talk now. Can we do something for a pitter tumour?
Is, is it feasible, this ppiratory target therapy, which are the options, pituitary surgery. pituitary surgery is the first option in people with, with Cushing with PDH. Another option is radiotherapy and today we have potentially also some medication that they could have some effects.
This is a, a, a picture of Harry William Cushing 1932. It was a neurosurgeon and, and, by the way, he did his first experiment, in dogs and, and this is Bjormey. Bjormey is a surgeon from the Utrecht University that was the first that started, doing it, I would say routinely it.
The procedure and, and is also very active at the moment in doing this procedure and also spreading the knowledge and, and, and teaching other surgeons doing this procedure. In the, the surgery is a transfedoidal hypophysectomy, so, we, in, in veterinary medicine usually is a full removal. Of the hypothesis.
In humans, they are able to do an adeno adeno adenectomy, so remove only the tumour. In, in, in veterinary medicine today, we are unable to remove only the tumour. We remove the whole hypothesis and here I show you how the, the dog is usually placed is they enter through the mouth and here is the How the, the, the dog is prepared and in this anatomical picture you see from this error, right here where the surgeon did produce a small hole here to enter in the in the ella Turchica is this one where the hypothesis is also in this picture you see, this is the hypothesis.
And the, the, the, usually the, the surgeon enters from this bone, the vasoshenoid bone, and remove the pituitary gland at this level. So, usually the soft palate is cutted at this level, till, the, the spinoidal bone is observed. Then, of course.
The surgeon at several, is looking at a CT for, for, to orientate himself and then he's producing a very small hole and the tumour is removed in small pieces. Here you see that for sort of equation of the tumour and then the hole is . I closed with this synthetic bone and, and then there is a closer in this, in this way.
The, the, the, the, the tumour is removed. This is an example of a big tumour pre-hypophysectomy, and this is the same dog, 8 months in dog with CT 8 months after hypophysectomy. Since we do a full hypophysectomy, we are removing also very important hormones, so we need to do a substitutive treatment.
So usually these animals as, soon after surgery, they receive levothyroxine, 10 to 15 mcg per kilogramme orally, twice daily. Cortisone acetate because before there was an excess of ACTH production, but now we removed all the ACTH production, so we have to give cortisone acetate. They don't need minerallo corticoids because ACTH is not controlling the mineral corticoids and vasopressin.
Usually desmopressin is administered because during this kind of surgery, frequently there is a damage in the hypothalamus and in the release of ADH. Not in every dog is permanent, the, the Desmopressin administration, but in most, it's, it's permanent. And here I want to show you some examples.
This procedure, for example, hypophysectomy now since about 10 years, we do it, I wouldn't say routinely, but 2 times per month also here where I work at the University of Bologna. And I show you which is an appropriate animal for pituitary surgery and which is not an appropriate candidate for surgery. For example, this is a Dutch.
So male, 7 years old, has an ACTH secreting adenoma, no neurological signs, but all the clinical signs of Cushing. This dog was a dog that was not responding well to treatment, and the owner decided to go for pituitary surgery. And this, I, I show you because this is a very good candidate because the tumour is not very big, the, the dog is.
Not too old. And I show you the, the, the dog less than 24 hours after, after surgery, usually they are fine. This is, the dog, just, 2020 hours after surgery, they start eating immediately.
They are doing really well. And, and, we removed what is very nice. This dog had a brain.
Tumour and we are able to remove the brain tumour. And usually when they, they, they, they, the, the surgery is successful, they are doing very well. This is the dog that we did surgery in 2015 and this is February 2023.
Now he's an old dog and and is still doing very, very well without this tumour. And, but We have to be careful in the selection of the patients. Where I work in Bologna, initially we were select, we were trying to operate also dogs where surgery was probably not ideal.
For example, this one, this is a mixer breed dog, 9 years older. Non-seting pituitary macrodeoma and this dog had already frozen cephalic neurological sites and you can see that this is a really bad tumour, very big, very irregular in the shape. So today, I wouldn't propose that the surgery in this dog because the prognosis with this kind of tumours is very For and you can see the dog, two days after surgery that the, the, the, the, is doing not well, is, it's very neurologic.
And this dog, unfortunately, after one week of hospitalisation, we had to do, the, the, we have to put to sleep. But because of the neurological deterioration. So which are the ideal patients for pituitary surgery?
Dogs without neurological signs for macronoma, pituitary mass has a regular shape on CT or MRI. The pituitary height is not greater than 1 1.5 centimetre.
There is absence of severe comorbidities and brachycephalic dogs are not ideal. We can operate brachycephalic dog, but it's not ideal. And I tell you, I like very much this kind of approach of this pedatory surgery and, and, usually, it's very, very successful.
I know that in the UK you have centres for sure the RBC that where this kind of surgery is, is done. What can we do at the pituitary level? What, what, which Other option do we have at a level?
So, radiotherapy, yes, for sure. The radiotherapy, is, we know that, is able to reduce the volume, usually, usually is able to reduce the volume of the pituitary gland. Usually we, we all, we go for this treatment option when we have big pigatory tumours, usually when there is various.
So we don't use the radiation treatment and, usually when we, we go for pituitary radiation, we have to go on with the Trilostine administration if this is hormonally producting tumour because we usually we are not able to block the ACTH production. I'm not an expert of of radiotherapy, so please don't ask me specific question of radiotherapy, but, everyone can understand this couplenmeyer curve and see that treated dogs are doing much more better than untreated dogs. And so this option, especially with the large predatory tumours, it's a very good idea.
There are different protocols, with different fractions and. But, and so, my advice is always to ask a specialist to to understand which is the best protocol to use for radi radiation, but, in most of the dock, we have an improvement, a decrease in the volume. Of the pigatory tumour and sometimes also just the reduction of the edoema that is around the pigatory gland is improving the, the, the, the, the neurological signs of this animal markedly.
And there are several studies, for example, in this one. It was observed that non-functional pituitary tumour, they have a better prognosis compared to PDH but still in PDH treated with radiotherapy, a pretty long survival, survival time. But I imagine that we have no possibly no access to hypophysectomy or radiotherapy is not the ideal or it's too expensive.
The big question is, do we have medications that we can use the at the pituitary levels, so something that blocks the ACTH production or ideally reduce the, the growth of the pigatory tumour. We know that the pigatory cells, they have several somatostatin receptors. The somatos routine receptors are 5, and we know that there are some, some medication that are working in, in only a few receptors for.
For example, oxreotide is working at a somatostatin receptor too. We have some other medication like Payottide that is working on somatostatin receptor 13 and 5 and so potentially this medication could be effective in reducing the ACTH production. So, the group of Utrech did, some, work on looking at the which are the receptor expressed by the predatory neoplastic predatory cells and, from this, in vitro study, it was observed that the expression and role of dopamine 2 receptor and so.
To stat in receptor in corticotropic pigatory adenoma was the most predominant form. And so this is something different compared to humans and from this study, it was concluded that probably ocreide is a good option. But we don't have many studies in vivo about ocreotide in dogs, but we have something about Other, medication.
For example, there is a paper published in Argentina, where 63 dogs with PDH were treated, some of them, 23 with ketoconazole. It was a counter group, so a target, an adrenal target medication and 4 were treated with Cabergoline. Cabergoline.
It's a dopamine agonist that it's, it's a medication that is used in, in humans, mainly for the, to treat the prolactinoma, but also for Cushing's syndrome, for PDH in people where surgery is not feasible or surgery failed. And, and in this study, Decided to try the Cabergoline in dogs and they observed that in 42% of dogs with PDH they respond well to Cabergoline. The only side effect was vomiting, but only after the the first administration or the first few administration of the gargolin.
And in this study, they looked at several parameters. For example, survival times of dog with Cabergoli was longer and they also look at the dimension of the pitary gland in this study, an MRI was done before and after Cabergoline treatment, and they showed that in most of the dogs that There was a decrease in the in the predatory volume after cabergoline treatment and also the ACTH concentration was low, lower and in in ketoconazole there was not this decrease. So they concluded that cabergoline is a potential treatment option.
. Another, another medication that could be interesting is Pairotide. Probably you are aware about the study on acromegalic cats, done with Payrootide. The, the Royal Veterinary College work a lot on it, but potentially.
Also Paroide could be helpful also for PDH, and there is this study published in JA where they treated nine client owner dogs with PDH and macrodeoma, and they dig in the pairottide Payottide, at the, the short acting at the 0.03 milligrammes per kilo subcutaneously every 12 hours, and these dogs were treated for 6 months. And the conclusion is that after 6 months of treatment, 66 dogs had decrease in MRI measured values of the pituiatric gland and in 3, there was an increase in the pitutric gland.
So when we see an adenoma, we expected that there is an increase in the volume over time and in this study, they were observing that giving Payrotide in, in some dogs, there was a decrease in the volume, not a huge decrease because look, these are the 9 cases and I show you the, the height was 25 millimetre, before, before treatment and after 6 months, was 21 or. In this talk was 7.8 and was 6.8, 18 and 17, so not a big difference, but at least was not a clear growth in the tumour.
So this is promising. The problem with Payroide is that this is an extremely expensive medication though, so this treatment is not feasible. But Cabergoline, going back to Cabergoline, Cabergoline is not such an expensive medication.
So, a few years ago, we had an idea, why don't we try to combine a medication that works at the level of the adrenal glands so and a very effective medication like Tridostan, and why not to try. To combine it with a medication that works in the pit, at the pituitary level and maybe is able not to, to block the growth of the tumour. So we are, we did this study that was presented last year in the, the AI Congress in Barcelona and this was a multi-centric study.
We treat the dogs with 0.5 milligrammes per kilogramme twice daily of Trilotine and Cabergoline 23 mcg per kilogramme every 2048 hours. The dosage of Cabergoline is a dosage that is higher compared to the dosage that we normally use for the pseudo pregnancy.
This is a 12-month study, so it means that every dog was receiving a CT at the time of admission and a CT 12 months after treatment. I don't show you all the results, we, we hope to publish this study sooner. But the preliminary results are not too bad.
In about 1/3 of dogs treat where Cabergoline was used, 1/3 is not a lot, but also not nothing. There was a mild decrease in the pituary size. In some dogs, there was no effect of cabergoline, probably because they don't have the receptor, but in 1/3, we observed a decrease in the pig size.
And this is an example of the dog that received trial. And Cabergoling together, and you see that dimension of the pituy gland and this was after one year of treatment and you see that there was not a growth and here also a decrease in volume of the pituitary gland. I decided to show you this data because we presented this data at a conference last year.
I, I, I'm not, I don't feel comfortable at the moment to tell treat all your dog with a combination of cabergoline trasan. We need to, to, to evaluate the full data of the staff. To publish it.
I would love to see other studies on this, on this topic, but I like the idea of doing something at the piety level. So the idea in this study was to use a very effective drug for Cushing's syndrome that is trying to stand with something that is not increasing the volume at the predatory, at the predatory level. So, finally, what should we do?
An adrenal target treatment or re repeatatory target treatment? Well, in the, in the future, also looking what what what is happening in human medicine, probably more and more we will search a prey target. And if I tell you I like very much the pituy surgery or maybe in the future some medication that will be really effective against the tumour at the pituator level.
So, in general, I like more the predatory target, but the adrenal target today, I have to admit works better. But if you decide to go for an adrenal target, that is fine. Most of my dog, I would say 90% of my dogs are receiving adrenal target treatment, so I would say Trilosan.
But please remember that the dog has a PDH, epidary adenoma, and it's extremely important to know what is going on at a pedia level to decide which is the best speed treatment option. So Trilosan mioten when the tumour is a bit bigger surgery and when a huge macroadenoma, it's a nonsense in my opinion to start Trilostine. If you treat a dog with macroadenoma with trilostan, if the appetite is not very good, the appetite disappears.
So be careful and do the predatory imaging all the time. This, I think was my last slide. I want to mention that every 2 years, the Society of, the European Society with Endocrinology is organising a summer school in Bologna, where I work in June this year.
We have still few places available and, yeah, that's it. If you have any question, I'm, I'm happy to answer. Thank you so much.
That was absolutely excellent. And we do have a few questions, so I will ask those now. Er Henrietta's saying try the stain sealing for starting dose.
Is there some sort of allometric effect? What do you mean, can you repeat the question? Yeah, what is the, how high can you go with your starting dose of Trilesta?
This was from Henrietta. So I don't know if I understand well the question. I, I suspect what she means is, that.
I mean, the starting dose is the normal dose that the data sheet says, isn't it? But I said no, no, no, it's not, it's not. The problem is that, you know, the people that are selling medication have to do a lot of research when they are registering the product.
The problem is that that the productrylostein was registered more than 10 years ago and now on the literature we have more than 100 papers published after that. So, my advice is always to look a bit at studies. For example, the company, the company proposed as a starting dose 2 milligrammes per kilogramme once daily.
In my opinion and in the opinion of many people, this is not the ideal starting, dose. We, there is a, I would say an agreement that a lower dose given twice daily, it's better. This derives from Many, many studies that were produced after the registration of the medication.
Yeah. So you would give a lower dose than 2 milligrammes, but give it twice a day. I, I, I, I start my starting dose is 0.5 to 1 milligramme per kilogramme twice daily.
And in the and in large breed dogs, I go for 0.5, so the lower in large breed dogs, yeah. Brilliant.
Katerina is asking what's the dose protocol for Cabergoline? Yeah, we don't know which is the perfect one. We decided to give 23 mcg per kilogramme every 2 every 48 hours.
This was extrapolated from the study of Castillo, the one that I showed you where the carbergoline was used in monotherapy, but I don't know if it's the right one. And you know, in humans. Because this medication is used also in humans.
In humans, they also increase the dose if it's not working. In veterinary medicine, we don't know really well when if we should increase the dose. So I, I, I, I, we had to find a dosage but be careful, we need further study to define the dosage of these kind of medications.
So it, it's as you were saying, you're waiting for more data to be able to really give absolute sort of instruction on that. Exactly, exactly, until now we have only a few studies. Of course, better than nothing because better than nothing, but I cannot recommend you this is the right dosage.
Yeah. It's, it's at the moment it's trying it maybe a bit of trial and error. Exactly.
Yeah, . When it's needed to increase the trialistta dose, Federico, how do you, increase that? Is that sort of 10% increase, 25%, 50%?
Yeah, we know that, Trilosan is in capsules, and this is, the problem is that we have 5, 10, and 30 milligramme capsules. So also this is, something, you know, ideally we say we would increase or decrease the increase. Those between 10 and 15% and 20%.
But often when you are giving, I would say 10 milligrammes twice daily, we go for 15 because it's very convenient to have the 10 milligramme capsule with the 51. So it depends, it depends. And also on the size of the capsule.
So give it from 5 twice daily usually I give 7.5, but in these cases, I have to ask the pharmacy to rebuild the capsule. Then 10 milligrammes twice daily, from 10 milligrammes twice daily, 15 milligramme twice daily, 20.
This is So it's playing around with the tablets that you have available unless you are gonna compound. Yeah, they, they are not tablets, they are capsules yeah yeah yeah yeah. And you can, can you take them out of the capsule and sprinkle on, or no, absolutely not.
Yeah, OK, so it's, it's going and having a compound or if you wanted to get a more. Great, OK. .
Let me see if some more questions have come through. We had a few people tell us where they were listening from, Federico, just while we're seeing if any more questions come up. Caroline is listening in from Chile, Lisa from North Wales, Gemma from Essex, Jennifer from Grand Island, Nebraska in USA, Suzanne from Melbourne.
Jimena from Chile as well. Now, let me just see, Cambria from Seattle, Craig from Cambridge in the UK, Denise from London, Twickenham, Trinidad. Pietermaritzburg in South Africa, Sweden.
Manhattan, Kansas, not in New York, Susanna in Slovakia. Henrietta in in Northern Ireland, Tina in Prague, and Ashley in Canada. And I just thought, we've got Charlene in Toronto, Edith from Camden.
Aryan from Canada. Anna is in Texas, so, Ireland, Lindy, Elizabeth, Oregon. Yanni from New Mexico, it's nice to see, so many people putting in where they're listening in from.
And, oh, Cathy from Tallahassee in Florida, so I think it'll be a bit warmer there than than with us Federico. So, yeah, what I wanted to do cos it was the last day and people had put their name in, was actually to offer a membership to somebody who'd who'd taken an action and put their name in, so I'm going to, Give a free membership to Janni in er New Mexico, so Dawn can er take some details and we'll sort out a membership for you as a gift at the end of the virtual congress and for you actually putting in where you were listening in from. So taking action.
Thanks so much for that Janni. Let's see if we've got any more questions coming up. I think a few more have .
I've turned up. Yeah, Ali's saying, could you please tell how much time does it need before you start seeing a response from Cabergoline in your experience? Ah, well, .
The point is that in, in the study that we did it was a combination of trilocine and Cabergoline. So the problem is that we were not seeing effects of Cabergoline. We were just measuring the predatory size with CT.
So the clinical signs, I think we were they. Disappearing because of the trials and the PUPD or the clinical signs connected with Cushing. In this study, so, the problem with Cabergoline that if, especially if you use a combined as a combined therapy, you don't have clinical signs to observe and And I've seen that there is a question, how you monitor the carbergoline.
This is a very important and relevant question because theoretically, the ACTH concentrations, since, since this is a medication that works at the editary level, I expect that ACTH decreases the The problem is that Trilostan is increasing the ACTH. So who is winning the Trilosan that is increasing the ACTH or the catergoline that is decreasing? This, I don't have this answer yet.
I don't have this answer. So one of the problem is the monitoring of this medication, yeah. Tina is asking, can you use cortisol creatinine ratios to monitor treatment?
No, there are, I would say 3 papers. The first was done at the University of Utrecht where they try to monitor dogs with a cortisol to create in ratio and was not successful. Another one, another 2, other two papers, and none of the papers were observing a good correlation between the clinical response and the urinary cortic to breathing ratio.
In humans, they use it. In humans, they use it. In dogs, it seems it doesn't work.
So, no. OK, that's great. We were talking this afternoon about potentially doing pre-pill cortisol, as a way of checking the dosage after trial of stay.
What, what are your thoughts on pre-pill cortisol instead of ACTs? It's it's something that can be done. I also did the, I, I also use it time to time.
It's not a perfect one. The problem, because the, the bigger, the, the, the message that we can. We need to obtain from a cortisol is to, are we have, are we, we have to avoid at the Adizonian crisis and so we don't know exactly if the post-SCDH or the pre-cortisol or pre-pill cortisol are appropriate method to tell us, be careful because this dog is developing an Adizonian crisis.
Potentially yes, but they are not perfect. They are not perfect. Both the post ACTH and the cortisol.
I, I, I like to measure both of them pre the pre-peel cortisol and ACTA post ACTH but I don't trust them too much, so I like to look at the clinical picture and of course, if I have also a good cortisol pre-pe or post CDH that are OK, I feel better, I feel better, but but I don't trust the numbers too much in this disease. Yeah, yeah, I think it's a really valid point, you know, it's looking at the animal in front of you. We can end up being too caught up with the, the, the lab results and not actually spending time looking at the dog in front of us.
Exactly, exactly. That's the most important thing. So the, the most important question to me when I see a dog on treatment, how is the appetite?
Is my favourite question because low cortisol determines. Low appetite, anorexia, a dog that is not well controlled is severely polyphagia, polyphagic. So the appetite to me is really, really important.
Yeah, brilliant. Henriette is saying thank you for summarising these demanding treatments. So yeah, thank you for that.
Can we use the pre-pill that we've answered that question as well? Oh, if the pet also has diabetes, so that just complicates it even more, doesn't it? Yes, of course, but it's not so rare.
We know that roughly 20% of dogs with, with Cushing's syndrome, they have also diabetes. What is really important is in this patient to give ridostine twice daily because the once daily is not covering the cortisol where in the 24 hours and we know that cortisol is creating problems with the insulin resistance. So it's important to get to treat them twice daily.
And usually we treat them, we know that there is a, a certain amount of insulin resistance. Usually, we need a bit higher dosages. Of insulin, but the monitoring method of this dog regarding the Cushing's syndrome and regarding diabetes is the same.
We try, usually in these animals, I try to put a freestyle Libre because I like the continuous glucose monitoring and, and I, I give trilostine twice daily and I use exactly the same monitoring method. We know that it's more complicated but but feasible. Fantastic, thank you, Federico.
Well, I think we will draw those questions to a close. Thank you so much, Federico for, for coming on, all the way from Bologna. It's been fascinating and and fantastic to have you on the webinar.
The penultimate speaker at this year's virtual congress, so thank you so much for agreeing, especially on a Friday evening where we. Could be doing better things like having a nice glass of wine in a restaurant or whatever, so I really appreciate it, Federico. It has been a pleasure and, and I'm so enthusiastic knowing that from all over the world are listening, so I'm very proud and thank you for giving me this opportunity.
Thank you so much, Federico. We are moving on to our next lecture, which is recorded so that we won't be able to answer questions, after this. But We are gonna be talking about the incidental adrenal mass.
Welcome to this lecture on the incidental adrenal mass. My name's Fiona Adam. I'm a medicine specialist.
I work at North Down's Specialist Referrals. And thank you very much to the webinar vet for asking me to talk to you today. So the first thing to address is probably the fact that the term incidental is not agreed upon.
It's a debated term. I am, so, generally speaking, one could classify anything that's incidental as perhaps something that wasn't entirely expected. I am but if we are, for example, I'm imaging a dog with non neoplasia, screening it for metastatic disease, and we find .
A mass in the adrenal gland. Is that incidental or or is it really found as a consequence of screening this dog for metastatic disease? So some of the literature will discount, any patient who has known malignancy because they would argue that the presence of a mass in a patient who is being screened for further malignancies and cannot be considered an incidental finding.
Important also to recognise that an adrenal mass is not incidental in a patient who has clinical signs, and who can be which can be attributed to the adrenal mass, but that depends on us asking the right questions, examining the patient carefully, and being cognizant that our patients can't talk. So some forms of endocrinologically active adrenal masses may not yield clinical signs that are particularly easy for us to recognise. So for example, if our patient is hypertensive, I'm, they're not going to tell us that they're hypertensive and they can't tell us that they're having headaches, for example, we have to go looking for the hypertension.
So the definition of an incidental adrenal mass is somewhat messy. I think if we go by, it's an unexpected finding, it is about as as. Kind of broad as I think perhaps might be appropriate for us to be.
Even the definition of what constitutes an adrenal mass in terms of what it looks like is debated. So some literature in cats and dogs will talk about a specific size. Some will talk about that any size is fine, but it is deforming the adrenal gland contour.
So it's all a little bit messy. Detection of an incidental adrenal mass by imaging could be achieved by many types of imaging potentially. Important to recognise, however, that some imaging modalities have much better sensitivity for detection of adrenal masses than others.
So for example, here's a radiograph of a geriatric dog referred for PUPD and abdominal distention. We can see that the dog has, generalised hepatomegaly, which is causing displacement of the stomach. But there's also some wispy mineralization in the mid dorsal abdomen below L1, L2, and that wispy mineralization is the only clue that we have that this dog, in fact, has a 4 centimetre adrenal mass.
So adrenal masses have to be very large or mineralized to have a clue that they're present radiographically. And so detection of adrenal masses radiographically is is really low. And with the advent of ultrasound and then later CT we have a much higher detection rate of adrenal masses, and also with improved technology and capabilities, and we detect far more adrenal masses than we ever used to.
It's well acknowledged that CT is a more sensitive modality for detection of adrenal masses than ultrasound. It will detect smaller lesions. So what do we know about prevalence?
So in humans, the prevalence unsurprisingly increases. I'm in an ageing population. I'm so around 3% in middle aged adults and, and that increases to 10% in a geriatric population.
In dogs, there's not a huge amount of literature. These are the two largest studies that I'm aware of. One is an ultrasound-based study, and the second is a CT-based study.
The prevalence of incidental adrenal masses in the CT-based study was a bit higher, and that would fit in with our, knowledge that CT is a more sensitive modality for detection of adrenal masses. These studies detected that incidental adrenal masses were more common in larger dogs and more common in older dogs, . So the age being not particularly surprising feature.
Detection of an adrenal mass during imaging can be a serendipitous discovery. So you've discovered something that was going to cause the patient some problems, and it was an important finding. However, there's definitely the potential for these type of findings causing lots of clinical noise.
So these findings lead us to have as many questions as we have provided answers. In the human field, I think there's a term for this called vomit, which is called victim of modern imaging technology. And so detection of something which may have, essentially no clinical bearing to the patient, but detection of this finding leads to consideration of lots of further testing, be that imaging, be that endocrine, etc.
Etc. And it's a potential problem for us. The, the more we, find, the more we have to work out whether or not this finding warrants, further investigation or not.
It can be disadvantageous to the patient, and to the client's wallet. I am pursuing lots of testing, for what is an incidental and potentially unimportant finding. So we have to be in a position where we can make some educated decisions as to what the likely nature of this finding would be and how important it is to proceed with investigations and how targeted those investigations perhaps should be for the individual patient.
From a practical standpoint for our patients, what we want to do is to work out whether the adrenal mass that we have detected is of consequence to the patient or not. We want to identify the bad guys, so to speak, and perhaps those bad guys need to have, consideration given to surgical removal or perhaps might need medication to help the patient deal with the consequences of a functional adrenal mass which has been discovered incidentally. But because of the potential risks of surgery, we would choose not to, pursue adrenalectomy in every, incidentally detected adrenal mass.
The mortality rate of adrenalectomy is around 22% in the literature, so it's not insignificant. So 1 in 5 patients may be expected to die as a consequence of adrenalectomy. So it's not a procedure that we would wish to pursue unless we had a good indication to do so.
So one important question for us when faced with an adrenal mass is how likely is it to be a bad guy. So, what is the rate of these masses being malignant, and what is the rate of them being functional? So how many of these cases do we expect to be considering adrenalectomy, a medication, etc.
In humans, unsurprisingly, and the data is well known. So in humans, adrenal masses are typically benign. So I am in a non-cancer bearing population, so a population where we're not worried about metastatic disease, 90% of them are benign.
And the vast majority are non-functional. OK, so in humans, benign and non-functional masses are the typical when an incidental adrenal mass is detected. What is the situation in dogs?
I'm sure you're probably not going to be surprised to, hear that our knowledge base is not as good as in the human medical field, but I'll show you what there is. So this is a very large postmortem study performed over 20 years from UC Davis. I am, and these looked at adrenal glands, of cats and dogs that were in the crop seed for every reason under the sun, essentially.
So in this population, basically, I am around 1/3 of adrenal lesions were derived from the adrenal cortex, be that benign or malignant. I am around 1/3 were functional masses from the adrenal medulla, so it's a fail chromocytoma. And around 1/3 were metastatic processes.
As we mentioned, the adrenal gland is quite an important metastatic site in humans, it's the 4th most important after liver, lung, and bone. And in humans, it's estimated that 75% of adrenal masses in a known cancer bearing patient will be metastatic. So really important consideration in a patient with known neoplasia.
The difficulty is, this is a postmortem study, OK, so the phaal chromocytoma group, we don't know their functional. Functionality is based on clinical science and endocrine testing. We're just telling, we just know that their tumours derived from the adrenal medulla.
The other important factor is that this study looks at lesions which are either grossly apparent, but also just microscopically apparent. Now, we would not detect them by CT or ultrasound if they're just microscopically apparent, obviously. What do they mean for our patient?
We don't really know. Of this study, only less than half of the lesions which they've reported upon there were grossly evident. And there's no figures for just the grossly evident tumours, so I can't tell you, the percentage of macroscopically evident masses, which were, derived from the adrenal cortex, drive from the adrenal medula or metastatic, for example.
So it's a useful piece of information, but it doesn't answer all of our questions by any means. This is another, very recent study that was presented at ACMM as an abstract in 2023. Unfortunately, it's not been published as a paper yet, so I there's lots of bits and bobs missing with questions that I have that I can't answer for you.
So there's about 50 dogs in here, and they define the adrenal mass as unexpectedly found, but they don't really define the population, whether or not these patients, . Had to be excluded, like they couldn't have an underlying neoplastic process elsewhere, potentially. So whether this was a group who would consider that an incidental adrenal mass is absolutely not possible in a tumour bearing individual.
I don't know. So basically in this population, they found that around half of the incidentally detected adrenal masses they found were phao chromocytomas, so functional masses derived from the adrenal medulla. And more or less the other half were adrenocortical lesions.
That's what they found. Some of the adrenal masses were defined following resection and histopathology, and some were defined on functional endocrine testing, so not all of the dogs went on to have adrenalectomy. But in this population of dogs, basically 50% of the masses were adrenocortical and more or less 50% were adrenal medullary.
So again, it doesn't answer all of the questions, but it's helpful information for us. For us as vets to have a really good handle on the prevalence of benign versus malignant and functional versus non-functional lesions, we'd have to have large population studies. And so the ideal scenario, would be that All the dogs with, adrenal masses detected, had functionality testing, and then they all had, either surgical resection or postmortem, when their death eventually occurred.
And of course it's it's not likely to happen. I am. Either in isolation, so either just considering postmortem studies doesn't provide us information about functionality, or if you just consider in studies which are presenting histopathological data from adrenalectomy, that's probably not representative of the whole population, because animals that go forward for adrenalectomy are probably more likely those with large masses, with functional masses, and probably dogs that are younger, because understandably, people are more, Progressive with undertaking quite a significant surgery in a younger, healthier patient, and we know these lesions are most common in older patients, geriatric humans, older dogs, etc.
So we don't know, and we have to join the dots with the data that we have. My best guess is from what's out there, and I'm afraid they are educated guesses because we don't have large population studies on this. I am is in an unscreened population, so I am.
Just dogs that go through the CT scanner, dogs that have ultrasound. I am probably around a third of adrenal masses are metastatic lesions, but these are typically animals with well-known neoplastic disease who have mets elsewhere. It would be unusual to have mets only in the adrenal gland without having mets in.
Nodes, lung, liver, etc. But metastatic disease in the adrenal gland is probably an important consideration, for the whole population of dogs that have adrenal masses. For dogs who, do not have cancer elsewhere, we're not worried about metastatic disease.
The rate of adrenocortical versus adrenal medullary I lesions. It's a bit unclear. It may be around 50/50.
Historically, it was said that adrenal cortical lesions were more common, but our ability to detect adrenal medullary lesions, so phao chromocytomas, has improved and continues to improve. So it may be that we've been underestimating these, so maybe around 50/50. Of masses that are adrenal cortical in origin is probably a little bit more common for them to be adenomas and carcinomas, but again, not too far off fifty-fifty.
So the population data is a A bit of dot joining, I'm afraid, . When we are considering a patient with an adrenal mass and we're thinking about, well, we want to find the bad guys, we don't want to present every animal with an adrenal mass as a surgical candidate because of the morbidity or mortality of the surgery. We don't want to perform unnecessary procedures in our patients for adrenal masses that are true, kind of incidental findings that are not going to cause the patient any dramas.
In an individual basis, are there things that can help us to predict malignancy and predict functionality in an individual patient because our population data is not as good as we would like. Yes, there there are well recognised factors that we can use to help an individual patient to predict malignancy, for example. So larger tumours are much more likely to be malignant.
Once the mass is more than 20 millimetres, so 2 centimetres, once it's more than 20 millimetres, it's considered highly likely to be malignant. I am it's a really strong predictive factor for malignancy. The size of the adrenal mass is not titrated to the patient.
So that 20 millimetre rule is presented as the same for a Westie as for a Great Dane, for example. The presence of vascular invasion is probably also a predictor of malignancy. It's important to appreciate that when it looks like there might be vascular invasion, there are a couple of different possibilities.
It could be that there's genuinely tumour tissue has grown into the vessel and is wandering up the vessel. But the other important consideration is that some of these diseases predisposed to the development of thrombosis. I am, so it's important if we can to try and understand whether an infill in a vessel is thrombus or whether it is true tumour invasion.
And true tumour invasion can infer aggressive or malignant behaviour. Where there is metastatic disease presents, so you've got a big adrenal mass and there's mets in the lungs, obviously, it increases the likelihood that the adrenal mass is an important, malignancy, primary or potentially metastatic as well. And likewise, if there are, you know, known tumours elsewhere in the body, so the most common type of tumour to make the adrenal gland would be carcinoma or melanoma, for example.
In cats we see lymphoma as well. I am, there's no one disease elsewhere, and there's no one other metastatic disease, that our interpretation of that adrenal mass is likely to be influenced by that. So there are features that can help us to predict malignancy in an individual patient, with size being the most robust of these.
What about functionality? Are there things that can help us to define whether an adrenal mass is functional or not? Yes, of course.
So what about functionality? Are there things that can help us define functionality from an adrenal mass? Yes, of course.
So the adrenal gland has, lots of histological layers to it. So the adrenal cortex produces mineralla corticoid, glucocorticoid, and sex hormones, and the adrenal medulla produces catecholamines. If there is an inappropriate secretion from any of these categories of hormone, we see constellations of clinical signs.
So, knowing clinical signs of our patient, what blood work changes there are, etc. Can help us predict whether we think functionality from an adrenal mass is likely. So for example, if we have a dog with PUPD and polyphagia panting and abdominal distention.
I and hepatomegaly are concerned that adrenal mass is producing an excess of glucocorticoids and generating hypodrenal corticism and Cushing's syndrome, of course, is much, much higher. I am for all of these types of adrenal, hormone, in excess, they are reasonably likely to produce hypertension. So blood pressure is a super important thing to check, in any patient with an adrenal mass, and we'll come back to this repeatedly through this talk.
So if one of the take home messages you take from this talk is what tests should I do in a dog with an adrenal mass? Blood pressure really near the top of the list. In terms of which hyperfunctionalities are most common from the adrenal gland, in the dog, of course, we recognise Cushing's syndrome, the most commonly, I am so glucocorticoid excess.
But we also know from the figures that we've looked at that catecholamine excess or phao chromocytoma is probably really important. I am, and it may be from the literature we've looked at that up to 50% of dogs, with an adrenal mass have a pailo chromocytoma. But it's really important to appreciate that our ability to detect that may be nowhere nearly as good as dogs with Cushing's.
So dogs with Cushing's come into the consult room and kind of help to tell you that they've got Cushing's. But a dog with a chromocytoma is much more subtle, and we're also much less, familiar with considering the clinical signs of what catecholamine excess might look like. And we're gonna talk about this more later.
In cats, adrenal masses are much less common in cats than dogs, but their hyperfunctionalities are different, so we probably see, aldosterone and glucocorticoids in, equal proportions, produced, in excess in equal proportions. But we know that both Cushing's syndrome and KOhn's syndrome are both relatively unusual diagnoses in cats. So we're gonna look at each of these, histological layers of the adrenal gland and what hyperfunctionality of each of these layers looks like clinically in a patient and just have a quick quiz through to refamiliarize ourselves with what clinical signs, what blood work changes might we expect to see.
So we're gonna look first at the most common one for the dog, which is hyperreo corticism, so an excess of glucocorticoid. We are, of course, all very familiar with what a cushionoid dog looks like, both physically and in terms of their clinical signs. Most dogs with Cushing's will look like what you expect them to look like.
They'll be overweight, with a pot belly, maybe some dermatological changes. The owner will probably be reporting PUPD, maybe some panting, polyphagia, etc. But less common manifestations do exist, OK?
So, I am, we might see that actually, in fact, the dog with hypogenic corticism presents with motility, problems. So this dog has a condition called pseudomyotonia, which is a problem today with, Muscle relaxation, which is associated with hypergenic corticism. So there can of course be less common manifestations, I am of what is a common disease.
In terms of blood work changes, again, you'll be very familiar with the common things, so we kind of expect them to have an ALKP elevation and hypercholesterolemia. But for example, about 30% of dogs with hypogenocorticism have elevated bile acids. Which is probably something to be aware of.
The scale of the elevation should be relatively mild, so we're probably talking about 2030, 40, something like that. 100 is, is probably pretty surprising would not be expected with hypergenic corticism. So cushing's something I'm really familiar with, .
Really important to remember that hypertension is common in this disease. So probably around 70% of dogs with hyperdrenocorticism have hypertension. The hypertension will probably not go away even if you address the hypogenocorticism medically with trilasine.
So important to go looking for the hypertension, because failing to detect it may lead to some problems for the patient. Just as a little reminder, in a patient that we think has hyperadrenal corticism, and what testing should we think about, I am, so there are a couple of different endocrine tests that are out there. I am.
The easiest one, I guess, is a urine test, is a urine cortisol creatinine ratio. But important to recognise this test is not for the diagnosis of hypogenic corticism. And it has really poor specificity, so the chance of you getting a false positive result, is really high, generally, OK.
I am particularly in a dog that has another illness. So let's say the dog was PUPD because I had kidney disease, the chance of you getting a false positive UCCR is quite High, not a very useful test. What we want when we do a UCCR is we're using it to rule Cushing's out.
So we want a negative result. We're using it in dogs that we do not think has Cushing's because a negative result is really useful. This test has such a high sensitivity, the chance of a dog with Cushing's disease generating a negative result is really low.
So we can consider a negative result very reliable, and we can use a negative UCCR to confidently exclude hyperreal corticism. So the UCCR, the urinary cortisol creatinine ratio, is not a test to diagnose Cushing's. The two most common tests used to diagnose hypogenic corticism are the ACTH stimulation test and the low dose de.
The low dose de suppression test is considered to be the test of choice from the ACVM consensus statement. It has a a better sensitivity than the ACTH stim. Although its specificity is not quite so good.
So there's a higher chance of false positives with a low dose deck suppression test, but you're gonna catch 19 out of 20 dogs with Cushing's syndrome. Although the ACTH stimulation test has attractions in that it's a quicker test, right? It's 1 hour versus 8 hours.
And so it does have attractions as a clinician and for clients. But in the setting of a patient with an adrenal mass, it's really not a good choice of test. The sensitivity of an ACTH stimulation test for detection of Cushing's in a dog with an adrenal form of Cushing's is only about 60%.
For dogs with a pituitary disease, it's like 85%. But if we're testing a dog for Cushing's that we know has an adrenal mass, so thus we're thinking, well I think it might have an adrenal form as Cushing's. ACTH stimulation test is not a good choice of test.
You definitely should be going for the low dose neck suppression test. So popping down the list to the next form of functionality, I am the next most common in the dog after Cushing's is probably pheochromocytoma. So let's look into this more.
Yeah So as we've mentioned already, pheochromocytomas are tumours of the adrenal medulla. They produce catecholamines to excess. And so catecholamines, adrenalins produce a fight or flight response.
In people, people with pail chromocytomas report their most common clinical signs to be tachycardia, anxiety, sweating and, and hypertension headaches associated with hypertension. I'm, we're gonna miss all of those clinical signs because they're not things that our patients can tell us about. So there's a huge potential for under-recognition of phaal chromocytomas in the dog.
This is a fairly recent case series of 53 dogs, who all had pail chromocytomas confirmed after surgical resection. So, around 1/3 of these dogs presented with PUPD. So you might traditionally think PUPD, adrenal mass, dogs got Cushing's, but it's important to be aware that a fail can be a really important differential in that setting.
The other important thing to be aware of is that quite a lot of these dogs presented with gastrointestinal signs, vomiting, abdominal pain, bloating, poor appetite, etc. I am, when there's an excess of catecholamines, blood is diverted away from the gastrointestinal tract, I am, you know, in preparation for a fight or flight response. I mean that's probably why the GI signs happen because of changes in the blood supply to the gastrointestinal tract, change, motility of the gut, etc.
But you might not intuitively think that GI signs were common in pheochromocytomas. Think again, remember, it's important. These patients can try and evade us when they present the GI signs.
You might not intuitively think about the potential for an adrenal mass or see their relationship. In this population, even when they went back and, and picked through the history with the clients and dogs that they absolutely knew had a fail chromocytoma because they'd had them resected, the dogs were considered entirely asymptomatic to the client. And so it goes back to the point that an excess of catecholamines is not necessarily something that we can recognise in our patients because they may not present clinical signs that we can appreciate.
So absolutely possible to have a pheochromocytoma, and the things that go alongside it, so tachycardia, anxiety, hypertension, but us not to recognise it, unless we probe further. So pha chromocytomas may be clinically silent unless you go hunting. As we mentioned, phaochromocytomas produce an excess of catecholamines.
And when we go to diagnose a pheochromocytoma, we don't measure, norepinephrine and epinephrine though, or noradrenaline and adrenaline, because their half-life is so short that they're no use for measuring. We measure their metabolites, so normetanephrine and metanephrine. It can be done on blood or urine.
And this is again an evolving process. So this was a pivotal study, from the RVC Group in 2013 that looked at dogs with fail and looked at their endocrine testing. And this is really where most labs use the reference range from.
And as you'll appreciate from, this little graph, there is some overlap between dogs with hao and dogs with non-adrenal disease. For this reason, the suggestion from the labs was to make the cutoff for phao chromocytomas a good bit higher than the reference range. But there's some very recent work come out from the Netherlands, from Van den Berg eta, which says you need to approach that with a lot of caution.
So they had a very well defined population of dogs, and lots of their dogs with fails had normeinephrine or metanephrine results that were fairly close to the reference range, and it certainly would have been missed if they had been only considered. Dogs with values, for example, 4 times higher than the reference ranges consistent with fail chromocytomas. So it seems likely that in the near future, there will be a tightening up of the reference range and an awareness that lots of dogs with fails may not have metanephrine and normetanephrine results that are miles higher than the reference range, and that we need to interpret those results a bit more critically.
Phaochromocytomas are considered to be malignant masses, so they have a reasonably high prevalence of metastatic disease, so 15 to 30% at the point of diagnosis, and they're considered to have a high prevalence of vascular invasion. So it's much more common to see vascular invasion with a pailo chromocytoma than with adrenal cortical mass. One of the reasons why we say that vascular invasion is a predictor of malignancy is because it might be.
We're actually just saying, well, vascular invasion is a predictor of phaal chromocytomas, and they are malignant masses. So vascular invasion is something that kind of escalates phao chromocytoma up the list of differentials when we have an adrenal mass where vascular invasion is present. So these are functional masses that can cause unpleasant clinical signs.
We can try to mitigate that with medication. So we use medication, to block the sympathetic effect, so we prevent the binding of these excess catecholamines. And the most commonly used drug in this setting is called phenoxabenzamine.
Pennoxabenzammine will irreversibly bind to alpha 1 and alpha 2 receptors. And it should very much help manage the hypertension that is such a common feature of this disease. I am so in this disease, we expect patients to be hypertensive because it causes alpha activation.
It causes vascular constriction. So hypertension is considered pretty much a universal feature of pheochromocytomas. Around 70% of those dogs will be consistently hypertensive, but around 30% are considered to be episodically hypertensive.
So a normal blood pressure reading one morning, at 11 a.m. Does not exclude hypertension being episodic and thus does not exclude a pheochromocytoma.
There was literature that strongly supported the use of phenoxabenzammine prior to surgery. So that in this paper from Herrera strongly suggested that pre-treatment, preoperatively with phenoxabenamine reduced mortality rates associated with the surgery. The thinking for that was that in patients with pailo chromocytoma who have chronic vascular constriction, They end up essentially being hypovolemic.
And when they have anaesthesia, and the anaesthesia drugs cause vasodilation, they can have real problems with blood pressure, so problems with hypotension, then problems with hypertension, relating to functionality of the mass, handling of the adrenal mass, etc. So this paper said, hey, we need to pre-treat these dogs with phenoxabenzammine, and that has absolutely been considered standard of care for the past decade or so. But there is a recent paper which says this is not the case.
So we're currently in a state of flux and disagreement as to whether dogs with known pailo chromocytomas who are going for surgery should definitely have phenoxabenzammine as a for two weeks prior to the surgery or not. Hopefully more literature will come out to clarify the situation, because there's certainly disagreement as it stands. So as a little summary on phao chromocytomas, because I'm guessing this is an adrenal mass with which you're a bit less familiar than a dog with an adrenal mass causing Cushing's, is that phao chromocytomas probably make up between 20 and 50% of adrenal masses in dogs.
They're important. And the clinical signs can be diverse. Don't forget they can look like Cushing's.
They can come in with PUPD for example. And the GI signs are quite common, but they may also be clinically silent, so the lack of clinical signs in a patient does not exclude a functional adrenal mass, particularly a fail chromocytoma. Hypertension's super common, really important, you need to check for it.
When we have hypertension, it can be unpleasant for the patient, we assume, so people can describe it as being unpleasant, headaches, etc. And we can see target organ damage to the eyes, the brain, the heart, the kidneys, etc. So we definitely don't want hypertension for lots of reasons.
It's really important that we check for it. Medical management to mitigate the clinical signs and the implications associated with excessive catecholamines are there, so phenoxabenzammine is our drug of choice. But strongly consider a surgical resection of a phaochromocytoma.
Their functional masses, resecting them would hopefully resolve that functionality, they're metastatic, they're malignant. So in a patient without metastatic disease, we should be considering surgical management of this patient. Hyperaldosterism, we see much, much more commonly in the cat than a dog.
In the cat, it's the, joint most common form of adrenal mass, alongside Cushing's. We see it very rarely in the dog. Typical manifestation is that we get, hypertension because.
Causes resorption, retention of sodium and thus water, thus expansion of the volume, but it also causes excretion of potassium. So we see hypertensive, sort of fluid loaded patients who have low potassium, and the problems associated with that, so typically muscular weakness, etc. You can see weird and wonderful functionalities.
So the adrenal gland, has a very complicated, endocrine pathway, so it produces about 40 hormones all in all. If you have a malignant mass, from the adrenal cortex, or a carcinoma from the adrenal cortex, it may be that it's metabolism is not normal. So we have aberrant metabolism.
We know that tumour cells can behave in funny ways. So for example, rather than having a dog producing excessive cortisol causing hypodrenocorticism, they produce something else along this pathway, sex hormones, another type of glucocorticoid, etc. How those patients look clinically and what happens to their blood work completely depends on what they're producing.
So this is a feature of malignant masses, so aberrant metabolism from malignant adrenocortical masses. This is an example, patient, beautiful dog, an older Labrador, 5 month history of PUPD and weight gain, a 2.5 centimetre adrenal mass.
Now, as we've talked about, we know that, a mass over 20 millimetres, over 2 centimetres, considered highly suggestive of malignancy. So a size alone would suggest this mass is malignant. Before I saw her, she'd had two ACTH stimulation tests done, both pretty weird, both kind of supporting hypoadrenal corticism, but that was absolutely not the clinical picture of this dog.
The assumption was this dog was producing some sort of glucocorticoid along the pathway that wasn't cortisol. After resection of the adrenal mass, these clinical signs resolved. So this was an adrenal, carcinoma, that was producing something that wasn't cortisol.
And just weird and wonderful cases to be aware of. As has cropped up in our discussion, plenty of times, hypertension with pretty much all the functional adrenal mass is really important. The incidence changes a little bit depending on which, adrenal hyperfunctionality you have, but hypertension really common.
Please, please, please look for it. So we talked about the clinical signs, the blood work changes, the prevalence of hypertension. Are there any imaging findings that can help us guess whether a functional adrenal mass is present?
Yeah. So, as you will know, dogs who have, adrenal dependent hyporeal corticism, so an adrenal form of Cushing's are expected to have contralateral adrenal atrophy. So if you've got a mass in the left adrenal, the right adrenal gland should be getting a bit tiddly, because it's essentially gone into retirement because of the overdrive from the autonomous secretion by the left gland.
We don't expect to see this with any other type of adrenal mass hyperfunctionality. So we don't expect to see atrophy of the contralateral gland in a fail, for example, or in, in hyperalosterionism, for example. So atrophy of the contralateral gland would be a, a big nudge in the direction of hyperreal corticism.
Other bits and bobs that have been suggested in various bits of imaging literature, if you are CTing them, it's suggested that haols have a higher attenuation value rather, compared to adrenocortical lesions. As we've mentioned, vascular invasion, something that's more common in a pha. We see mineralization rarely in phas, a bit more common in adrenocortical lesions can be present in either benign or malignant lesions.
And it's been muted that rupture of an adrenal mass is more supportive of an adrenal cortical mass than a fail, but rupture does definitely occur in fields too. So just a few other bits and bobs that crop up in the literature that at some point might help you. Yeah So what about cytology?
And for many, many types of masses, that we detect on imaging, we make progress in understanding their nature by taking an FNA of them. Can we do the same for an adrenal gland? Can they help us identify the bad guys?
So cytology is good for defining what is the cell line of origin in the adrenal mass. OK, so, and for example, on the left, we have here adrenal cortical cells. And on the right, we have adrenal medullary cells.
And if the adrenal mass was comprised of, a metastatic pancreatic carcinoma, you'd also expect that to be identified. So it's good at defining the cell line of origin of the adrenal mass. So an FNA of an adrenal mass is good at telling you the cell line of origin.
So it will distinguish adrenocortical from adrenal medullary, which is great. If you see adrenal medullary cells in a mass, we're gonna say, OK, this is a pailo chromocytoma, and we know that phao chromocytomas have malignant behaviour, so we're gonna infer malignancy. But cytology of an adrenal mass is not considered to be an appropriate way of defining, I am the cell population as benign or malignant, I am by looking at the cells.
OK, so for example, if you had an adrenal mass, and the pathologist comes back to you and says, well, that's an adrenal cortical mass. You cannot use cytology to distinguish a benign adenoma from a malignant carcinoma. So where it's a pailo chromocytoma, we infer malignancy because they behave in a malignant way in dogs, OK, but where it's an adrenal cortical mass, cytology will not allow you to distinguish benign and malignant.
Aspiration of adrenal masses is something which divides opinion, OK, both in medics and images. There are the potential for complications. So haemorrhage is a potential complication in part because, the adrenal gland lives around a whole bunch of very important and large blood vessels, but in part because adrenal masses can be very friable, we recognise some of these patients because they present to us with rupture of their adrenal masses.
So haemorrhage is a potential complication. The other complication which divides people more so is aspiration causing a catecholominergic crisis. So causing ventricular tachycardia, hypertension, etc.
It's not really well described, so I can't tell you how common this is. And it's definitely described in the human literature, and most people know of the odd case where it has happened in a dog to somebody, OK? .
Some imagers feel very confident aspirating adrenal masses and will do so quite happily without exclusion of much else. Some imaging diplomats will not aspirate adrenal masses full stop for this reason. So, I am, there is a study, this Petal study in 2020, where a third of the images would not aspirate an adrenal mass full stop.
OK. In humans, they would be cautious aspirating endogenal mass if there was a strong suspicion or an an uninvestigated suspicion that it were a pailo chromocytoma. I am for me, I, unless I had a strong reason in the patient to think I understood the lesion.
So for example, let's say the dog had a gastric carcinoma and it had a lesion in the liver that I thought might be a met, and I thought the adrenal mass might be a met as well. I am. Otherwise, I probably would not aspirate an adrenal mass without having first done endocrine testing, because endocrine testing to understand if it's a fail, may also answer my question and may also make me think, OK, well this is a fail, I, I'd rather not poke that, let's not poke the bear.
So it's not without risk, and it's something which very much divides opinion. So after all of the information that we have talked through, if you find an adrenal mass, what next? What's the plan?
So I put together a little sort of action plan to hopefully help all of us move through these cases when we encounter them. So step one, I am, could this be a met? OK, so we said that adrenal metastases are common in cancer-bearing patients.
Most commonly carcinoma, melanoma, etc. Typically, adrenal mets occur where there's other metastatic disease present, so liver, lung, etc. So it'd be unusual for there to be a primary mass somewhere and just an adrenal met, but not impossible.
So, could this be a met? It's an important consideration, and so definitely have that potential on your radar. The next questions are going to start to address finding the bad guys.
OK, we want to find the functional ones, we want to find the malignant ones. I am, so rule out functionality. Definitely an accurate history.
I think about the clinical signs and a biochem, good start point. We're looking at the electrolytes, we're looking at the cholesterol, we're looking at the ALKP, all these things in particular. We definitely, definitely want to check the blood pressure of our patient.
Lots of these functional adrenal mass, conditions will have hypertension associated with them. Knowing hypertension is present will help us to, begin following the pathway of understanding what this adrenal mass is. But also knowing hypertension is present lets us treat our patients appropriately.
We don't want them running around with hypertension, getting target organ damage. So, always, always, always check the blood pressure of a dog with an adrenal mass. And demonstration of hypertension makes it much more likely this mass is functional.
If we think that this dog does not have hypodgenocorticism, but it has an adrenal mass, we can't find anything. The dog has no clinical signs, the biochem's boring, the dog's not hypertensive. You just want to tick the box and say, yeah, this is not hypogenocorticism.
Then a UCCR is a great way of doing that. We've said a negative result allows us to confidently exclude hypodgenocorticism. If, of course, we thought that this dog did have hypergena cortices and the UCCR is not the test for us and a low dose dex is where you should be heading.
And think about pheochromocytoma testing. Plasma metanephrines is the most common way to do this. So these would be the recommended tests in terms of thinking about functionality.
Of course, if something crops up on your biochem, the dog's got a sodium, a potassium of 2.3, maybe you're gonna change your track. Maybe you think, gosh, I, could this be a mineral corticoid excess?
I'm gonna look into the dog's aldosterone and maybe renin, etc. But when we're sort of screening for functionality, we're trying to look, go hunting for functionality. These would be the tests that I would strongly recommend.
What predicts malignancy in terms of thinking about the bad guys, we know that large masses, so more than 20 millimetres, strongly predicts malignancy. We know that the presence of vascular invasion should make us worry about malignancy. Other metastatic disease being present supports the adrenal mass also being malignant.
Of course, if other metastatic disease is present, adrenalectomy is not gonna be on the cards. If all of these things are boring, this dog doesn't have any other neoplastic disease, we don't think this is functional. We've done some testing.
This is a small mass. I am, then our hope is that this is not a bad guy. There's nothing telling us that it's a bad guy.
There's nothing telling us that it's functional and needs to be medicated. There's nothing strongly suggesting malignancy, then probably a conservative approach is the most appropriate at this point. So keep an eye.
So repeat the ultrasound in 6 weeks, and then perhaps every 3 to 6 months thereafter. If the mass is getting substantially bigger, then that's gonna change our tune. So if we're seeing marked growth, that's gonna change our tune.
In humans, when adrenal incidental masses are detected, very few of them go on to show an increase in size. But in humans, we have the figures that say most of these are benign and non-functional. In dogs, we don't really know, but functionality is probably fairly common, and in malignancy is probably much more common in dogs than in people.
So those figures probably don't flip over to dogs. But keeping an eye is important. Also important to be aware that functionality may become apparent at a later date.
So it might be you've detected a tiny little adrenal mass. You can't find any functionality. You've done the tests.
You're keeping an eye on it, and actually the dog becomes PUPD, and then it becomes apparent, in fact, the dog has hyperreal corticism. It just took a while to become clinically apparent. So the picture may change, as the disease process continues.
So in summary, incidental ommas probably occur in 4 to 9% of image dogs, so like ultrasound and CT. The distribution of, incidental ommas in terms of how many of them are benign, how many are the malignant, how many are functional, and how many are non-functional, we don't really know, OK, and it's probably unlikely that that information is going to become readily apparent to us unfortunately. Mass is bigger than 20 millimetres suggestive of malignancy.
If there's other malignancy in the dog, think strongly about the potential that this adrenal mass may be met. And think about pha chromocytomas, have them on your radar. Think about the endocrine testing.
Think about what they mean for the patient. Check the blood pressure in every, incidentally detected adrenal mass. If it is a small adrenal mass that has no apparent functionality, then it just sits there for a long time, months and months on end.
Then hopefully it is genuinely a benign and non-functional mass, but keeping an eye on it is a good idea when we don't have the population data to be able to see how common benign and non-functional masses are. I really hope that's been helpful. And it's provided you with some information and a framework of how to approach patients with incidentally detected adrenal masses.
And helped to guide you through what information is out there, what we know, what we don't know, and yeah, I, I hope that's been helpful. Thanks so much for joining me.
