Thanks, James. Well, it's a pleasure to be here today. I hope over the next 45 minutes or so just to give you a feel of some endocrine lab interpretation, if you, if it's something you are not fully confident with, hopefully it'll get your confidence up.
Try and also just get across the concept that, as I'm sure many of you who have joined today have already realised that endocrine interpretation is often not a black or white thing. It often has a grey area, which is I think what causes People some concern about whether or not they're able to do it well. However, what I'm hoping to show you today is that there are times when we can be very confident with our endocrine lab results and And it's only a limited period or a limited number of occasions where, where it really is equivocal.
And we need to just recognise what we're confident with and and what what we need to put a bit more investigative effort into to make our diagnostic judgments. So as James said, one of my previous lives was working at Michigan State University. I did that for 7 years in their endocrine service lab.
That laboratory received between 3 and 500 endocrine submissions a day, which we needed to provide written interpretation for and or and answer the phone to about 30 endocrine interpretation calls a day. So over the space of 7 years, I certainly saw an awful lot of material. What we've got the opportunity to do today is for you to choose what it is that you'd rather listen to.
And we'll pull this question in a second. Well, we have some choices. So the items that are listed short thyroid, short adrenal and short calcium cases will cover a little bit of background to interpreting thyroid, adrenal and calcium.
And then we'll give you some example cases that are sort of welcome to my world when I worked in an endocrine lab. So it's not a kind of situation where we'd have an awful lot of investigative information about the animal. Pretty much all we have is its signalment and it's lab result.
And just trying to see if we can come to at least a lab diagnosis based on the results that then you could take away and apply to the larger batch of information that you would have about an animal. So more like How it would be for for me in my world, sitting in a lab, not actually seeing the animals, but seeing the lab results and being expected to provide some diagnostic support. There is this section there called longer cases.
There I've got a little bit more information about the animals, but again, I've got that information by still sitting in the lab and being told that information rather than having You know, like lots of radiography or ECG or other material about the animals, so sort of longer stories but still with a laboratory emphasis. And then just as an opportunity, seldom taken, but the opportunities there if you guys are interested, just to really refresh ourselves on laboratory statistics, that is diagnostic sensitivity, specificities and predictive values. Those have got particular relevance to endocrinology because Most of our tests are not perfect tests and therefore we have to really understand what the false positive and false negative rates are because we're going to come across them more commonly than we would for other types of diagnosis.
So I think James will open up the poll now and we'll just get a sense of what people would prefer to do. We'll go with the majority decision. You should be able, if we have set this up as We plan to, you should be able to choose more than one option.
So don't feel you just can choose one thing. You can choose any of the things on this list. And we'll order the presentation according to that, and we'll see how far we get in a 45, 50 minutes.
All right, is the poll open, James? OK, thank you. The poll is open, yeah, people are voting now, actually, most, most people have voted.
I'd encourage you all to vote. It's not, not often we have this level of democracy and in choosing what your CPD is gonna be on, so that's good. So I'll just let let the final few people vote.
Are we just gonna cover one of these topics, Peter or are we going to do, what I'm hoping, James, is you'll tell me, what the What the order of popularity of the choices are, and we'll start with the most popular and work our way to the least popular on the basis that we probably won't get to the least popular in the time that we have. OK, that's fine. If anyone else wants to vote, then do so now, otherwise I'm going to stop it.
So you have got a, you have got a clear leader, which is the short adrenal cases, please, Peter, and I'm afraid the others are very closely split and so the next most popular are the lab stats one and the short calcium cases. Your longer cases were the least popular. So I think adrenals, adrenals one.
OK, longer is least popular and is thyroid down with the longer? Thyroid is, is the 4th most popular. So you've got adrenal then calcium and lastats are equal, and then thyroid and then longer cases.
OK. Right, what I might do then perhaps is start at Labar cause it's got a lot of relevance for adrenal. James, can you tell me on my screen, is there a little bar from turning point that says polling stuck across the middle of the screen?
No, not that I can see. OK, excellent. OK, so if I click lab stats, we'll start there.
And we'll run through this, which will then help us with thinking about adrenal disease because this is where it has a big impact. And the example that I use to explain the lab stats is an adrenal example. So I think that will cover elements of the first two quite well.
So whenever we're using a diagnostic test, we are getting a set of results. Can you guys see an cursor on the screen, James? Can you see a cursor highlighting?
Yes, we can see the tester. Excellent, the test is working fine. Brilliant.
So we're going to get a positive or a negative result in our, in our test, and if it's not the kind of test that behaves like that, then we can use a cutoff value in a numeric range of results to force it to behave like a test that's going to give us either a positive or negative result. And we're also gonna have a population of animals which does have the disease we're interested in, and it is possible that the test could be applied to animals that don't have the disease because at the point that you run the test, you don't know which is which, which animals have it and which don't. So.
If we were to develop a new test for something, we might go and find 100 animals with the disease that that test is designed to detect and find how many of them give a positive result with our new test, we would call that diagnostic sensitivity. So in this case, this test where 89% of the animals with the disease gave a positive test result, this would be described as having a 9 89% sensitivity. We might also, when we're developing a test apply our new test to a group of animals that don't have the disease but look like they might have, but that we know that they don't, and we would see how many animals.
Give us a negative test result. And this would be our specificity. So we would have a 75% specificity in this case.
So that's what sensitivity and specificity are they relate to how likely it is. That we're going to get a positive result in an animal that genuinely has the disease, or how likely it is we're going to have a negative result, a true negative result in an animal that doesn't. So In a situation where a test has got a very high diagnostic sensitivity.
This box here is close to the maximum, which means this box here is very small. And this box is our false negative box. So we've got a very low number of false negatives being generated.
That means that because false negatives are really rare, when we do see negatives, they're much more likely to be true, we're much more likely to believe them. So when we've got a test with very high diagnostic sensitivity, we have extreme confidence in the negative test results. And that's where that little mnemonic sensitivity helps us rule out disease comes from snout.
So sensitivity helps us rule out disease. Because we've got lots of confidence in the negative test results. Alternatively, if we've got a test with very high diagnostic specificity, then this number is very high, which means there's not very many cases left to fall in this box, and this is the false positive box.
So in a highly specific test, the false positive number is very low, which again, Means that if we do see a positive because false positives are rare, we're much more likely to believe our positive results. So when we've got a high specificity test, we've got extreme confidence in the positive test results, which is where that other Mnemonic comes from spin. Specificity helps us rule in disease.
So we've got snout and spin. Specificity good for confirming, ruling in disease because we can believe the positives. Sensitivity is good for ruling out disease because we can believe the negatives.
So let's just have a look at. A more kind of clinical application of that information. So we're just gonna compare two vet scenarios here, a Tessa Tealloti.
She's got on-site pres pre-anesthetic screening and health screens that she does. But maybe she's not so good at knowing her differential diagnosis for a high alkaline phosphatase and one of the differentials that she knows for that is Cushing's disease and so she recommends a low dose dexamethasone suppression test for all of her patients that get a high alkaline phosphatase. So clearly an unlikely scenario, but it helps me prove a point.
So if we look at that table that we just looked at before, if we say that because in reality, we know there's an awful lot more reasons why an animal might have high alkaline phosphatase than Cushing's disease, possibly, if she was to do this over a long period of time, it might be a very low percentage of animals that genuinely did have Cushing's disease. And for the purposes of this example, we're just going to pluck a number out of the air and say that maybe only 5% of them have that. And then we can go to the literature and find out what the literature says about the Lodoex mesone suppression test that says that it has a high sensitivity.
So let's pick one of the numbers from the literature and go with 98%. But it says generally it's got a less good specificity, false positives are relatively common with this test, and a representative number from the literature might be 73%. Because we're estimating that perhaps Tessa will only come across 5% of her tested animals that have got the disease, we can work out what proportion then are in the diseased or the not diseased category.
And then we can use these percent. Apply to those numbers to fill in these other boxes. So up till now, we've talked about the situation where you're kind of developing the test and you've got these animals that are either have Cushing's disease or don't, that you've defined by some method that's independent of your low dose demethasone suppression test.
But in the real world, you don't know whether you've got Cushing's disease in an animal, that's why you're doing the diagnostic test. So if we look, instead of looking at the proportions in the disease and normal category, if we look at the proportions that are in the negative result category, so of all the negative results that test is going to generate over a period of time, if she's applying this test to 1000 patients, she's going to end up with 694 negative results, of which 693 are genuine negative results that genuinely come from animals that don't have the disease. So she has a very, very high negative predictive value.
That means that she's got 99.9% confidence in a negative test result. So if she gets a negative test result on a low dose dexametone suppression test, she should believe that and move on and go find some other reason for the animal's presentation.
If we use that same approach for positive a positive test result, positive low dose text messagepression test. Over the course of this period of sampling 1000 animals, just by the way that we filled in all these boxes using reasonable numbers from the literature, we discovered that she's going to generate about 306 positives. Of which only about 49 are going to genuinely be coming from the disease category.
If we make a ratio of that 49 and that 306, we get 16%. That's a 16% positive predictive value. That's a measure of how confident she can be that the animal genuinely has Cushing's disease when she gets a positive test result.
And you can see that's a very low number. I used to run diagnostic lab services in the UK and if I came to your practise and told you that I've got a great new test for Cushing's disease, I think you should buy from me because it's, it's fabulous that if you run the test and you get a positive test result on it, that you can have 16% confidence that the animal actually had the disease. I think it's very unlikely that any of you would be wanting to buy that test from me, but that's the reality of the situation of the low dose dexamethasone suppression test that many people are using in their practise on a daily or weekly basis.
And it, this, the consequence of this very poor confidence in positive test results really is driven by it being a poorly specific test. And there are ways that we can try and increase our confidence. We'll just exam show an example of that.
So let's think about somebody else by comparison, who recognises that the low dose demethasone suppression test has got poor specificity. He recognises that false positives and over diagnosis or a genuine thing he needs to be cautious of. And so he's decided in his policy that he's going to only use the low of methyl suppression test when, yes, maybe he has got a high alkaline phosphatase in a patient, but he's also got two relevant clinical signs.
A polydipsia, a thinning hair coats, some other clinical signs that would be relevant to Cushing's disease. And also he recognises that generally, not completely exclusively, but generally this is a disease of geriatric animals. And so he's going to restrict his testing population to animals that are greater than 6.
If he does that, I really don't know for sure what the consequences, but for the purpose of illustration, if we, if he's able then to get his population of animals that he's testing narrowed down to a situation where he's much more likely to find animals with Cushing's disease in there, or another way of wording that is that in his clinical judgement, it's kind of got to a fifty-fifty between having Cushing's disease or not having Cushing's disease. Then let's say that that means he's got his, his prevalence in the group of animals he's gonna test for Cushing's disease is going to be much higher. And if we pick this 50% number, We can then fill in these boxes.
And again using exactly the same sensitivity and specificity numbers, we can fill in these other boxes. Which allows us then to look at what the situation would be with the negative results he's going to generate. So of all the negatives he generates, around 375.
365 are genuinely from animals without disease, so he's still got pretty high confidence in his negative test results. Not perfect, but it's still pretty impressive to be 97% confident that the animal doesn't have the disease. When he looks at his positive test results, though, he's got much greater confidence than that 16%.
He's now got nearly 80% confidence. That he's going to get, that he can believe is positive test results for a lot of sex when he gets them. So 80% is still not great, but it's .
It's very much better. And if we extend that a little bit further, if you wanted to have more than 90% confidence that your low dose methyl suppression test result positive genuinely meant the animal really had Cushing's disease. If you, if you really wanted to have that degree of confidence because you're going to use, so you're going to use a drug that had some potential adverse effects.
You want to have a high degree of confidence, then to achieve a positive predictive value more than 80%, if you want to get into the 90%. Then this prevalence figure needs to get bigger. That means you have to really restrict the animals in which you do the testing for for Cushing's disease with the low dose decks.
You really have to restrict that to animals that you already have a very high degree of confidence that Cushing's disease is there, probably more like 70 or 75% confidence that Cushing's disease is there before you can have 90% or more confidence in a positive test result. So it is a test, is a little. Flawed because of this diagnostic specificity and the only way to get around that is to to either limit the cases that you test, or when you get a positive test result, have a really strong healthy degree of scepticism about that positive test result, that it could be misleading you and look for some additional evidence before you go further.
OK, so we have Checked or finished that section. I don't know, James, is any, any questions come through about lab stats before we move on to anything else? No, nothing's come through.
I think you were very clear. OK, so I'm happy for you to move on. If anyone does have any questions, then we can always ask, ask them at the end if they do come through.
Excellent. So let's have a look at the next thing on the list, which was short adrenal cases. Here is a cocker spaniel with poly polydipsy and mild alopecia and it has had a low dose dexamethasone suppression test performed.
We don't have the opportunity to pull all of these examples, but we have given you some kind of multiple choice. Potential answers on the screen. What we might do, as a bit of experiment for the rest of this session is if you, if you feel comfortable, if you can use the chat box and just type the letter of the answer, and we'll just see if 10 or 15 of those answers flow through to James, if, if he's seeing them, he can give me a sense of what kind of answers people are providing.
Yeah, people would like to put that into the chat box. It's probably better than the Q&A box, please. Cool.
So there's a just a couple of answers coming through and The majority are C and there's a few. Bees OK. So this one follows on quite nicely from that labsat conversation that we've just had.
I would say. That hyperadrenalcorticism is ruled out with a high degree of confidence. I would, I would prefer answer C out of the available answers here.
And that's because as we, as we demonstrated using the low dose X methone suppression test data in that lab stats example. The lays methone suppression test has a very high negative predictive value. Because of its high diagnostic sensitivity.
That means when we get a negative test result for Cushing's disease, we really want to believe it. We really should believe it and we should move on and find another explanation for the clinical presentation. There is the possibility, although an extremely, extremely small possibility that this animal does still have Cushing's disease, but it's, you know, particularly I, I think my thought process on that would be if you're seeing this in general practise, then that's a headache you want to pass on to somebody in referral to, to make a Cushing's disease diagnosis against a set of results like these because this is such strong evidence against Cushing's disease that you really wouldn't want to go down the route of spending any more money investigating it, I don't think.
So it certainly doesn't, in terms of going through the answers individually, this certainly doesn't confirm Cushing's disease. And so this, some people did answer B there it was still quite likely. I think even though there's clinical signs that fit it, then those clinical signs could also fit with some other conditions and we really need to be exploring those because Cushing's disease has been really well, really well ruled out.
OK, see. So, again, if we hadn't done the lab stats part first, then perhaps we wouldn't have been completely aware of some of this information that's in the literature, but sensitivity is reported up to 100%. Some endocrinologists define Sort of say by definition, the low dose methine suppression test has a sensitivity 100%, but others generally believe it's high.
And then there are specifics to reports, even as low as 44% when applied in peculiar populations, but generally believed to be in that sort of 70% range. So here's another low dose dexamethasone suppression test. And again, if you want to take the opportunity of of entering something in the chat box, we can have a quick scan through what kind of answers people are giving.
So we're starting here at . A high value. We've got some suppression at a 3 hour time point, but by 8 hours that's come back up again and it's well above the less than 30 cutoff value that this particular lab.
That this particular lab is using. So we're getting some A's and some D's and that is good, that's very healthy set of answers. I For me, the answer that I would give from a laboratory point of view is answer A, this could support pituitary dependent hyperadrenal corticism.
A few people have answered the hypogenic corticism, but they're not sure which kind and they might like to use a high dose dexamethasone suppression test. We'll have a little look at how those tests work, . But fundamentally, if an adrenal tumour is autonomously producing glucocorticoid, Then that excess glucocorticoid, the adrenal tumour will have been producing will already have shut down pituituitary production of ACTH through negative feedback.
So when we come and give our dexamethasone, In a low dose dexamethasone suppression test, what the, what the point of giving dexamethasone is, is to try and suppress pituitary production of ACTH but in an adrenal adrenal tumour animal that will already have been suppressed. And so we, our dexamethasone isn't going to have any effect because ACTH is already low. We can't lower it any further.
And so that adrenal tumour is going to continue to do its thing, producing its cortisol at the level it's, it's producing it for its own autonomous reasons and we can't influence it very much with our low dose of dexamethasone because we can't further shut down pituitary ACTH production. So that means that if this were an adrenal tumour producing this, we would get a flat line. We wouldn't get this substantial dip.
And the rule of thumb that most endocrinologists use is a 50% decrease because this 57 is less than 50% of this 211, we say that this is decreased by more than 50%, which is something we couldn't really expect to happen with an adrenal tumour, which means this has to be pituitary in origin. So it's always a two-stage interpretive process. The first stage is, do I have a positive result based on this 8 hour.
Value and this cut off. And then the second stage is with that positive result to have any evidence of suppression, is there any point in that test where the results are 50% less than they started. And in this case, yes, we do, and therefore we can, we can say this is pituitary dependent.
So just running through what that suppression's going to do when we give to a Regular dog, we get ACTH decreased, which is going to decrease cortisol output and so we're going to get that decrease in. Cortisol results. Whereas if we've got a dog with pituit dependent Cushing's.
There's, it's not as responsive to ACH we get less of a decrease. So either really not much of a response or we get a response that's, that's just not as good as it would be in a normal animal. And so comparing against the pituitary form, if we've got an an adrenal form, ACH is already low, dexamethasone can't make it any lower.
So because it can't get any lower. And because cortisol is being autonomously produced, cortisol stays the same. And so in adrenal tumour case, we expect kind of a flat line response.
So this is What adrenal tumours will do. And pituitary dependent, if it's a very resistant pituitary mass could do the same, or we get a suppression. But in that last example, we got a suppression, which means we have to be in the pituitary circumstance.
We can't be in the adrenal circumstance. So I hope that for the, for the people that answered D with that last case, that that that makes complete sense. If it doesn't, then just pop a question in the Q&A box to James and we'll, we'll have another look at it later.
So here's another example of a low dose dexamethasone suppression test. Again, if you feel comfortable popping some answers into the chat box, that would be great. In this case, we've started with a high value, which, which really has not suppressed in response to Dick Smith.
So and if anything it's, it's increased, but I think it's, it's better to think of that as no suppression rather than really overly focus on the increase. OK, so, We have got some. D's and some C's.
So we'll just go Back a screen. Oh To here, this animal on the right hand side is supposed to represent an adrenal tumour case, and this animal on the left side is supposed to represent a pituitary case. I didn't really emphasise particularly well that if the pituitary mass is really resistant to the dexamethasone that you inject, it may fail to respond and it may fail to reduce its ACTH output.
So you can sometimes get a flat line response with some. Pituitary dependent cases, maybe about 40% of pituitary dependent cases will give this pattern. And all adrenal tumours we're going to give that pattern.
So I can see why people are answering the way that they are. So it's possible that this is adrenal tumour. Which is why some people are answering C, but because some pituitary masses could be resistant to death methasone, it could still be 40% of pituitary masses.
So that means that the Best answer in this case is answer D because we could get a flatline response either with a resistant pituitary mass or an adrenal tumour, we need to go on and and look a little bit further. So this is a case where going on with a high dose dexamethasone test or an endogenous ACTH would be an appropriate thing to do. In that last case, where we could diagnose pituitary dependent disease just from the low dose X alone, it would be a waste of your time and the owner's money.
To go with a further differenti test and that was one of the things that I used to come across a lot in the labs. Where I'd see results being come across my desk from animals that had unnecessary high dose dexamethasone or endogenous ACTH test because the the information that that was going to be gained from that had already been gained from an earlier low dose methone suppression test. So if you've already got differentiating information, pituitary versus adrenal from the low dose texts, there's no need to progress.
Whereas in this case, we don't have differentiating information. From these results. And so we would want to progress to a differentiating test and there's a Some, some different ones you could choose, you could choose the high dose dex methone suppression test which Doesn't .
It doesn't. It may be only it's only another 10 or 15% of pituitary cases that will respond to that higher dose. So it, it, it still leaves us with some doubt in a significant proportion of cases, which I think is why it's falling out of favour a little bit in favour more of the endogenous ACTH.
With endogenous ACTH it's a more label hormones, we have to be set up with our freezer packs for our sample and being able to carry our sample overnight to a lab that can can run this sample still cold. So it looks like some people are already Putting their thoughts out there in terms of interpreting this result. We've got a result of 18.
We've got a reference range of 6.3 to 25. Now bear in mind that's a, that's what we expect from normal dogs.
Now what we, we don't have a normal dog. We have a dog with test results consistent with Cushing's disease, and we're using this test to differentiate between whether they've got pituitary or adrenal. So the reference range there is more just to give us a sort of ballpark of what a normal dog's result looks like rather than necessarily to help us decide whether this is better fits with adrenal or pituitary.
So we've got quite a mixture of responses here. We've got A's. Bees C Even a D.
So, My Recommended answer in this circumstance would be. Would be a So What's the rationale for why is that a? So we've already talked a little bit about it.
If, if we had an adrenal tumour that's autonomously producing excess glucocorticoid, then the effect of that. Glucocorticoid on the pituitary would be as a negative feedback mechanism, it would already have shut down ACTH. And when I say shut down, I mean significantly below the bottom of the healthy dog reference range.
So if you've got an adrenal tumour, we'd expect that ACTH to be very low. And because we're in a situation where we're using this test to differentiate, that means we've already made the decision that we think Cushing's disease is there. We're not using this in any way to help us decide whether Cushing's disease is there.
We're just using it to help us to, or I should more correctly say, hypergenocorticism is there. We've already made that decision that it's there, we just now need to know which type it is. So we're not using the test to help us decide whether it's hypergenocorticism is present.
So when faced with the two choices, pituitary or adrenal, and we know this can't be adrenal because it's not been completely suppressed, that leaves us with the only other possibility which is pituitary, which is why the answer here is answer A. So we don't need to see results above the healthy dog reference range in dogs with Cushing's disease, pituitary dependent Cushing's disease, and that's really because the excess of ACTH that's coming out isn't necessarily above the over. The range that a normal dog could experience in its normal normal day to day life.
The kind of excess that we get are the pulsatility changes. So there's the overall impact of the ACTH is higher, even if at any single point in time it's not numerically higher than the highest value you could get in a normal dog. So we don't need to see a result above the reference range to confirm pituitary, we just need to see that it's not been completely suppressed.
So here's that expressed in a diagrammatic form. If we look at animals that had pituit dependant Cushing's and look at their ACTH results, some of them, yes, could be above the healthy dog range, some could be in the healthy dog range, and even some could be slightly at the bottom, or maybe even slightly below the healthy dog range, but the adrenal cases are all very suppressed below the healthy dog range. So hopefully that that that helps solve some of the confusion that we sometimes come across when people are interpreting their endogenous ACTH results.
OK, now here is an ACTH stimulation test, one of the other. If you like screening or first line tests for Cushing's disease that we might consider its its use is controversial in different parts of the world and in some parts of the world that ACTH is too expensive for us to use it routinely for this purpose. But here's an ACTH stimulation test.
We've started with a high baseline. We've given ACTH, which in a normal dog should stimulate those adrenal glands to pump out a lot more cortisol. And in this case, really nothing's happened.
Those results are from a laboratory point of view, pretty much identical. That is if you were to run that same test multiple times, you would get a range of results and it's, it's not unlikely that that these two results could almost overlap. So that's no change.
In cortisol. So we're getting some A's and we're getting some B's. Coming through So the traditional way in which we would interpret An ACTH stimulation test, the kind of traditional and and literature.
Assessment of whether the test works or not is based on whether or not this result is above this cutoff value or above 550 or above 600, depending on what lab and recommendation you use. And so some people would say, well, that result's not above 500 or 600, therefore, this doesn't fit with Cushing's disease and I'm going to move on. But other people would say, well, hold on a minute, why, why is this animal giving no response at all?
To ACTH administration. And yet is, is producing an excessive amount of cortisol. One of the situations we might see that is an extremely stressed, extremely sick animal whose adrenals are working at their maximum already and they can't be forced to work any harder.
But in those circumstances, that number is generally much higher. We'd be looking at, you know, 800s or 900s rather than 300s. So although this doesn't fit the classic interpretative rule about whether this is positive or negative, this is still an unusual.
Circumstance. And so for me, I, I would prefer answers B or C, in fact, possibly C because it's It's so, So unusual. This animal actually then went on to have a high dose dexamety suppression test, which isn't maybe what you would expect.
But if it had a low dose dexamethasone suppression test, the results wouldn't have been any, any different. So if this amount of dexamethasone can't suppress cortisol, then a lower dose wouldn't have been able to either. So what this tells us is the animal is unable to respond to dexamethasone and the adrenal tumour is a possibility.
And when we look back at that cortisol. Response to ACTH then I think adrenal tumour is a possibility there. What we're seeing is the animal is producing an excess amount of glucocorticoid.
Therefore, from the adrenal gland, but in a way that is independent of ACTH that giving it ACTH is not responding to and that's, that's the case. About 40% of adrenal tumours don't respond to ACTH which is one of the arguments against using the ACTH stimulation test. To diagnose Cushing's disease where adrenal dependent.
Tumour is a possibility. So, so that's it if you like a little bit of advanced level interpretation of an ACTH stimulation test. It's not a set of results you're gonna come across every day or every week.
But just to let you know that that just looking at the one hour post, most of the time is going to give you your answer for whether that's a positive or negative test result, but occasionally we'll come across these cases where we've got that high flat line response to ACTH which do turn out to be adrenal tumours. This is Still adrenal, but we've stopped talking about Cushing's disease now. We've got somebody who's concerned about Addison's disease.
Well they say they're concerned about Addison's disease in the piece of paper they sent to the lab, but they also say it's polyuric and has fit so. Whether that high distance is highest on your list, I'm not sure. OK, so, they took the opportunity to measure aldosterone as well as cortisol when they did their ACTH st for Cushing for Addison's disease, and that's becoming an increasingly recommended thing to do, I think, still not that common, but if you have the opportunity to do it, then it may provide further information, particularly if you have an animal you suspect of having Addison's with.
That does not have electrolyte abnormalities. If you've got normal electrolytes, it's useful to find out whether it still has a pituitary. Sorry, a pituitary failure type Addison's, like a secondary Addison's or whether it genuinely has adrenal cortical destruction.
So yeah, we've got. Some fives and twos. Twos, yeah, and I, I think I would be happy.
Sorry, I've got two versions of the screen. . I would be happy.
That hypoadrenal corticism is ruled out. So if the adrenal cortex Has been destroyed, then we wouldn't be able to get this cortisol response. So that tells us this animal does still have an adrenal cortex.
But something is suppressing as all the ste on output. Aldosterone is mediated through angiotensin and potassium. So either this so what this animal turned out to have was it was also on ACE inhibitors and so which will reduce.
And you tensein2 which will Reduce the adrenals capacity to make aldosterone and that seems to be a temporary effect. That's not a permanent effect. But here's an example where it just came out a little bit odd.
We ruled out Addison's disease based on the animals able to produce cortisol and the aldoster one result we had another explanation for. OK, that's Taken quite a while, but we've covered the two most popular topics. I am happy to have a quick look at calcium as the 3rd most popular topic.
Has anyone posted any questions so far, James, that we can, that might help us decide what whether we need to spend any time on the the topics we've already covered before we move on to calcium? No, I think you're explaining it too well. There aren't any questions on those so far, but again, people feel free to, to ask any questions, and we can answer them at the end, but I think a short bit on calcium would be popular.
Cool. And I'm aiming to give us a few minutes for questions before handing over to Ian at about 12 o'clock. So we'll aim to spend the next 10 minutes or so on this.
There should be a handout available to you for this session which includes a chart that looks like this. If you're in the circumstance where you're investigating animals with calcium disorders and you get to the stage that parathyroid hormone analysis is necessary to help you work out what's going on, then this chart will give you the answer. Or at least an initial answer.
So using this chart, you decide whether your ionised calcium is high or low, and you pair that up with a high or a low PTH result to end up conceptually with a result that indicates primary hyperparathyroidism. Secondary hyperparathyroidism, which might be nutritional or renal in origin, primary hypoparathyroidism, or one of the parathyroid independent hypercalcemia, which is where generally the extra work needs to be done to just try and define whether that's to do with granulomatous disease, paraoplastic. Neoplasia, like a lymphoma or a vitamin D intoxication, all of which could end up with a result in that box.
So with that simple box, we can have a look at some results. If you have that to hand, that makes interpreting these results even easier. Again, if you want to use the chat facility to pop in your thoughts with these, that's that's absolutely fine.
This is a 13 year old female golden retriever. And we don't know anything about it. I presume it's been sampled because it has polyure polydipsia, they've identified a calcium, but not identified anything else obvious about the animal that that tells them why it's got high calcium and so they've submitted.
For parathyroid hormone and parathyroid hormone related peptide analysis as well as an ionised calcium analysis. So yeah, if, if you're able to see that chart and you were to take your ionised calcium result and go along the bottom of the chart towards the right and then take your PTH result and go. Up the chart, you would end up in the primary hyper parathyroidism box so answer D would be the most appropriate answer here.
So I think this is a relatively straightforward, the animals producing more parathyroid hormone than it should, and therefore that calcium. It's not surprising that that calcium is high and we have an explanation. For that.
So what we're seeing there is that when the Because of the There's an elevation in PTH causing Will cause a hypercalcemia. Whereas if we've got some other cause like a lymphoma or a granuloma disease process or a vitamin D intoxication, then that's the mechanism that's causing the high calcium. And so in that situation, through negative feedback, PTH is going to be decreased.
I didn't make that big of a thing of it when we're talking about adrenal disease and and adrenal tumours versus pituitary. But in the interpretation of any endocrine test, negative feedback really is your friend. If you're not sure what's going on, remember negative feedback and think about what negative feedback should result in in in a normal animal to then decide whether or not you're seeing that, whether that helps you decide what the pathology is.
So here what we're saying is that if we've got a situation with high calcium. Then if the PTH sorry, if it's a non-parthyroid reason then that PTH value should be really shut down and low. And if it's not shut down and low, then we're thinking parathyroid dependent.
So let's just look at another example and think about that. This is a keyson with high total and ionised calcium. The PTH is in the reference range.
It's towards the top of the reference range. It's in the reference range and PTHRP is negative. Again, if anyone wants to start thinking about what they might choose as an answer for that.
OK, so. I'm not getting anyone agreeing with me, so that obviously. Completely confused folk.
Let's Just have a look at that ionised calcium in that PTH value. We'll do it kind of the chey way first and then we'll come back and we'll have a think about the path of physiology. But if we go back to that.
Table that was a situation where we had a high ionised calcium, so we're coming up here and then we've got a result which is in the top part of the reference range for PTH which puts us in this primary hyperparathyroidism box. And why is that the case? Well, because If it was a cause of hyper sorry if it was a cause of hypercalcemia that was not because of the parathyroid, we'd expect PTH to be really shut down.
So we'd be expecting this PTH value to be right at the bottom of this reference range or below if this was coming from lymphoma or granulomatous disease. So this, this result, although the PTH is in the reference range, it's inappropriate for that degree of hypercalcemia. That degree of hypercalcemia should really have shut down parathyroid hormone production.
And it's not done that. So this is primary hyper parathyroidism and also key horns as a breed are are highly predisposed to that condition. So anyone answering E would also be.
Would also be right. OK, so we're getting Getting there on time. Let me just cover this, this last one, a 5 year old male golden retriever also has a high ionised calcium.
His PTH is suppressed. And he has a positive PTHRP result. OK, so.
This is a very helpful device because I now know that we haven't covered PTHRP today. We didn't. Really start the calcium section with any kind of background or introduction.
So quite a few people are saying what is PTHRP? PTHRP is a factor that's produced mainly by neoplastic tissue, which is identical to parathyroid hormone in its biological activity, but structurally is a little bit different. So essentially the end of the molecule that interacts with the PTH receptor is identical between these two molecules, but then the rest of the molecule varies, which allows us in the lab to detect them as separate entities.
And and they don't interfere with one another's analysis. But biologically they have similar activity. But the main source of PTHRP is is neoplastic tissue.
So if we went through this in stages, if we look at this result, we've got high calcium, is that appropriately suppressing PTH? Yes it is. So that tells us it's not the parathyroid gland that's The problem that tells us that the calcium is coming from somewhere outside the parathyroid gland parathyroid gland's doing its job and shutting down, which if we use that table and we go along to the right for high calcium and up just a little bit for our low PTH result, we're in the box of parathyroid independent hypercalcemia, where we've got neoplasia, vitamin D, toxicosis.
And granulomasis disease and because here we've got a positive result for PTHRP that helps us make that distinction in that box. So in that box of those possible causes. Which are hypercalcemia of malignancy or vitamin D toxication.
This PTHRP tells us it has to be the hypercalcemia of malignancy. So the best answer here is going to be answer A, but I do recognise that we didn't really spend any time explaining what PTHRP was. OK, I think in terms of time now.
We really should stop, see if there's any questions, get time for Ian to get organised and ready to take over, . And, and see how we've, how we've done. Thank you for your, thank you for listening.
Thank you very much, Peter. I think you've provided a really clear summary of all of those tests and highlighted just how challenging some of these interpretations are when we have reference ranges that, that are for normal dogs rather than the dogs with, with these diseases, . There are a couple of questions, coming through, if you're happy to answer them, the, the, first one, is about how commonly you think we see vitamin D toxicosis, is that something that you.
OK, I can certainly answer vitamin D, toxicosis. There are a couple of classic examples that are worldwide and so there, there is a topical medication for human patients that have got psoriasis, which goes under a variety of trade names like Dovinex, Dovabet. The active ingredient is a vitamin D analogue called calcipotriene or Cal.
Something along those lines, there's another version of it in one of the packages. . And it seems that either by licking owners that have applied psoriasis cream to their body or in most cases, I think actually the animal, usually a dog, sometimes a cat seems to enjoy the taste of this medication.
Dogs have chewed through tubes of it and given themselves vitamin D intoxication by that mechanism. Other causes that we have to consider depending where in the world you are. If you're in the United States, rat poisons, rodenticides, maybe colicalcierol, that's vitamin D based, those, as far as I know, are not, a common rat poison in Europe, so unlikely in Europe and the US would be a significant consideration.
Also, it's been reported several times circumstances where, pet food manufacturers have got their formulations wrong, and that's applied both to small Not heard of very much manufacturers, but also occasionally to some very, very big and famous manufacturers where they have occasionally released a batch of pet food with far too much vitamin D in. And so it's something we always just kind of have to have in the back of our minds as a possibility. Speaking to the calcium and vitamin D labs is a useful thing to do if you are thinking that because they will likely have had a little bit of a burst of diagnosis of vitamin D intoxication if If there's been a diet with any degree of consumption out there being used.
There are some vitamin D, toxic plants, there's a particular type of, lily house plant which is vitamin D. Toxicity. And then that's great.
OK, mechanism of granulomas's disease is also vitamin D based, so you have to still think about vitamin D even though the underlying cause is granulomas's disease. Perfect, thank you. I think we're nearly out of time, but I'll just ask you 11 final question, which sounds quick and easy but may not be, which is Louise has asked whether you recommend an ACTH stimulation test or a low dose dex for the initial test with a dog that you think has Cushing's.
So there is a a The answer to that is it depends. I think you just have to recognise, sorry? I said I thought it might be.
I think the basic principle comes down to recognising the false positive rate with the low dose de and recognising the potential for the false negative rate with the ACTH. So there are circumstances where you might have to do both to feel comfortable with your diagnosis. If you've got an animal that doesn't look very much like it's got Cushing's and you know it's got something else wrong with it, let's say it's a diabetic or it's got some evidence of renal dysfunction, then the chances of a false positive for the low dose des are much higher in that patient and therefore you might choose to use it more specific ACTH stim in that case.
If you're in a circumstance where you're not convinced it's got Cushing's disease at all, but you feel like it's something you have to rule out and have something objective to help you rule that out. And where you're already thinking Cushing's disease is unlikely, then if you got a negative result back on a low dose decks, that would really confirm that with a high degree of confidence. And so in situations where you really just want to rule it out rather, and it's kind of lower down your list of differentials than a low dose is very useful.
So that's what I mean by it depends. If you're trying to rule it out, low dose X is really good. If you have circumstances where the false positive rate is going to be increased, which is other non-adrenal illnesses or medications, then the ACTH that might be a better choice.
Hopefully that answers this question. That's perfect. Thank you very much, Peter.