Good evening everybody and welcome to a Thursday night members webinar. My name is Bruce Stevenson and I have the privilege of chairing tonight's webinar. I don't think we have any new people on tonight, so, no need to do the housekeeping.

As usual, we'll keep all the questions over to the end. And we do have some poll questions going through. So remember the polls are anonymous, so don't be shy.

Give it a vote and we'll have fun as we go through. It gives me great pleasure tonight to introduce our specialist for this evening. James Warland graduated from the University of Cambridge in 2009, and he spent a couple of years in general mixed practise in Bedford.

He is currently a European and RCVS specialist in small animal internal medicine, having returned to Cambridge to complete his residency training. After his residency, James worked in a specialist referral practise as a senior clinician at the Animal Health Trust in Newmarket. And then in October, James started a Wellcome Trust funded PhD at the Stem Cell Institute as part of the University of Cambridge.

James, welcome to the webinar vets and it's over to you. Thank you very much, Bruce. Thank you for that very kind introduction, and thank you everyone for tuning in to listen to me talk about, hypercalcemia.

It's one of my favourite subjects, so I hope I'll do it justice. It's quite a big, subject area though, . As you can imagine, so, to outline what we, we're gonna talk about, I will briefly discuss, some normal calcium metabolism.

I won't go into huge amounts of detail because, that's, a bit dull and we want to make it clinically interesting. But we'll go through the causes of hypercalcemia, my approach to a hypercalcemic patients, including, the diagnostic tests that we should run and any emergency treatment, and then we'll touch upon the specific management of, of certain conditions. Unfortunately, it's probably an hour is not long enough to go through in huge detail all of the different conditions associated with hypercalcemia, but we'll, hopefully get, get some interesting points through on, on these ones.

So, normal calcium homeostasis, calcium is, incredibly abundant in the body, but 99% of it is, is stored in bone, . So it's, it's tucked away, as a, as a storage mechanism there. In the serum, which is the, the calcium that is going to actually affect the body, on a minute by minute basis, is found in three forms.

The ionised calcium is the biologic. The active calcium and if that, that is what will cause you your clinical signs of hyper or hypocalcemia, and it's very tightly regulated by the body. But complicating the measurement of calcium, you also have about 40% that is bound to protein, .

Mainlyin and then as much smaller proportion that is related to other things such as lactate citrate bicarbonate. And calcium is incredibly important for a wide variety of functions, nerve conduction, neuromuscular transmission, muscle contraction. Hemostasis, and that's why we see such a wide variety of clinical signs, both, specific ones, to do with, kind of muscle contraction and twitching, and some very non-specific ones because those are so wide ranging.

Calcium is very tightly controlled in the body, short term through bone resorption and mineralization that happens very rapidly and longer term control through excretion and absorption control. So there are 3 main, hormones that are involved in calcium homeostasis. There's the parathyroid hormone PTH, which is produced by the parathyroid glands, as its name suggests.

There's also vitamin D, which is, activated. In the kidney to form this 125 dihydroxy, vitamin D, which is the active form. The body takes it in mostly in the diet, and then it is partially activated by the liver to with that first hydroxylation, and then it's fully activated by the kidney.

There's also calcitonin, which has a much more minor role, in, in most calcium homeostasis, primarily acts to decrease the level of calcium, although its role is quite complicated. So, PTH, is mainly going to be the one that we're, interested in, in the low calcium situation. It acts to increase calcium metabolism from bone and also acts to, Increase the production of active vitamin D in the kidney, which then in turn will increase the, increase the absorption of calcium from the gut and again, have an action on the bone.

On the kidney itself, there's also a decreased calcium excretion and an increased phosphate excretion. So it, it will lower phosphate levels and increase calcium, levels through that mechanism. And the vitamin D and the calcium will both have a negative feedback effect on that PTH level.

So that's what's keeping it kind of in a homeo space, in a homeostatic mechanism. The calcitonin, will act in the high calcium states, particularly if it's acutely, to increase calcium deposition in bone and lower the, the serum calcium level. Calcitonin's actions are actually quite complicated and it's only really, Does that in that acute setting longer term cal calcium, calcitonin, sorry, doesn't, actively reduce the calcium in the same way.

And that's why, we don't really see, disease associated with, calcitonin deficiency or excess, in, in reality. The clinical signs, of hypercalcemia, are Mostly non-specific actually they often cause lethargy, weakness, inappetence, anorexia. And in cats, those are particularly vague.

So the cats, usually present with very vague, non-specific signs. One of the major ones in dogs, but less commonly in cats is, polyuria and polydipsia, and we'll discuss that later. Urolithiasis is an important, consequence sometimes of hypercalcemia, and, and then, subsequent increases in calcium excretion through the kidneys.

We sometimes see other, gastrointestinal signs such as constipation, vomiting, and gastric ulceration, and sometimes, arrhythmias. Some of the presenting signs also will relate to the diseases that cause hypercalcemia, but, really in this slide, I've talked about the ones that are associated with the hypercalcemia itself. When we talk about measuring calcium, you're obviously doing this in blood, and the the calcium level that you'll be detecting in most, of your samples, on a standard biochemistry profile will be the total calcium measured in a serum tube.

It's important that you, that you do do that in the serum tube because, things like EDTA, will slate, the calcium and produce a falsely low reading. So it needs to be serum. But in, and that's the kind of the easy calcium to measure.

It's the one that we can measure, easily in practise. The ionised calcium, however, is the, biologically active form as I already mentioned, and it's the one that is probably more interesting for trying to, determine the severity, and the presence or absence of hypercalcemia in our patients. Some practises can measure it in-house, particularly if you have, blood gas analysis, .

And if you're sending it away, then it requires special sample handling. It's not particularly difficult, but, contact with air can affect the pH and that affects, the ionised calcium level. And it's worth discussing it with the lab, how you want to ship that to them.

Hypercalcemia is important for a number of reasons. One, all those clinical signs we just, mentioned are enough in themselves to, to significantly impact on, on quality of life. Clearly some of the diseases that are causing the hypercalcemia will be life-threatening, some more so than others.

. In themselves and actually hypercalcemia is a very significant finding from a diagnostic point of view because, it has a relatively short differential list. You may not believe me in a few slides' time when we discussed that, but it's, it's relatively short compared to, to many of those non-specific clinical signs we saw. But the other reason that hypercalcemia is important is because, it can cause knock-on effects of renal tubular injury, and intrinsic renal failure, .

And particularly if it's severe or long standing, then we can see renal failure results, can also cause, urinary obstruction if there are, urolithiasis, and can cause significant morbidity through that. I've mentioned hypophosphatemia People often talk about the calcium phosphorus products, and that's meant to be a measure of, of, how likely hypercalcemia is to damage the kidneys because it's, a marker of how likely they are, it is to form insoluble complexes that are going to cause that damage. In reality, the the utility of the calcium phosphorus product as an actual number and measurement is, has not been very well, proven, although it's it is fair to say that, the diseases associated with hypophosphatemia and the concurrent hypercalcemia and hypophosphatemia, is likely to cause more damage, but I, I wouldn't, just kind of go on an arbitrary number of, of times in those two together.

So the differential diagnosis list, is, easily remembered with this pneumonic on the right hand side hard ions, which cover the most common, ones. I've split them up on the other side to the, on this side, the most common thing so spurious, a lab error, it's worth making sure that they've been handled correctly and that, the hypercalcemia is, repeatable, if you detect it. Malignancy is the most common cause in dogs, particularly lymphoma and anal sac adenocarcinoma.

In cats, they do see, you do see hypercalcemia associated with malignancy. Actually, often they have, they have it associated with squamous cell carcinomas. But the thing to remember is that malignancy, Almost any malignancy can cause hypercalcemia.

So, carcinomas, of the mammary glands, transitional cell carcinomas have all been associated with malignancy. And essentially, if you find any tumour in a dog that's hypercalcemic, or a cat, then, but particularly a dog, I'd be suspicious that it may well be the cause. Primary hyperparathyroidism, more common in dogs than cats.

Renal disease is an important cause, hypoadrenal corticism, so Addison's disease, and in cats, we'll discuss idiopathic hypercalcemia as well as an important cause of, of hypercalcemia. Moving on to the less common, causes, toxicity. Particularly a vitamin D, is, is an important differential, particularly for acute hypercalcemia.

So, rodenticide toxicity with vitamin D, rodenticides, not, really very common in the UK compared to, many other countries where they, use these vitamin D, based rodenticides more common. We, we usually see, the anticoagulant rodenticide toxicities, but potentially, if, if a dog ingests that, then that is incredibly toxic and can cause acute, hypervitaminosis D. Sometimes owners will be supplementing their, their dogs for vitamin D.

And another common one is psoriasis cream, . That the owners will be using themselves and for some reason they think it's a good idea to let their dog lick that off them after they've applied it and that's a surprisingly common cause of of hypervitaminosis D in dogs. .

The, and then there's a few other causes, houseplants, treatment for hyperparathyroidism. And sometimes, dietary causes, can, dietary contaminations can be a cause. There have been reports of, of, pet food being contaminated with vitamin D.

And if you see a kind of outbreak, if you like, of vitamin D toxicity, then that's worth considering. Granulomatous disease, again, not such a big problem in the UK, in many countries where they have a lot of, infectious causes, fungal disease, particularly, we can see hypercalcemia related to that. I guess the big one in the UK, and, and rising up everyone's differential lists generally is angiostroullus the zorum in dogs, a lung worm, which, has certainly been associated with hypercalcemia, and I'll discuss that later.

Osteolysis, is a less common cause than, the PTHRP related, hypercalcemia or malignancy, but also can cause, hypercalcemia. And it's also seen in young animals, as a, as a normal finding. It's important to take a, a really full history when you've detected hypercalcemia.

So I just mentioned the young animals, it's considered normal to have a mild hypercalcemia and certain diseases will be more common in different ages. Breeds. I don't want you to make any assumptions.

Actually, with hypercalcemia, particularly, most of these diseases can occur in any breed. So things like cancer, obviously hyperparathyroidism can happen in any breed, but there are strong predispositions, particularly in the keys to primary hyperparathyroidism and, in things like cocker spaniels that will get anal sac adenocarcinomas. It's worth questioning the owners carefully about the possibility of toxicity.

And it's also worth thinking about, parasite treatments and travel history, particularly when you're thinking about granulomas disease. Physical examination is clearly going to be very important, given that we've, talked about a lot of things, particularly, neoplastic causes. The first point I would make is that it's worth repeating your physical examination.

Everyone's busy, you're gonna perform a quick physical examination when you first see an animal through the consulting door. But the finding of hypercalcemia should really be a trigger for us to go right back and go over that animal with a really fine tooth comb looking particularly at the lymph nodes for lymphoma. It may only be a single lymph node that's that's enlarged, it may not be a multicentric lymphoma.

Do a full rectal examination to look for the anal gland adeno carcinoma that can sometimes be very small, and still be producing, hypercalcemia, and it's worth palpating the ventral neck as well to look for a parathyroid mass. Any other cutaneous oral abdominal masses that you find are worth considering as a potential cause because as I say, any tumour can cause, the, the hypercalcemia of malignancy. Next step I would, I would go down would be diagnostic imaging, again, looking for all of those different, causes.

The thoracic radiographs you're looking particularly for neoplastic causes, mediastinal masses that again, they may not be a multicentric lymphoma, but there may be a large mediaspinal mass. You may see, granulomatous disease in the lungs, you may see, signs of primary lung tumours or metastatic lung tumours. On the ultrasound, you may also, you're again looking for those primary causes of hypercalcemia, including, lymphadenopathy, intestinal thickening, but you're also potentially looking for consequences of that hypercalcemia and, particularly urolithiasis is worth looking out for, in this, abdominal radiograph, you can.

See, sister lip in this cat's bladder, as a result of the hypercalcemia that, that they have. So it's worth considering those possibilities and not just trying to find the cause of the hypercalcemia, but also, the consequences of it. Sometimes the other blood blood results that you already have can be very useful in trying to narrow things down.

Phosphate, we already mentioned that parathyroid hormone, Which will come on to discussing the measurement of, can lower the phos the phosphate level and therefore in diseases that are driven by that, we often see a low phosphate, whereas in, diseases such as renal disease, where phosphate retention is a problem, and vitamin D toxicity that is going to increase the phosphate absorption, We often see hyper hyperphosphatemia, so hyphosphate, and that can be a really helpful thing to look at to try and differentiate those causes. You may see other changes in electrolytes, to indicate that Addison's is a possibility, and you may see evidence of azotemia to, give you a concern about renal disease, but remember that the azoenia could also be pre-renal or potentially post renal in these cases where, a urolithiasis and obstruction is a possibility. And on that subject, the urinalysis is very important that, because, the effect of hypercalcemia is to cause, polyuria, that happens through an antagonistic effect on anti-diuretic hormone.

These animals don't have an ability to concentrate their urine normally, which means that even in, in a pre-renal aenia. They will still have dilute urine and it's really important to remember that because you can't, you can't reliably, differentiate between a pre-renal cause and, renal azoenia, from the urine specific gravity as you kind of normally would when you're assessing renal disease. Haematology is really to look for, another cause, such as, a lymphoma or leukaemia in the bloodstream, and it's worth doing that.

I just put culture at the bottom, for the urinalysis, . A lot of dogs with hypercalcemia, will have a urinary tract infections, either related to the polyuria, and incontinence or related to the urothiasis that they have. And I think it's worth assessing these dogs for a urinary tract infection as a complicating factor, for their condition.

So moving on to kind of first disease that causes hypercalcemia, Addison's disease, an uncommon disease in dogs, even rarer in cats, but worth bearing in mind, for these often vague clinical signs, or sometimes more dramatic if they have the kind of full blown, Addisonian crisis. We see hypercalcemia in about 30 to 40% of dogs with, with Addison's disease. Typically it's mild and actually, we don't see the hypercalcemia as being the cause of any of their clinical signs, really.

The clinical signs are due to their Addison's disease, aside from the, the calcium imbalance. But the, seeing that hypercalcemia can be a, a, something to alert you to the fact that, hypoadrenal corticism is a possibility. This study that was, from the RBC, about 10 years ago now, Found that both the total and ionised calcium concentrations were elevated in dogs irrespective of their sodium potassium ratio.

So it's kind of separate to those electrolyte abnormalities and therefore the atypical Hadisonian dogs, those ones that present with no electrolyte abnormalities and just vague waxing waning GI signs, weight loss, poor appetite. They are ones to consider still as, as being possibilities for Addison's disease. The cause is unclear, but, it's, it's an important thing to rule out.

Diagnosis, of course, definitive diagnosis is an ACTH stimulation test. If you're not too suspicious and it's not an emergency, then the alternative that's a little bit cheaper is to do, is to run a or cortisol, so an unstimulated cortisol level, which is useful because if it's over about 55 nannomoles per litre from a reputable lab, then that will rule out Addison's disease and you can move on with your, diagnostic test. Unfortunately, if it's below that level, it doesn't confirm the diagnosis because some normal dogs will have a low basal cortisol, but it, it's a useful rule out test.

So more things that we commonly test for in a hypercalcemic animal. The next one's, the parathyroid hormone PTH. I'm sure all of you have, measured PTH, as, as an investigation for hypercalcemia.

It's produced by the parathyroid gland as I already mentioned, and does that normally as a response to hypocalcemia. And potentially to hyperphosphateenia and is reduced by vitamin D concentrations. Handling of the sample is important and similarly to that ionised calcium measurement, you need to discuss with the lab the best way to handle it.

But this one is measured in EDTA plasma, and needs to be handled carefully and shipped, correctly to, to be able to get an accurate measurement. The other thing that's important is that it's, it's necessary to have a concurrent calcium level at the same time, to be able to interpret this result. So make sure you, even if you know the dog's hypercalcemic, it's worth getting a sample at the same time as you take the PTH sample to be able to, document what its calcium level was at that same time.

So just a practical example for you, this is, I wanted to introduce you to Smudge. This is Smudge. He's an 11 year old male muted terrier.

He has quite a typical history of these hypercalcemic animals of being quiet, inapetent, and polydipsic, with nothing really found on physical examination. You've quizzed the owners carefully and he has no history of toxicity, . But looking at his biochemistry, you can see that, he's got quite a markedly elevated, total calcium and ionised calcium, and they're both well above the reference range, with a phosphate that's at the bottom end.

You find nothing with his urinalysis and you rule out Addison's disease with a basal cortisol that is normal. . And you do some imaging as well that, that you find no evidence of any neoplastic disease.

So at this point, you measure his parathyroid hormone, and that's the result you've got, 50, 51 be ounce per mL. And my question for you is how would you interpret this result? Right, folks, so we're launching the poll.

You know how it works. Click on the result that you feel is most appropriate for the answer and we'll give you a minute to vote and then we'll show up those results. Remember it is completely anonymous, so don't be shy.

I just wanted to also say to you, if some of you are hearing slight variations. In James's sound. We did have some technical issues earlier, so James is on the phone at this stage.

So, it's nice and clear, James. So it was a good decision. Thank you.

Right, come on guys, let's get voting in another 10 seconds or so. Right. Let's close that poll quickly.

And share those results. Can you see those, James? Yes, I can see that.

That's interesting. OK, so yes, we've got about, I assume no one else can see this. So about 25% of people have said that they think it rules out hyperparathyroidism.

Most people, 71% have said that it might be hyperparathyroidism, but you'd like to do some more tests and the, the last one is the least popular, only 3% said that it confirms hyper hyperparathyroidism, . I, that's an interesting result. I assume everyone thinks that it rules out primary hyperparathyroid oh sorry, that a lot of people have said that it rules out primary hyperparathyroidism because it's within the normal range, .

And actually, I would go with, with answer 3 in this case, which is the least popular one, because that parathyroid hormone level is, is inappropriate for this dog. So the calcium level is, is very high, and in a normal dog, if their calcium level goes high like that, the parathyroid hormone should be very low. So it should be well below the bottom of the reference range.

Remember that this reference range is for, It's kind of for all dogs, all healthy dogs rather than dogs in a particular, scenario with their calcium. I, I. Agree that it's, that maybe we need to do some more tests, but actually, in reality, we've got no evidence of, of significant kidney disease and the phosphate is low, which is consistent with it being parathyroid related.

And for me, this would be enough to confirm that the dog has primary hyperparathyroidism. So, to discuss primary hyperparathyroidism further, it's usually going to be caused by an adenoma or hyperplasia or carcinoma, of the, parathyroid gland. You can get secondary hyperparathyroidism due to renal disease, nutritional disease, or adrenal disease.

I said to that previous case that we have no evidence of renal disease. He was on a normal diet and we had no evidence of the adrenal disease. So I would be quite happy that he has, primary cause.

It can happen in any breed of dog, but cusins are predisposed. Often has an insidious onset, with many of them being asymptomatic. In fact, in this large study of, of, dogs with the condition, 42% of them were found completely incidentally when they were in other things like dentals.

Urolithiasis and urinary tract infections are common, and, as I just said, A lot of them will have a PTH within the reference range, so 73% of them will have a PTH within the reference range, and that's really important. It's about whether this is a an appropriate PTH level for for the, the case. Moving on to PTHRP, the biological effect is similar to PTH in terms of its activity to increase the calcium, decrease the phosphate, but, it's only in, in life found in the foetal development, and it's therefore undetectable in adults.

But it's ectopic production of PTH by tumour that drives hypercalcemia of malignancy. So we're, when we're looking for PTHRP we're really looking for, evidence that there's a neoplastic process going on. So the next case I wanted to introduce you to and, and get your feeling on is Maxi.

He's a seven year old male neuter springer spaniel. He has, again, his, a fairly vague history with PUPD lethargy and. You found nothing on physical examination.

You went back and you did a rectal exam. He also has a fairly high calcium, 3.6 and ionised again, a fairly markedly elevated 1.7, mmol per litre.

Phosphate towards the bottom end of normal and again his renal parameters are normal. Once again, he ruled out basal cortisol and this time, your PTH measurement is what I would consider to be appropriate for his hypercalcemia. So this rules out in having a a parathyroid.

hyperparathyroidism in this case. So the next step is that you, measure his PTHRP, and you get this result 0.25 grammes per mL, so less than the reference range.

So similar question, how would you interpret this result? Right, there you go folks. The poll is open.

Feel free to vote. James, just to let you know that when we show the results, all the delegates and participants can actually see them as well. OK, thank you.

Folks, just a reminder there on the typing of the poll question. I apologise. A or one should read this rules out a neoplastic cause.

We left out the word out when they typed it on. Sorry about that. Right, 5 seconds more.

Right, let's close that poll. And James, there's your results. OK, great.

So, so we've got a fairly even split between the ruling out and ruling in the neoplastic causes. I'd, I'd say that I don't think it can confirm a neoplastic cause because it's actually within the reference range. It's, it's lower than, lower than 0.5, so it's, it's a kind of normal result.

So I don't think we can confirm a neoplastic cause with it, . But I would agree with the majority that have said that it might be due to neoplasia, and some cases of, hypercalcemia or malignancy are not due to PTHRP, so, it's important to still consider malignancy as a possibility in these cases. So this is Maxi's, .

Jurassic radiographs, and I deliberately chose one that's a little bit subtle compared to the one I showed earlier that a huge mediastinal mass. But Maxi has a, slightly smaller mediastinal mass, that, would be something that you would find if you'd imaged this dog, and is the cause of his hypercalcemia. So as I said, hypercalcemia is driven by PTHRP from the tumour, but it's not always elevated.

So for a normal result, we can't rule out neoplasia. There are other mechanisms, some of them are not fully understood, so some, some of these cases will have hypercalcemia and we find no real reason. Sometimes bony lysis can be the cause of the myeloma, osteosarcoma, and some metastatic bone tumours, there, that can be the reason for there being a hypercalcemia without an elevated PTHRP.

Lymphoma and anal sac adenocarcinoma in dogs are particularly the important ones for causing hypercalcemia, but as I said earlier, any tumour can cause, hypercalcemia or malignancy, and I wouldn't rule it out for any, . And the treatment for this is really going to be to try and address the underlying cause. So whether that's treating the lymphoma, whether that's surgically removing the tumour, what, whatever that tumour requires, and it's, it would be too much to try and go through all of those in this webinar, that's gonna be the way to address the hypercalcemia of malignancy.

And if you can't do that, if it's a palliative treatment or it's got, there's too much disease and you're, and you're just wanting to Improve their quality of life, and things like this phosphonates or glucocorticoids would be the way to try and treat those. Just wanted to show you this case. This is a dog with multiple myeloma, showing some lysis of the, vertebral, bodies, particularly at that cranial end on the left-hand side's got some quite nasty lysis of, of those vertebrae and that again was, was a cause of hypercalcemia in this case.

Vitamin D is another thing that, that you may want to measure. You can measure both the 25 hydroxy vitamin D and the activated 125 dihydroxy vitamin D and the pattern will vary depending on the toxicity. We don't actually find that we end up measuring vitamin D that often, because the history is usually diagnostic for most toxicities and it's then not necessary to confirm it.

But if you need to, then you can be. It's also worth remembering that vitamin D can be measurably increased with other conditions. We mentioned granulomatous disease because of the activation of vitamin D by macrophages.

And the PTH and PTHRP can drive up, the activation of vitamin D. So sometimes dogs with primary hyperparathyroidism or malignancy can actually have elevated vitamin D levels as well. So it's worth remembering those, and I would say that your history is going to be the, the way to, to really discover, vitamin D toxicity.

A few other tests to consider. Hyperthyroidism, I think is worth ruling out in cats. Not a common, presentation of hyperthyroidism, but hyperthyroidism is common, and, some of these cats will have, neck masses if they've got.

parathyroid mass or a thyroid mass, and it's worth, hyperthyroidism has been reported as a cause in cats. We've mentioned angiostrongulluspozorum, and, I would, I would want to rule that out in any dog that's showing consistent clinical signs. And then in dogs, particularly, you want to look for occult neoplasia.

So again, Another examination, potentially biopsies, potentially looking in the lymph, aspirating the lymph node, liver, or spleen. It's worth considering whether you've had a really good look around their mouth, maybe when they're sedated for their imaging, make sure you've had a really good look for a small tumour or a tonsillar tumour. And in some cases, if we're really struggling to find a cause, particularly in dogs, we may turn towards doing things like bone marrow, aspirates or biopsies, or further imaging like a CT, but it's quite uncommon that we won't have found something by the time we've done all of this stuff before then.

Just wanted to mention feline idiopathic hypercalcemia, as its name suggests, it's, idiopathic, so we don't know what causes it. And it's unfortunately, the most common cause of hypercalcemia in cats, . They usually have they mostly have mild clinical signs that are vague, but the hypercalcemia be completely variable from mild to quite severe.

Because it's idiopathic, it's a diagnosis of exclusion, and This is where it's a bit of a balancing act because I've just listed a whole load of tests that you could do, including doing bone marrow aspirates and things on, on animals, to try and find a neoplastic cause, for example, of the hypercalcemia, and then I'm telling you that the cats, it's usually idiopathic. So for cats, particularly, I I would usually stop unless I had a, a reason to go looking in their bone marrow, such as, haematology abnormalities, or I was really convinced that there was something else going on, I would stop at having done routine bloods, PTH PTHRP which should both be low, and kind of screening imaging, of them. A detailed physical examination, detailed history, and I'd consider measuring the vitamin D.

And after that, I think it would be reasonable if you found nothing else to diagnose them with idiopathic hypercalcemia. Emergency treatment is, important for these cases, or for some of them at least, because the hypercalcemia increases the risk of renal injury. Unfortunately, it's difficult to predict which cases are, are high risk, .

I said earlier that hypophosphatemia, alongside hypercalcemia is a risk factor, although the actual product of calcium and phosphorus is not necessarily, that useful, but if they are hypophosphia, hyperphosphatemic as well, then I would, I would be more concerned about them. The primary hyperparathyroid dogs seem to be, at relatively low, low risk of renal impairment, . But the, the animals that I would treat are the ones with severe hypercalcemia, and ones with, hypophosphateenmia as well, and the ones that are particularly sick.

If they're, if they're showing very mild clinical signs and you think it's been going on for a long time, then they probably don't need urgent treatment. If it's more acute than that, and they're very unwell, then you want to be trying to bring down that calcium or if they have evidence of, of renal injury already happening, so aemia. Or other indications that there's, there's acute kidney injury.

The main, treatment to start with is going to be fluid therapy, correcting any dehydration and volume deficit, and then inducing diuresis, making sure that you don't overload them. 0.9% sodium chloride is going to be your fluid of choice because it's going to be the, the one that doesn't contain any calcium and it is going to increase the, the excretion of calcium the most.

Be careful not to overload their sodium and the, the ones that I wouldn't do this in are ones that are hyponatremic, so some of those other sodium ones, I would worry about raising their sodium too fast. But otherwise, sodium chloride is going to be your treatment of choice. Once they're hydrated, and if that hasn't brought down their calcium, then you can think about adding other medical therapy.

Rosemide, is usually the second choice, because it, will induce calcioureesis, but you must only use that once they're optimally hydrated, so they should be on fluids and make sure that they're well hydrated before you do that, because otherwise you risk dehydration. And bisphosphonates, particularly IV formulations if they've got, very high, calcium and a, and a danger of, of renal injury then are a good option to bring down the calcium. I would steer clear of using glucocorticoids, at least to start with, because until you've reached a diagnosis, they can seriously mess up your diagnostic tests.

So particularly for dogs with things like, lymphoma, some a dose of dex is going to really, mess up trying to diagnose that potentially, because it may shrink the tumour quite dramatically. It will work. It will drop the, Calcium, but, until you've reached the diagnosis, I would steer clear of giving glucocorticoids because they'll make your life much more difficult afterwards, .

If you have an acute toxicity case, then, you could also think about, inducing emesis, gastric lavage, activated charcoal to try and reduce that, vitamin D, intoxication. And I've just mentioned here acute kidney injury. It's obviously a whole webinar in itself to talk about acute kidney injury, and the management of that.

But if you have got a case that it rather than just being preventative by hypercalcemia that you actually have evidence for that. Have developed acute kidney injury, then you need to be particularly careful with your fluid therapy, monitoring their urine outputs, their acid-based status and their electrolytes, and some of those cases of vitamin D toxicity, can be very severe and, and dialysis may be a consideration. So just have a, a summary of those, of those steps, but, I think we've been through most of, of this, that's really you want to be, .

Looking through most of your history, examination, blood results, imaging, . And then going down a route of ACTH stimulation test and your strongulus T4 PTH PTHRP and vitamin D, and in most of those cases you will find the cause of, of your hypercalcemia other than in cats and you'll put it down as idiopathic. Going back to some of those specific causes that I said we'd talk about, going back to smudge, the dog that we diagnosed with primary hyperparathyroidism earlier.

So I said that I was fairly convinced that that was the condition he had. It's very nice to be able to, to document an enlarged parathyroid gland and also that's necessary to be able to plan out your surgery. So our next step to these cases that we've diagnosed primary hyperparathyroidism would be to perform an ultrasound of the ventral.

Neck, it does require experience and then a high frequency transducer. So, but it is something that you can try and do in practise, but, maybe with some, with some practise, the normal parathyroids, there's obviously one at each end of the thyroid glands, so there are 4 in total. And they're normally going to be less than 3 millimetres in diameter.

So this is smudges one, that's 0.6 in one plane and 0.4 in the other, so markedly enlarged.

In 85% of dogs then they'll have a single nodule, and some of them will have a smaller percentage, 12% will have two nodules. It's worth considering if you find more than one parathyroid nodule, whether it's possible that it's a secondary hyperparathyroidism because, as you can imagine. And if it's being driven rather than being a something like an adenoma or a carcinoma that is autonomously secreting, it's being driven by a secondary process, then you'd usually get more parathyroids enlarged.

And certainly, if you're getting up to 3 or 4 looking like they're enlarged, then I'd really be thinking about whether this could be a secondary cause. And some of them you'll find no nodule, in which case, it's reasonable to monitor them, try and, get a more experienced radiologist to look at it or MRI of the neck, or in some cases, we will, if I'd be convinced enough from the diagnostics as we discussed earlier that this dog had primary hyper hyperparathyroidism and we could send them straight to surgery. I just wanted to mention that, there are, studies that have looked at the incidence of thyroid nodules, that are incidental in dogs with hypercalcemia.

I think in this study, they found about 15% of dogs had an incidental thyroid nodule, that was unrelated to their hypercalcemia. So it's worth, being sure about your anatomy. That what you're looking at is indeed a parathyroid gland, and I would usually reserve imaging the neck and for when I actually documented that I have a case of hyperparathyroidism rather than going for a kind of fishing look, for an abnormal parathyroid when I haven't got that PTH result back yet.

Treatment of primary hyperparathyroidism is most commonly surgically surgical removal, particularly if it's large, you should remove the abnormal glands leaving at least one, and that ultrasound can, can help identify. By the abnormal parathyroids success rate is usually high, 94%. The other option is that you can do ultrasound guided ablation.

It requires quite a lot of skill, so, something that most people would refer refer for. It is less invasive, but obviously you do need to be able to see the, the parathyroid to be able to ablate it using ultrasound. Just wanted to mention the perioperative management because actually this, the medical management of these cases is probably harder than the surgery, because they are at fairly high risk of developing postoperative hypocalcemia, whatever method you use to get rid of that parathyroid gland.

The normal parathyroids will have had a negative feedback on them and be completely suppressed and not producing any PTH and therefore, as soon as you remove that abnormal parathyroid gland, you'll get a rapid drop in the PTH and the calcium will follow suit. So it's a life threatening condition. I think it means that we shouldn't really be doing this sort of treatment in hospitals where you don't have 24 hour care and you don't have the ability to measure ionised calcium because it can happen quite quickly.

So these dogs really need to be monitored quite carefully. There have been various attempts to try and predict which cases are going to become hypocalcemic after treatment, and it unfortunately is not an exact science, but if they have a high pre-treatment calcium, they have a longer period of hypercalcemia, then those are the ones that are probably at most risk. And that risk period is, about 2 days to 7 days after surgery.

And, and when we're treating these dogs, we would keep them hospitalised for that entire period. So even though they look like they're, they're doing well after surgery, they're still at high risk of developing hypocalcemia. And those ones that are considered particularly high risk, we would actually start them on preventative treatments.

With vitamin D supplementation, prior to surgery, they're at high risk for about 24 hours. You obviously don't want to start it too early because you'll actually kind of raise their calcium and put them at more danger of, of renal injury. But 24 hours, the effect of the vitamin D is not really going to have kicked in before you then remove the, the parathyroid gland.

If they're low risk, then we'd, we'd start them if they became hypocalceemic and we'd be monitoring them once or twice a day. Emergency treatments, is with IV calcium, usually calcium gluconate, over 20 to 30 minutes if they start showing signs of hypocalcemia, which includes, muscle fasciculation, space rubbing, hypersensitivity, And a few other signs. It's worth being really careful with this.

This is a little dog that actually has hypoparathyroidism and we we're treating with IV calcium. It's very irritant outside the vein. So, particularly if you're doing it as an IV infusion, then it's worth being very careful and being, really inspecting the IV lines because this one's all of its skin, necros and, and.

Ended up having a lot of reconstructive surgery. Feline primary hyperparathyroidism is uncommon. It's usually in older animals, like the dogs.

Clinical signs are usually more vague, but interesting, they often have a palpable a palpable parathyroid mass, in, in the case series that have been, published and similarly to dogs, they have hypophosphateenmia, and the PTH can be within the reference range. This is Victoria, who has hyperparathyroidism. We've documented that with the fact that she has a, high calcium, and she also has, a high PTH, a very high PTH in fact.

So she definitely has hyperparathyroidism, but she also is aoic. So she has a, a creatinine of 170, aura of 18.3, .

And she has evidence of chronic kidney disease from her imaging and her elevated urine protein creatinine ratio. So she presents a bit more of a challenge because my question for you on her is whether her hyperparathyroidism is primary or secondary to her renal disease. Right folks, you know the drill, the polls are open.

Another 15 seconds. James, I'm gonna give them another 10 seconds or so. This one's got them stumped.

We've got some late votes coming through. This one is quite hard. I can't see what you say.

Right folks, let's close that poll. And there's your answers, just about a middle down the middle split. I was gonna say that's, that's a very even split there.

So virtually fifty-fifty as to whether we think that's primary or secondary. So I'm going to tell you that I think, that she has primary hyperparathyroidism. And the reason that I say that is, is her phosphate results.

So. Hyper hyperparathyroidism driven by renal disease is typically, driven by the phosphate, so phosphate retention in, renal disease and, . That increases, that, decreases the ionised calcium and that then drives the two together, then drive, the hyperparathyroidism, kind of consequence of that.

So typically in a case of secondary hyperparathyroidism, from renal disease, then they should really have an ionised calcium that is low or normal, rather than high and their phosphate should be higher than, than that, . If you were being really smart, then you could tell me that potentially it was tertiary, but that's never been documented as far as I'm aware in veterinary species. So I was going to ignore that one.

I would say that she has, primary hyperparathyroidism. I did also slightly cheat, because I also She knew that she had a, palpable, mass, on her neck that I didn't tell you about. She had a, a palpable mass as those primary cases do, and, imaging shows this large parathyroid, mass, cyst that she had, there.

Cervical imaging potentially could be a way of trying to differentiate those primary from secondary cases as well, as I already mentioned. Typically with primary disease, we'll see a solitary mass, whereas the secondary one we'll see multiple ones. So in her case, she had a primary hyperparathyroidism, but she also had chronic kidney disease.

Now, whether that was a kind of a consequence of her hyperparathyroidism or whether that was just incidental, she's an older cat, it's not unreasonable for her to have, kidney disease, we don't know. I just wanted to kind of talk a bit more about renal disease and hypercalcemia, because it's not uncommon that we will reveal renal disease and hypercalcemia at the same time. And it's a real clinical challenge to try and determine whether the hypercalcemia is due to renal disease, whether the renal disease is due to hypercalcemia, or whether they're completely independent.

And also remember that we can't really differentiate whether the azoenia is pre-renal, because of that USG being, difficult to interpret. So don't beat yourselves up about it. It's not all, it's not easy, and it's not always possible to differentiate, but the, the main thing we'd be doing is trying to, to rule out, rule out another cause in the renal disease, .

The, the big thing in dogs particularly is that, actually, if you measure that ionised calcium in renal disease, they should be low or normal. It's very rare in a dog to have an ionised hypercalcemia that is, that is due to renal disease. And therefore, if they've got a really high ionised calcium, then I would be looking for a different cause, of their, of their hypercalcemia and, and treating their renal diseases, either being pre-renal, post renal.

Or, or due to the hypercalcemia that they have. And the phosphate can also be useful, as I already mentioned, if it's low, or normal, and it suggests that there's, something like primary hyperparathyroidism or malignancy and an elevated phosphate drives that secondary hyperparathyroidism. I've had a bit of complication to this, this story, with this recent publication, in the Journal of Ethn Internal Medicine, that came out last year, that found that in cats, They, we used to always teach everyone that the, cats are similar to the dogs, but their ionised calcium would be low or normal, and only the total cal calcium would be high.

And actually, this study, they found a lot of the cats had ionised and total hypercalcemia with chronic kidney disease. Usually it was still mild, but some of them, they were severe. It didn't seem to be related to hyperparathyroidism, so actually their PTHs were usually low, although they weren't measured in most of the cats in the study.

So it's kind, it's unclear as to why this was found. It's worth thinking about how the study was conducted and it was a retrospective, and it was looking at cats with chronic kidney disease. And, I wonder whether there's an effect of things like phosphate binders, or idiopathic hypercalcemia that, that couldn't really be detected and most of them were on phosphate binders because they had, because they had kidney disease, and then they developed hypercalcemia.

. One thing that was also in the study was that we couldn't really assess the effect on the prognosis of these cases. So it's worth bearing in mind that that Hypercalcemia in cats may be due to kidney disease, but If it's causing disease, then we'll probably still need to treat it and we'll discuss that later when we get onto the idiopathic ones. I just wanted to again go back to Angios strongullus.

I said it had been reported, in a small case series, that's now quite old, 2005. Most of them had respiratory signs. What we don't know is, is what the prevalence of hypercalcemia is in, dogs with angiostroullus because it's only been reported, as I say, in this, in this case series.

But it's worth thinking about in any age, any breed, pretty much anywhere in the country nowadays, . Showing respiratory signs, clotting disorders, or, . Kind of all the other signs that have been associated with lung worm.

And if you're, trying to diagnose it, then you can do faecal testing, you can do, blood testing with the IEX, snap test or, or an Eliza, and sometimes you'll find them on BAL, and there are some cases that, we still struggle to, to find, and if you're suspicious with clinical signs and, and your testing is negative, then, then trial treating them is also a possibility. Just wanted to introduce you to the last case of the evening. This one is Little Bear.

He's, mainly Tomkinese, quite old. All of the cases seem to present the PU with the weight loss and vomiting tonight, I guess that's hypercalcemia. He has a quite a significant, hypercalcemia as well, 1.7, and again has evidence of, of azotemia with creatinine 220 and, urea that's high, and again, phosphate that's kind of middle of normal, .

And you've tested him with PTH and PTHRP. They're both low, and your imaging has not found any evidence of tumours or granulomatous disease or anything like that. But what you do find in him is that he has evidence of, Euroliths.

So, we can see some uroliths here in, in his kidney, and in a position that's consistent with being in his ureter, on the left-hand side. And ultrasound here has confirmed that he's got a ureit, causing a ureteral obstruction, in his, of his left ureter. So he's a challenging one to manage because you've diagnosed him both with the urethral obstruction, which we need to decide whether we're going to intervene on or try and manage conservatively.

You've diagnosed him as being asotemic. We don't know whether that's, how much of that is post renal. He has a urethral obstruction, so some of that's post renal.

He does have evidence. That, at least some of it is probably intrinsic renal failure because that obstruction is only unilateral and if he had a, a, a unilateral obstruction and a normal other kidney, then he shouldn't become asotemic because of aotemia only developing once kind of more than kind of 60% of the kidney function is lost. And he also has hypercalcemia.

Now, he actually presented two years ago, so we just treated him as idiopathic, before that paper that I just told you about had come out. I guess with that in mind, then it's possible that he, that his hypercalcemia is related to his intrinsic renal disease, but in reality, he fits with being, what we would term an idiopathic, hypercalcemic, . Cap we found no other cause, and probably in his case, his hypercalcemia has, has caused him to, be more prone to producing calcium oxalate or calcium phosphate, urolys, and then that has led to a ureter, urethral obstruction.

So in his case, because that was causing a, a complete obstruction and it didn't shift with, with some conservative management, he ended up having a, subcutaneous ureterral bypass, surgery performed for this, connected tube, from the renal. Held this to the bladder. I'll admit that this is actually an X-ray from a different cat if anyone's confused by the way it, looks, and allows you to flush, that system with a, a small port under the skin.

And that effectively bypasses the, the fact that he has, the urethral obstruction and allows that kidney to flow, . But you still need to try and do something about that hypercalcemia to reduce his risk of producing further stones. So the treatment for idiopathic hypercalcemia will depend on the number of clinical signs and the severity of those clinical signs that they're showing.

So, this isn't set in stone, but I would suggest, that the indications for treating idiopathic. Calcamia would be if they've got clinical signs, including urolethiasis or if they have a marked ionised calcium elevation over about 0.25 over the reference range.

And if they're asymptomatic or that hypercalcemia is mild, then I would monitor it. In Little Bear's case, he has a risk of elethiasis recurrence and so he has those clinical signs, . And he also has significant hypercalcemia over that, that, level that we would want to intervene.

Treatment for idiopathic hypercalcemia, typically with, dietary management, you can use renal diets, high fibre diets have been reported, and urinary diets. And typically we'd start with a 6 to 8 week diet trial, if they have very mild clinical signs. In, in Little Bear's case, we actually were quite worried about the fact that he had these, neoliths and we didn't want to kind of keep forming those.

So we started him on medical therapy and changed his diet at the same time, . And we started him on alendronate, and again, a recent study, 2015, the treatment of hypercalcemia in 12 cats using, perros alendronate is quite interesting. It showed very good success.

All 12 of the cats showed a reduction in their calcium levels. And it's, Relatively easy to give. It's 10 milligrammes, which is one capsule a week.

The problems with alendronate are that it has very poor bioavailability, so they have to be given on an empty stomach with at least a 12 hour fast before and 2 hours afterwards. And although it wasn't reported as a side effect, They can, it can cause esophageal irritation and GI signs, and they described, buttering the cat's nose, in order to increase salivation and then syringing them water afterwards. The dose can be increased if they, if that's ineffective after a month, up to a maximum of 30 milligrammes, I'd go up to, they come in 10 milligramme catcher.

So I go up to 20 and then potentially up to 30. Unless they're getting side effects from the from the treatment. And then the alternative medical therapy for idiopathic hypercalcemia really is prednisolone, and you can combine those two.

So, in Little Bear's case, we ended up with him onendrelate and prednisolone to try and control those, those, diseases, and he didn't get a recurrence of the stones, which is good. So just finally I wanted to give you some take home messages it's obviously an important problem in practise . In dogs, you want to be really looking for malignancy, really look carefully at the examination and the imaging, and remember that a normal PCH does not rule out malignancy.

If you've got prolonged or severe hypercalcemia, consider the renal injury and treat them as an emergency if you need to, but don't give them glucocorticoids before you've diagnosed them. Primary hyperparathyroidism is not common, but has a good prognosis, and it's worth spotting because those dogs can do really well and cats can do really well after treatment. And remember that that PTH can be in the reference range, but they require careful management perioperatively and, idiopathic hypercalcemia is the most common cause in cats, that can be managed with diet and alendronate.

I just wanted to acknowledge, my colleagues, former colleagues at the Animal Health Trust and at the vet school where I did my residency in Cambridge, and, these people have all helped by providing images, particularly of the X-rays and the ultrasound images, from Marriott. James, that was absolutely fascinating and I know I've learned a lot. I'm sure most, if not everybody on the on the webinar tonight has picked up some valuable, valuable information.

So thank you for taking the time for sharing this with us. We have a a question that's come through from Sue. And she says, a strange question, please.

I don't have any access to blood results, but my friend in Cyprus has an old dog that has become unwell. Primary diagnosis is tick-borne rauketsia, and he is improving on treatment, but not as well as hoped. They found an asymptomatic bladder stone during during examination.y unknown.

Could there be an underlying neoplasia somewhere? Oh, that's a difficult question. Do, do we know whether the dog is hyper, do we know if the dog is hypercalcemic?

I know that's the topic of the webinar. I kind of assumed it was. Yeah, she doesn't say, she just says she doesn't have any access to the blood results, so I don't think we know that at all.

OK. Oh, I see. I mean, I guess from, from the point of view of having tick-borne disease or potentially another exotic disease like Lemania, in Cyprus, then they certainly could be hypercalcemic from that, .

I mean, the bladder stone could be related to, if they're hypercalcemic, then, then be related to that, but it could also be kind of entirely unrelated, just like any dog could get a bladder stone, I guess, would be my, would be my feeling. And I think it would be worth ruling out there being a urinary tract infection because that could then be a dissolvable, stone if it's a streamite stone. .

And otherwise try and there are difficulties diagnosing a bladder stone with . On a urinalysis and looking at the crystals, but it may be, it may be possible. If she wants to send me some more details, then I can try and answer it better for her.

Great, thank you. That that was a real tough curveball to start the questions off't it? Have you got any?

Oh, we've got now. Jill wants to know when you're rehydrating an animal, at what PCV would you consider acceptable to start diuresing? Also, she wants to know what intervals for monitoring, you know, for, for hours of dependent on urine output.

So the first part of the question, I wouldn't The problem with PCV is that it's, it's gonna be very as a trying to assess diuresis is going to be that it's, it's gonna be very dependent on things like stomic contraction and stuff. So I wouldn't, I, I'm not sure I quite understand what she's getting at with what I would aim for. I wouldn't actually aim to hydrate to a PCV as such, .

I would be aiming to hydrate to the point that the, the dog was well hydrated, and, clinically, as in looking at it, no skin tint, moist mucous membranes, but without it becoming overhydrated, and then want to I read it. I don't know if that answers the question. OK.

There's a message just popped through from Sue to say thank you very much. It goes, with what her gut feeling was. Christian wants to know, do you use calcitonin for treating hypercalcemia?

So personally I've never used calcitonin. It is reported as a treatment for hypercalcemia, particularly acutely, so you can, it does very rapidly reduce the calcium and it can be very useful in those . Those acute toxicity cases where you want to bring down the, the calcium rapidly, potentially, calcitonin is helpful.

The problem with calcitonin is that it, it only works, for a very short period of time, and it seems to be an effect of the, receptors that it then stops having that effect of lowering the calcium. So it, it works initially, but it can't, it doesn't really work as a, as a longer term treatment, but it is potentially a treatment, yes, in the hospital. Excellent.

We've got loads of comments coming through about what a wonderful webinar that was and so interesting and such good information. So, James, thank you very much for your time tonight and we do do definitely want to see you back on webinars in the future. I see.

Folks, that's all we have time for for tonight. Thank you very much for your attending and as always, good night and see you on the next one.