Hi, everyone. First of all, I'd like to thank the Webinar vet for the invitation to be here. Lettering on hyperaldosteronism pheochromocytoma the less frequent adrenal disorders.
My name is Rudolfo Oliva Dal. I am Portuguese. I a veterinarian.
I got a PhD degree from the vet school in Lisbon and I'm board certified internist with a special interest in endocrinology, gastroenterology and respiratory medicine. I'm currently an invited assistant professor at the faculty of Veterinary medicine in the University of Lisbon. And I'm really happy to be here with you to talk about these, less frequent Adonal disorders.
So these are my conflict of interest. So I don't have any conflict of interest to declare concerning this webinar. And, yeah, and these are, my, yeah, consulting and speaker, speaker engagements.
So, the plans. So we'll meet Cyrus and Billy. Two interesting cases that existed in real life.
one of them was during my residency and the other one already here in Lisbon. And we're gonna briefly describe pheochromocytoma and hyper allosteric concerning physiopathology clinical science diagnosis and the treatment of these diseases. So let's meet Cyrus Rose.
He is a golden retriever. 11 years old Mel castrated I've seen in my last year of residency. And I did remember really well this case.
So the main chief complaint it was attack it, mia and two episodes of, collapse. And it was the first time that he developed these episodes of collapse and I. I was really worried in the beginning, whether it was the collapse or a weakness, actually.
And, yeah, overall, speaking with the with the clients, I had a bit a bit. I was a bit confusing. Then I discussed with cardiology and neurology again we to find out it was probably a weakness episode that he had, he had two episodes, not related to anything.
He was walking, and, he he collapsed. And, speaking with clients, we also identified that this dog had a decrease died over two weeks and a weight loss of 2 kg. Comparing to the last appointment in the referring fat.
So there was no vomiting or diarrhoea, no real dyspnea. So it was, no or any abdominally fort or any breathing issues and urine was normal. So no truly polyuria nor even polydipsia on my clinical examination, the dog had a pin of me brains.
The normal C RT respiratory cult was, with a high heart rate with the 180 which is abnormal for a golden retriever. And it was indeed Tak nake, on abnormal palpation. It was slightly uncomfortable, but not really not really painful.
And I decided to start with my problem list. So I OK, so I have a golden retriever with tachypnea weakness, tachycardia decrease appetite and weight loss, decreased appetite and weight loss were found to be probably secondary problems to the primary cause That was causing tachypnea weakness and tachycardia. And I decided to make my differential diagnosis, as we all love in internal medicine.
So tachypnea can occur in cases of metabolic disease, namely acidosis with compensatory alkalosis endocrine disease. Namely, Cushing's syndrome, pheochromocytoma and, cardiovascular disease, pain, hypertension, anxiety or fever for weakness. Indeed, it can be anything but, talking about weakness.
We can have weakness due to metabolic disease. It's just kidney disease, endocrine disease, just hardison disease card, the respiratory immune mediated neuromuscular, tumours, hypertension, anaemia, pain and so on. Focusing on tachycardia tachycardia may be due to increase sympathetic tone a decreased vascular resistance as occurring anaemia, fever and hyperthyroidism and heart disease.
So we were a little bit lost in this case, so we decided to Let's move on and consider a CBC full biochemistry profile, including irons, urine analysis, chest X rays to check for respiratory disease. Systolic blood pressure. Since hypertension may induce an endocrine diseases associated with hypertension may induce, tachycardia and T.
Yeah, and abdominal ultrasound. And here we have the results for Cyrus. So we have a CBC biochemistry renal analysis completely and remarkable.
With the exception of US C borderline low, borderline appropriate. We like to have specific gravity, higher than, than dirty, more or less in dogs. We like to have it around this valley.
And it was low wish, but still not completely abnormal. Since US G may vary over time and glycemia was 180 so a bit as well, and it's not common. It was a happy dog, not really a stressed dog.
We said, OK, we may have here hypoglycemia, but there was no glycosuria or nothing. Chest X rays were unremarkable Yeah, probably a slight cardiomegaly, but not really relevant. On the eyes of diagnostic imaging team and systolic, blood pressure was 180 which is indeed, already considered, hypertension, systemic hypertension.
Even if we need to verify this. Well, because we always like to check it twice, three times and four times in different time points to verify the consistency of this, of this, systolic blood pressure. Have the ultrasound.
So let's have a look on the abdomen of these, dogs. So left adrenal was normal. Size, 4.6 limits, normal size and no other significant findings on the right adrenal.
We had a no large lesion indeed. That changed the shape of the gland and with an overall increased thickness of, 14 millimetres, which is high. And so at this point, we say, OK, we probably have here an endocrine disease.
And the question that we have when we find out this lesion is whether this is functional or nonfunctional in talking about the activity of adrenal glands, we may have functional and nonfunctional causes. So, talking about functional tumours, we may have a tumour in the cortex or a tumour in the Metula the cortex. We know that cortex produces cortisol, aldosterone and sex hormones, so you may have a cortisol and aldosterone of sex hormone producing tumours.
And in the Metula, which is responsible to produce epinephrine and norepinephrine, we may have a functional tumour called the Pheochromocytoma. We can also have a nonfunctional tumour, meaning that a tumour is there. But it's not producing any kind of hormone, namely adenoma carcinoma, hyperplasia, metastasis.
It occurs in 20% of dogs and 40% of cats or others, such as myelolipoma cysts, Emma Toas or Granulomatous disease. The other question we're wondering is, Does it look benign or malignant? And in most of the time, when we have any lesion lumps bumps in the body, what we do to assess if it is benign or malignant is an FN a an aspiration of the lesion and the question arises.
Can we do adrenal FNAs in these cases? Indeed, we know that adrenal FN ASE is not distinguished between benign and malignant neoplasia, but it helps us to determine the origin of the tumour, whether it is in the cortex or in the medulla. There is this interesting paper, of Italian team led by Federico Fracassi from the University of Bologna about se curacy of cytology and like distinguishing AOC cortical tumours from pheochromocytoma in companion animals.
Which is interesting, because if we have a suspicion of fo, we may indeed consider to FN a these patients. But it is really controversial because we should avoid FN a pheochromocytoma because it risks to have and hypertensive crisis. So this is something that that divides a bit our diagnostic imaging teams all around the world.
Indeed there are, these two other papers that are useful or interesting about adrenal FNAs one published on Js A about in 2018 about the clinical safety of percutaneous ultrasound guided FN a of a gland lesions in 19 dogs. And then a really interesting study again headed by Federico Fracassi and Pascaline, which is a brilliant diagnostic imaging, lady that actually assess the safety of percutaneous ultrasound guided FN a or original lesions in dogs, the perception of the procedure by radiologists and presentation of 50 cases. And overall, they say that it is safe to FN a the adrenals even in cases of eo cyto.
But more studies are indeed, needed so far. So if we don't want of, we are. If we are scared of FN a our adrenals, we may consider to use diagnostic imaging tests to allow us to help us on the decision.
Whether this looks like more benign or malignant, can we have a definitive conclusion? This is clearly benign or malignant with diagnostic imaging? Absolutely not so far, unless we decided to move forward to more specific techniques, such as contrasting a ultrasound and so on and so on.
But we send top tips from our adrenal ultrasound imaging or AC TS that may help us to clarify whether we are facing a malignant lesion or a benign lesion. First one is local invasions. In theory, if we have a local invasion, it will more likely chance to be malignant because benign lesions do not necessarily invade, but they can occur so benign lesions can also invade, so it's not the of anything but local inflation.
Yeah, it's more common in malignant ones than in benign ones, but it's not a sign of malignancy that's important to state. The second one is the presence of a thrombosis thrombosis in the vena cava. This is more likely to occur with pheochromocytoma rather than with adrenal cortical tumours.
Again, Acute is also creating tumour can also, invade and induce a thrombus in the vena cava. But it's more common in Pheochromocytoma. A third ST Point is calcification classification.
We have this idea that OK classification is more frequent in malignant lesions. It's not predictive of malignancy, but we know that in between, the Cort is also creating tumours and pheochromocytoma. It's more common in adrenal cortical tumours rather than in pheochromocytoma, so pios rarely calcified, and the fourth one is a regular margin.
So when we have a no with the regular margins, then a priority. It's a malignant lesion, and the and the last one last but not least is the size because higher than two centimetres or 20 millimetres, we are when we assume there is more likely to be a malignant tumour. That's really interesting points that can help us to prioritise whether we may be dealing with a malignant lesion rather than a benign lesion.
So in practise what we should do when we have a nodule. In this case, I don't call it Incidentaloma because I was seeking for something on endocrine, system in on our glands. But if we jump on something, we find Oh, this is an incidentaloma.
The work up is similar. So first question, is it function or nonen? Second question.
Is it benign or malignant? So is it functional for functional? We need to measure the blood pressure.
We need to exclude cortisol producing tumour, exclude PO and exclude Aldo Noma. In this case, we're going to dip a bit further in cats. But in dogs, it's extremely rare and often associated with kalmia.
So wondering about there is hypokalemia or not. And the third one is it benign or malignant? So let's check for ultrasound findings and FN A.
That does not help to distinguish between benign or malignant, but that helps on assessing whether it is a cortical or a mi lesion. So if we work, if we talk about probabilities, if we talk about functional tumours in dogs and cats, what are the most Commons in dogs? We have cortisol producing tumour, far the most common one, and second the pheochromocytoma in cats, the most common.
The far most common is Aldo Senoma, the second most common is cortisol producing tumour cortisol. Asteroid hormones producing tumour to be, more rigorous and pheochromocytoma are in the least, frequent, which are considered to be extremely, extremely rare. So what it is the pheochromocytoma.
So pheochromocytoma is a tumour, considered a catecholamine producing neuroendocrine tumour, although in humans they tend to call it adrenal paraganglioma. Now they try to change the name We always call him fo in, our day to day practise in veterinary medicine so it affects the adrenal medulla, namely the chromo cells. Let's we also known as Foch sites.
That's why we call this pheochromocytoma, and they tend to be unilateral tumours, although in some cases that rarely can be bilateral, there is this brilliant review paper headed by Sarah Galla, one of the best endocrinologist in the world is one of my inspirations as a person is Rocko. Sara Galic is brilliant. There's a lot of research on adrenal tumours, and she published this review paper on veterinary comparative oncology called Pheochromocytoma and Paralia in humans and dogs.
And that's really brilliant and you should read it if you love endocrinology and if you love Fels and yeah, about the malignancy. We believe that until proven otherwise, it is considered malignant because they are, malignant. In more than 50% of cases, pheochromocytoma have an unexpected growth, and around 40% of them show vascular invasion at the moment of diagnosis.
So it's not a great thing to diagnose, Unfortunately, a pheochromocytoma, because most of the times it is malignant and shows vascular invasion in around 40% of cases about epidemiology, it's more frequently adult to geriatric dogs with an average age of 11 to 12 years. There is no racial or sexual predisposition, although we do believe that rode rich vs boxers, labour retrievers and shih-tzus are indeed or seem to be prone to it. There is a report that is under research about shih-tzus due to the fact that they have chronic hypoxia and the arising of a pheochromocytoma because we have some epoxy inducible factors that may act as in the physiopathology of Pheochromocytoma.
But it's still something on an ongoing research clinical signs, So this results in an excess of catecholamines and namely epinephrine, norepinephrine, so clinical signs you often affect the cardiovascular system and neuromuscular system. Namely, they induce weakness, lethargy, tachypnea and collapse and sync of episodes. Only 5% of these cases have hypertension, meaning that this is not Pato noone.
They don't need to be hypertensive to have a pheochromocytoma that's important to be aware of. Only 50% of them have hypertension, and hypertension can also occur in some cases because sometimes they have a peak hypertension, and then they may develop hypotension. So again hypertension can occur.
But it's not paic of pheochromocytoma. And don't we forget that it can also occur in also in other endocrine diseases, namely in Cushing syndrome, about clinical pathology. We have inconsistent results.
The most common laboratory findings are anaemia in 45% of cases, increased liver enzymes ism that may also occur in dipersia and dial anaemia. We may also have proteinuria and a decrease urine specific gravity, or that stays around ISOS inia or IPO inia. But in some cases we may have minimally concentrated urine so borderline low about the ultrasound.
There is no specific ultrasound pattern that may lead us to say OK, this looks like Sophia. Mineralization is rare, is more frequent in cortical tumours. Local invasion, as we've said, is more frequent in F OS.
So 43% of cases and distant metastasis in 20% of the cases variable size. But it's mostly unilateral, with less than 10% of the cases being bilateral. So in 90% of them, we have a unilateral tumour.
That's interesting because, the ultrasound has been progressing and with the research on ultrasound progressing towards the contrast in an ultrasound ultrasonography. So that's mainly based on the assessment of adrenal glands, after the injection of a contrast. And the findings and the ultrasound findings after the contrast changes and may help us distinguish between types of adrenal tumour, whether it is a carcinoma, whether there is another no.
And it's probably the future for us is with using CS the contrasting acid ultrasound, we're gonna have an easy way to improve our likelihood to diagnose either a carcinoma or an adenoma in these patients about CTCT can be useful, especially in large or obese breeds in which adrenals are difficult to assess. Big dogs, in which the diagnostic imaging team don't, need to push a lot to find out where the adrenals are, so we can use the CT scan the contrasting AC CT is better than surgery or pathology, according to some studies, to detect vascular invasion. So that's really mandatory nowadays to do AC T, ideally contrasting acid CT to assess the vascular invasion of these cases, sensitivity runs around 92% and specificity around 100% about the use of MRI.
We rarely use it for adrenal disease, but indeed it looks superior to CT to assess vascular invasion. So as all in endocrinology imaging help us a lot, I must assume, But diagnosis is only confirmed using functional tests and we need functional tests for the diagnosis of pheochromocytoma. And as we know, is that norepinephrine and epinephrine are produced in the medulla of the adrenal gland by the thyroxine metabolism.
So we need the thyroxine and the thyroxine is metabolised, to dopamine and then dopamine to norepinephrine. And the pine and norepinephrine and pen is are really label on blood, meaning that, it can, increase really fast. But it can also decrease really fast.
And it's half life by itself. It's really short, so sometimes you can't measure these metabolites appropriately. But we know that under the mechanism of its degradation, they are degraded in, nor norepinephrine in normetanephrine and PINR in Metanephrine.
So this these degradation products have a longer of life. Reason why? To assess whether we have an increase of epinephrine and norepinephrine, we check the metanephrine and normetanephrine, respectively.
So we check what? That's what we call the metanephrines in plural that includes the metanephrines and normetanephrine. Then these are the metabolites of the degradation of norepinephrine and epinephrine.
This is a, a scam or beautiful scam from, textbook of medicine, from Ettinger. The, not the last, but, before last edition. OK, so we need to dosage metanephrines and normetanephrine in our dogs when we just have a suspicion of pheochromocytoma.
And what can we use? We can use indeed, urine. So we can have urinary metanephrines and normetanephrine.
And the the one of the first research teams that launched this, dosage was from Zurich University. Sorry. And the problem is that, to do this, we need, ideally to acidified urine, before measuring, which is not really practical in daily practise.
And, that's the weak point. But most of the times even I know people that don't necessarily acidifies it, and it doesn't change a lot of results, so we can consider during a metanephrine nomine IFR dosage. But there are not a lot of labs that, does it, and the other one is using plasma metanephrine normetanephrine dosage so we can use plasma, dosage.
And indeed, that is the first paper published in 2013. So 11 years ago on Journal of Medicine by the Rat College team Professor Hati sign on the use of plain metanephrines and free normetanephrine, in dogs. And recently, in 2015, there is one paper published on GVIM that compared urinary and plasma kolam means saying that normetanephrine, assessment is better than metanephrines assessment overall, meaning that normetanephrine are potentially higher and more evident than metanephrines in dogs.
And the second one is that urine seems to be better than plasma. But again, it depends on the methodology used for urine. We know that in urine, we can use HPLC.
So I performance liquid chromatography. And this is available in human labs versus LC MS MS. It's a low chromatography spectrum mass, with tandem.
And, as far as I know, one of the labs that does It is AM L in Belgium. That's where we send it from Europe. And it's really great.
So HPLC versus LC MS MS Don't forget that According to papers, HPLC in theory requires acidification needs to be, urine needs to be protected from light. It needs to be refrigerated and frozen in blood. We can use, frozen EDT a plasma.
And we can also measure it using HPLC, which is available in several labs and even veterinary labs versus LC MS MS. So please be aware of the methodology and contact your local lab in case you consider to measure the metanephrines, either in plasma or urine. To be honest, I tend to use now here in Portugal the blood, metanephrines, because it's practical and easier.
I also try to check urinary metanephrines. But if we need to use the human lab and it's really difficult to manage the shipping of of the sample some considerations in practise is that phenoxybenzamine and corticosteroids. Some drugs, namely these two ones, increase the metanephrine levels, and that's important in humans.
When when a FO is suspected, people struggle a lot because there's a DI a difference between people is standard or is, in, the human, position And, the the changes and that changes the values of of, of, no metanephrines and metanephrines. And the second step is that cortisol is needed to reproduction of norepinephrine and epinephrine, namely to the conversion of norepinephrine to epinephrine. Reason why in excess cortisol scenarios, namely in Cushing syndrome, on our dogs undergoing steroids, metanephrines in general tends to, increase.
So be aware of concurrent medications if we are suspecting a few cyto. So, back to S we had this blood pressure of 180 with hypertension, and we have this nodule and considering the most common ones in dogs the cortisol, secreting tumour and pheochromocytoma, we decided to perform a dexamethasone suppression test that's indeed discussable because, the dog didn't have any other clinical signs of cushings. Neither PPD nor polyphagia and we have the results in Portuguese.
We can understand the numbers anyway, 2.3 on the basal less than one on the T four less than one on the T eight. We use the chem lain level, namely the emu light 1000 from Zieman, in which the cut off was less than 1.4.
So it was a complete suppression pattern, meaning that this is not in favour of a Cushing syndrome, as we were expecting. Indeed, it's discussable to to measure, to do this test, but, we decided to do it. And dexamethasone suppression test is not compatible with hypercortisolism.
And here the question is wondering about the pheochromocytoma. And let's check the plasmatic, metanephrines and normetanephrine. You have the results so free, nor is around 15.05 and we have the KO, which is around 1.59 to 4 point point 17.
So it's almost five times more around 44 times times more. Sorry. And, metanephrines were, normal.
Curiously, Curly. And, indeed, we have this GV I MP that talks about these plasmatic levels. And as you can see, the norm ther is all around or, higher than 10.
So this is 15. So the disagreement with a few chromic toma And what's the treatment to consider? We are to proven otherwise.
Consider it is malignant again. It has an unpredictable growth. There is a risk of vascular invasion, namely and adjacent tissues.
So adrenalectomy is recommended. Despite the fact that it is a high risk procedure and surgical experience is required, we need a rigorous post operative monitoring. That's an important point as well.
So that's we need to, trust one of our surgeons to do this adrenalectomy because it's not an easy procedure, especially in a dog that has an anaesthesia, risk that is not neglected at this point. So the question is, Do we need to stabilise these patients? And historically, we have this idea, and we we still have this idea nowadays to consider the use of phenoxybenzamine.
What's phenoxybenzamine. This is an alpha blocker, and it's gonna do. It's gonna counteract the effects of norepinephrine and epinephrine in the alpha receptors, so animals need to be treated with foxy benzine and dogs treated with foxy benzine at six times more likely or more chances to survive.
To adrenalectomy, the dosage starts with a low dosage and see how it goes and then progressively increase to one milligramme per kilo. Twice. Daily surgery can be done, usually two weeks after the start of the treatment, the last dose that should be given the night before the surgery.
So on the day of the surgery, the dog does not receive the foxy benzine. That's all really interesting, because over time and still nowadays, I tend to prescribe Foxy benzine before surgery in my patients. But the question wonders now, is that really necessary?
That's what some authors were seen and published on that surgery 2022 so two years ago about the short and long term survival after Renal Elect Toy in 53 dogs with pheochromocytoma, with or without alpha blocker therapy. And what they found is that alpha blocker therapy was not associated with increased survival. Science is what it is, so it's questionable that we need to treat previously these dogs with foxy benzine.
Anyway, So far, my own opinion is that I still treat these dogs with foxy benzine. Whenever it's possible about beta blockers, we should consider to give it on, beta blockers. In case of tachycardia or arrhythmia, we can have beta blockers, namely a Tenolol 0.2 to one milligrammes per kilo every every day or every two days.
But the problem is that we only may or need to add beta blockers only after starting fox benzine first and after a few days on phenoxybenzamine, which cannot start animals with fear with beta blockers without having phenoxybenzamine. And why is that beta blockers We gonna block the better receptors and better receptors usually counterbalance vasoconstriction. So again, these dogs as an increased risk of vasoconstriction and the better receptors, counteracts this vasoconstriction.
If you're gonna block the, these better receptors by using beta blockers, we're gonna have an no vasoconstriction. And, in this sense, the dogs may have a massive hypertensive crisis. So I'm gonna repeat again this because it's really important if we want to plan to start better blockers in a dog with pheochromocytoma, we should initially start with, foxy benzine.
It uses an alpha blocker and only later on a few days later on with beta blockers. Why? Because in you, physiology, knowledge, the better receptors and the better stimulation is responsible to counterbalance the vaso constriction.
Because when while alpha stimulation Vasa constricts better stimulation, vaso dilates and it's counterbalance this vaso constriction of, induced by alpha receptors. So what happened? If we use beta block, we're going to block the better, better receptors which are counteracting the vasoconstriction.
So if you use beta blockers, we're gonna block these receptors better, and we're gonna increase the risk of even more vasoconstriction gonna have a lower vasoconstriction. And the dog may die with a hypertensive crisis. So always given peny benzine first and beta blockers later in cases that it's non manageable In terms of surgery, we may use the tyrosine Kass inhibitors TKIS the best friends of our oncologists.
Indeed, there is this paper about retrospective evaluation of doser phosphate palaia using the treatment of inoperable, metastatic or recurrent canine Fels in five dogs. I presume that now this there are new studies upcoming, but indeed, in cases that owners do not want to move on with surgery, we may use the TK ice. So the prognosis depends on several factors, then the tumour size endocrine activity, vascular invasion, depress of metastasis, and the previous treatment with foxy benzine, albeit this last one apparently, is discussable point.
But we know that until proven otherwise, it increased. The survival of dogs went into surgery about Cyrus. So Cyrus, Unfortunately, owners did not want to pursue it with surgery.
So we started using Kass inhibitor, and it still lived, longer on. And, with the the natural progression of the disease, I after I ended my residency, and I didn't get any news from Cyrus. But indeed, this was a great fomo atomic case by the book case that I use in my presentations.
Because I'll never never forget Cyrus, in my life. So again, that's an important case. And, let's move on for, Billy.
And, we're gonna sum up on the end the main top tips. But don't forget that fo exists in dogs, and we need to be aware of it. So let's mean, let's meet Billy.
Billy is a 16 years old cat, an indoor cat with the chief complaint of muscle we weakness and neck ventro flexion. He went to his vets. And, the vets have already did, have already done some, work up, namely a urine analysis with the US G of 1020 a creatinine that was 1.7.
And the potassium that was 2.5. He was referred to as Z to hypokalemia.
So differential diagnosis of this laboratory finding hypokalemia in cats we may have as the first one hyperaldosteronism second one, chronic kidney disease DK a ketosis even do the disease or due to insulin treatment because, as we know, insulin is responsible for several, ionic actions and interactions, namely a switch of, the potassium towards the intracellular, space and digestive diseases and diarrhoea, vomiting and anorexia. So these are the main causes of hypokalemia in, Cats. So we decided to explore a bit further.
And indeed, we have, systolic blood pressure of 222 150. And this is relevant to, verify, but it's a massive hypertension. I like to have a fund examination of the high as soon as possible, and we need to manage systolic blood pressure.
And the Donald's was sound. We had the right adrenal of 9.6 millimetres.
So not really an all lesion, but overall very, very enlarged for a cat and left adrenal of four millimetres. And the brief echo, only showed a left ventricular thickness. So facing this despite the fact that we are being probably with a tunnel vision towards the hyperaldosteronism because other causes may induce this hypo hypokalemia We decided to measure Rin and Aldosterone and indeed, concurrently with hypokalemia Aldosterone was massively high.
And, renin was, low. So this is in agreement with the primary hyperaldosteronism. So it was a no production of aldosterone by the glomerular Riza of the adrenal, glands So briefly speaking on the physiopathology.
So we have, the aldosterone and the main stimulus for aldosterone synthesis hyperkalemia. So as far as we have an increase of hyperkalemia in blood, we may have an increased secretion of aldosterone, meaning that if potassium is low in terms of physiology, we were expecting a low aldosterone because we know that aldosterone among its main actions is responsible for the excretion of, potassium by the kidneys. So if it is low, potassium is low.
It is expected allo to be low as well, which is not the case in our in our, cats. So, al secretion is also, in part affected by AC TH in a minor extent because the, the main extent is potassium and the renin angiotensin system. So as soon as we have any kind of vasoconstriction and hypertension.
We have an activation of renin which stimulates conversion of angiotensinogen to angiotensin one in the liver and then angiotensin one to angiotensin two in the vascular pili. And these is in two can even be converted each other in three. But this one already is an interesting and potent stimulator of aldosterone.
So don't forget to remind that aldosterone is mainly, stimulated aldosterone production by the action of renin angiotensin aldosterone system. So renin adios and hyperkalemia and in a minor extent in third place, the AC TH. OK, so what can lead to aldosterone hypersecretion?
So if we have an hypovolemia crisis, we may have an activation of renal renin Adios ao system that we gonna end up with an increased renin and then with an increased aldosterone. And in these cases, in this situation in which renin is activated, we call this increase in aldosterone secondary hyperaldosteronism. On the other hand, if we have an autonomous secretion of aldosterone, usually by a nod or a mass or the wall gland that is producing, the glomerular azona is producing aldosterone.
We're gonna have a decrease running with an increased aldosterone. And in these cases. We call it Primary Ado.
As it was, the case in, bili. So secondary aldosterone is what can lead to the activation of rin angiotensinogen and gins. Systems.
So first one heart disease. So, the heart disease may induce the kidney to produce renin angiotensin aldosterone system. So, they may activate the RSS renin angiotensin angiotensin and allo system and chronic kidney disease.
So chronic kidney disease may lead to the activation of, renin as well and obesity in fact, adipose tissue producing tens in two that may lead to vasoconstriction and later on hyperthyroid. Because we know based on this paper from Tim Williams, a brilliant pathologist working on the Cambridge University that in GVIM published on 2013 that renin angiotensin aldosterone system is activated in hyperthyroid cats even with or without hypertension. So these are the main causes of secondary hyperaldosteronism.
And what about primary hyperaldosteronism Primary hyperaldosteronism is due most of the times to night persecution of aldosterone and or the oxy corticosterone by unilateral adrenal tumour. 95% of cases either a nodule or an enlargement of one of the glands. The zolo laws are per place it may occur as well, or a bilateral tumour in 15% of cases again, Most of the time we have a unilateral adrenal tumour.
Most frequently it is unilateral. It may have vascular invasion of the code of in a ka if we may have decent metastasis. And most of the time similar to PO is malignant, anti proven.
Otherwise, since malignant is more frequent than benign about clinical signs, it's common in senior cats with the median age of 12 years, often domestic short hair. So there is no sex or breath. Transposition and cats may show plenty great stance of back limbs, reluctance to walk in the neck, vent flexion or muscle weakness, especially if hypokalemia is severe.
So this is a case that I had during my residency in FRA in Paris. And as you can see, the cat was completely, completely weak due to a massive hypokalemia. But don't forget that similarly to hypertension in fields, cats with asterism may have normal potassium and systolic blood pressure.
These are the tricky cases, So most of the times we have flexy, pais, muscle, hypotonia and signs of systemic hypertension. They may appear with intra colar haemorrhage seizures polydipsia in less than 20% of cases and variable appetite if there is a concurrent secretion of cortisol or progesterone, which may occur so sex steroid hormones. So a mix producing tumour, namely hyperaldosteronism and, Sexo hormones.
We may have signs of hyper cortices, diabetes and cutaneous signs. OK about the lab findings. What can help us to target our diagnosis of hyperaldosteronism?
So the most consistent findings in our cats is an hypokalemia, so less than 3.4 present in 85 to 90% of cases since aldosterone. More than increasing the potassium excretion.
It also increases H plus excretion. So hydrogen excretion in the tubular in tul in the kidney and, trying to saving bicarbonate so it might induce an hypokalemic metabolic alkalosis. That's interesting as well as well as hypophosphatemia, due to the fact that an excess aldosterone exfoliates the phosphate, so eliminates the phosphorus as well as a magnesium.
And there is an increase creatinine in ace. And it's curious because in some cases we may have a zoom as well on the same point, which becomes a challenge in terms of diagnosis because sometimes we may have, chronic kidney disease, which can induce a secondary parlon. And then, it's difficult to diagnose unless we measure Rin.
But if we're going to see the assays to measure Rin in, our companion animals are really discussable, so eia in about 50% of cases. But there is one top tip that I would like to share with you. Is that you?
A zoom associated with primary ado? Have low phosphorus cases have low phosphorus while in conventional chronic kidney disease, phosphorus tend to be high, so have a look on phosphorus in these patients. If phosphorus is low, then think about primary hyperaldosteronism.
What about sodium? So indeed, since Aldosterone exfoliates or excretes or poten Cate discretion to be better of potassium and retains sodium, were we expecting Hypernatremia? Absolutely, yes.
But Hypernatremia isn't common due to the phenomenon called aldosterone leakage. What's this aldosterone leakage? OK, despite the fact that there is some retention of sodium, the presence of hypertension and volume expansion because there is some water that is retained as well, overcome the sparing effects of aldosterone and cause nais, meaning that regardless of the fact that it is, the slight increase sodium the fact that is volume expansion.
And there is a hypertension makes the the again counterbalance causing natural reis and the sodium is normal in these patients. That's called the aldosterone leakage. So we don't care as much to, sodium as we care, of, potassium.
So how do we establish diagnosis? So we have a nodule on the ultrasound of our adrenal glands, So we need to establish a diagnosis by having our hormone dosage and what we measure here. That's simple.
We measure potassium and aldosterone in the same sample What we were expecting physiologically, if potassium is low, aldosterone would be low because potassium high stimulates the secretion of aldosterone. So potassium decreases. And with the potassium low with aldosterone even within the reference range or a high, we consider it is inappropriate because we're expecting aldosterone low.
So we have. If we have potassium low and aldosterone in the Reference range or Apne reference range, or even a higher reference range, that is inappropriate comparing to what we were expecting, if you logically. Therefore, we need to interpret all potassium and aldosterone together and aldosterone even in the within the reference range.
Facing a concurrent hypokalemia we find aldosterone inappropriate. Aldosterone is measured by radioimmunoassay all over the world. Is the gold standard now to measure aldosterone anyway, so contact your local lab to check.
Aldosterone. There are some studies measuring aldosterone via other techniques, namely LC MS MS. We tend to run away from radio immuno SAS not only because this is an old methodology, but also because it can have some health issue associated diseases in humans.
So that's important to avoid Rhea. But aone is still measured by Rhea so far. So what about RR?
Activity is helpful and we expect her to be decreased within the reference range in primary hyperaldosteronism. But we also know based on this paper from the Royal Vet College Team Professor Rosanne Json brilliant nephrologist endocrinologist, that indeed hypertensive cats have significantly increased aldosterone with decreased running activity. So we know that hypertension have a negative feedback effect that decreases running.
This was published in 2014. So don't forget that we have other differentials for, running increased or decreased. In this case, if we have a decreased R, you think about primary apparatus rig or hypertension, systemic hypertension, even if you have an increased ring that reinforces a secondary parathyroidism as we have spoken before.
So hyperthyroidism, obesity, cardiac disease, renal disease. OK, methodology is debatable. In dogs and cats, some labs do it.
Some don't. So that's important. We seek for more validated methodology to assess running in our, cats, we can calculate aldosterone winning ratio, and the conventional aldosterone winning ratio is about in between, 0.3 and 3.8.
So if it is above 3.8 this is in agreement with hyperaldosteronism urinal. Doster.
Creatinine ratio is another hypothesis, but it's mainly used for renal purpose. So in daily practise, we check adrenal glands. We If we have an hypokalemia, we measure aldosterone.
And if it is high, we, got diagnosis of likely diagnosis of primary upper pyro. Don't forget that, if feasible, if you can have the ring, that's great. But methodology is difficult so far, so usually we stay with the baseline or the initial values.
Checking checking aldosterone in concurrency with, potassium. We can also consider to have dynamic tasks so dynamic test consist on the administration of a axis suppressor and then with the flu. Cortisone versus Toys are T.
So, some medication that is gonna affect this equilibrium of aldosterone and rensin. Systems and Pluto cortisone, we might consider to use dynamic test. There is, two pipers on its use and salt, or for of course, is on a state.
Test. Then you can. You can indeed.
And then I have the protocols. More detail in literature. I didn't, waste too much time on this because we don't.
It's something that we don't use very often in daily practise. And just to tell you that the tell me our 10 have been explored by all four team from Paris and indeed the first paper about the evaluation of war told me is a suppression test for diagnosis of primary hyperaldosteronism in cats. It was found out that initially it was great to distinguish between healthy and primary hyperaldosteronism cases.
But there was only 16 cases in total with with the health C, cats and the I think as far as I remember, 10 healthy cats and six with aperto. So this was promising paper. But from the same research team, That's interesting.
They also published the prospective evaluation of auto art suppression test, a diagnostic tool for primary hyperaldosteronism confirming that it does not. This test does not distinguish primary hyperaldosteronism from concurrent diseases or secondary hyperaldosteronism. So unfortunately, this is not a great test at all for what we would like to have a dynamic test for our primary hyperaldosteronism cases.
Mhm. So conventional imaging. We may consider the ultrasound CT or MRI, useful in the morphological assessment of the adrenals.
Check for vascular extension. Don't forget that. It's curious that contralateral is usually normal in these cats, and the fact that there is no vascular innovation does not correlate the adenectomy.
So these cats would need an adenectomy in the future about the specific findings of the disease. So a place it does not have to be large to induce hyper. We may have a really small one, and you may have an upper place of the sort of the los, which may not be identified by conventional imaging.
If it's not visible, it's not excluded. So tumour is small enough sometimes to be, visible. But if you can't see it, it does not rule it out.
Disease. It's only the functional tests that confirm it and get the diagnosis. There are models as well.
That can be nonfunctional, namely the incidentaloma. So we need always to interpret our diagnostic imaging findings in combination with functional tests. OK, in humans, they use the pet scan, the positron emission tomography, which mark the secretion of aldosterone.
This can be nuclear medicine. This can be the future in veterinary medicine as well. And an interesting find that I always like to share with you is the blood collection from adrenal veins.
It's a technique that was introduced in human medicine in the late 19 sixties, and it's the gold standard to assess laterality of hormone overproduction in humans. This is especially relevant for those cases that we have a bilateral enlargement of adrenal glands, or we have the No. One that is higher than the other.
But there is no no, lesion visible as such was the case on bili. But it we have a massive one massive increase, so to go to surgery, it was this one rather than the other. But if in human medicine, what they used to do in the sixties was that each adrenal vein was SC and blood collected simultaneously and comparing the aldosterone concentrations they would manage to identify which adrenal would would be pulled out by a surgery in vet medicine is not feasible and let reality is determined using diagnostic imaging, which hopefully we have been progressing a lot.
And with great ultrasound probes, we may have further info on whether there is probably a no or something that may be inducing this upper Aaron. So all in all in daily practise, diagnosis is usually straightforward. If we have clinical signs comparable with the poly myopathy or polyneuropathy with hypokalemia in high aldosterone or or better say inappropriate aldosterone.
And this is, incongruent. And this is an agreement with an with an aldosterone overproduction. And if you have it a low running, we can have some labs that still run running activity, which is discussable in terms of methodology once again.
But if you want to measure it, if your name is low, then we may have a R activity low. We may have, the extra plus to reinforce our suspicion. If you don't have the lowing Sorry.
If you don't have the low Renne, you can still, have a robust diagnosis when we have clinical signs hypokalemia high aldosterone and a mass lesion identified on ultrasound. But it can be difficult mainly in capturing a zoom. Azotemia may complicate because azotemia may always lead to a secondary hyperaldosteronism and even, may induce, ultrasound enlargement of the, adrenal glands.
So it's not always straightforward. The most common straightforward is this scenario when you have clinical signs hypokalemia inappropriate all Oster and a lowering and the mass lesion identified on the ultrasound. So what's the treatment of these, cats?
So if we have a unilateral, lesion most of the times it is unilateral. We need a unilateral adenectomy when it is not identified when diagnosis does not reveal metastasis because some of them may metastasize. So we need to stage the disease before surgery.
So let's do, thoracic CT and abdominal CT. We combine both actually, before sending these, guys to surgery. And the surgery may be done via laparotomy or laparoscopy.
But once again, since around 10 to 20% of them metastasize at the moment of diagnosis later on, we need to stage before, surgery. If we do the unilateral adenectomy before and during the intervention. Let's have a look on potassium.
We need to evaluate potassium and correct the hypokalemia the best we can, either perros or intravenous. After intervention, we may require a nice salt diet. This is a top keeping humans to counterbalance the possible IPO aldosteronism.
We can use fludrocortisone if needed. OK, or even DOCP meaning that if we pass from a no productive aldosterone when we remove the tumour, the, the other adrenal gland is probably the the glome laza region is probably hypofunction, and we need to give some eventually support. Even if most of the times is not, necessary, as you would expect to be so after the intervention.
What's the prognosis? The prognosis is excellent, and no medication is further needed in most cases that have a survival time of more or less three years. Indeed, the cats may become asymptomatic for one to several years, with some complications that may occur.
It's only the inter abdominal bleeding during the perioperative period. So after the surgery and after the post of period, we may have a great survival time estimate in around three years, which is fabulous, fabulous. But since most of the cats are geriatric, so we may have a survival That is almost, the expected formal lifespan of a patient.
So there are this paper on, the, treatment and the surgical findings published in the Journal of Feline Medicine and Surgery. A lot of surgeons that, were, in this paper and showing describing a median hospitalisation of four days. 97% of the cases survive the procedure.
Hypertension resolved in 21 of them, in the majority of them in apoca, solved in 24 of them with a median survival time of of 1082 days, 1082 days. So brilliant, Brilliant, brilliant survival time. If owners do not want to pursue due to financial concerns in case of comorbidities distant metastasis in case of bilateral hyper place of the son los in which we can find out from which side is the tumour or in case the tumour is not extracted, we may recur to medical management.
And how can we do it? We can use an aldosterone receptor blocker. So the most common one is spironolactone, which is great.
So we're gonna block the aldosterone receptor and we're gonna have a potassium implementation. There are not I don't know how this is work in the UK, but there are not a lot of formulations in Portugal. Only one liquid formulation.
We need to, start as well. And the third one, the treatment of systemic hypertension. Systemic hypertension is what we call the, we need to address, systemic hypertension, using calcium, channel, inhibitors, namely the amlodipine.
Following the guidelines. OK, survival. We, the hyper treatment, by itself is a bit lesser than the surgery, and it's estimated in around 2.5 years.
So what we expect is from the medical treatment If bilateral apply identified, usually spirolactone is enough to normalise hypokalemia. We don't necessarily need potassium, but that depends on a one by one case basis. Prognosis is again less favourable, favourable than surgery.
Again, prognosis is less favourable than surgery with 2.5 years comparing to three, years. So just almost finishing.
Let's talk about rare diseases. The question Can dogs have hyper Doster, And can cats have pheochromocytoma and they already know the answer. So absolutely yes, it can.
And but if they are extremely, extremely rare. And this is the zebra here because first of Sara gak always tell this and it's a really thing that I'd like to share with you as well Is that when I am here? I'm here and I heard, a horse walking, I think in my, common sense.
OK, this is a horse, a horse walking on the street. But that can be a zebra as well. And pheochromocytoma hyper are our zebras.
And if we change the species, this is the most uncommon zebras. Even more so, can dogs have hyper? The answer is yes.
Can cats have pheochromocytoma? The answer is yes. So, in dogs, typically, aper is mis caused by unilateral adrenal adenoma or carcinoma.
Few cases of idiopathic bilateral hyperplasia already reported middle age to elderly dogs, clinical signs, lethargy, anorexia, weakness and PUD. We may have similarly to to cats, hypertension, hypokalemia and suspicion of adrenal tumour which may or may not be feasible. Similar approach to the cat From an endocrine perspective, we need, doone measurement in these cats, plus, in these dogs.
Sorry, plus renin dosage. But rine measurement again is debatable. A case I've seen recently from a dog.
We have renal mass and, Hypokalemia and, Seed. We have a massive hyperaldosteronemia with an, renal activity of renin activity of 0.21.
So, low. So it was not secondary. It was a primary upper aldosteronism.
It was a mixed tumour, I guess. And few in cats can occur extremely, extremely rare. And I present Teresa Preg one of my former mass students.
That was with me on clinics when we identified a cat that was referred due to exploration of an adrenal mass. And the cat have episodes of weakness and lethargy. And, indeed, it was diagnosed with a pheochromocytoma.
It's extremely, extremely rare. It was a big mass, and we did measure metanephrines metanephrines. Metanephrine plasmatic was highish than normal.
Melasma normetanephrine was extremely extremely high around 8 to 9 times the maximum value of the reference range. And we went to surgery. We discuss this is the This is the adrenal gland.
And we had the confirmation in vivo, one of the first cases described in the literature because we sent the pathology to rac and Res university Professor Sarah Garak did coloured the finials. Special stains, namely Cina doyin and Chromatogram in a for, the mono of chemistry for this tumour. It was a confirmation.
The dog was the cat. Sorry. The cat was still alive on the moment of the, diagnosis.
So that was one of the first premortem diagnosis of pheochromocytoma. And we published the case report, on JZ app. So free for you to read it and to show you, that also due to these cats, we also try to develop with the Belgium lab and the track University, the feasibility of plasma and urinary metanephrine and normetanephrine in cats showing that it's feasible.
We published this paper on Journal of Oral Medicine, last year. And as you can see here. So we we took 10 healthy cats, and we we tried to establish the range of these cats And how it was the cat from our study from the pheochromocytoma.
And as we can see by LC MS MS it was the healthy cats. This is a pet. There was an overlap here, but the normetanephrine ones we have here, the 10, cats.
And then this is the foc cat here and again, the urinary, is similar is similar. Metanephrines and normetanephrine, as you may see similar to dogs, urinary normetanephrine seem to be better than, metanephrines in blood. That's curious and interesting.
And this is measured by LC MS MS These, ones. The plasmatic ones was measured during the for the diagnosis of this cat was measured initially by the, HPLC as well. And comparing both, it was only one, cat.
Sure, but the results were similar from the FOC, as we called him. The results were similar using LC, MS, MS and HPLC. Reinforcing that LC MS MS is a promising technique, and it's feasible as well in cats.
So what we've learned over these webinars. So, Cyrus, case of Cyrus, showed us that although rare, we should include pheochromocytoma in our differential diagnosis, So don't forget weakness Dogs, dogs with hypertension. Don't forget that only 5 50% of hypertensive dogs have, have indeed AC, O.
And, sorry. Only 50% of fo dogs have hypertension. It's It's this OK, so, we may have pheochromocytoma without hypertension and don't forget adrenal tumours are not always Cushing syndrome.
Don't forget, we hear the horse noise that's likely to be a horse, But we can have a zebra. So don't forget that pheochromocytoma is the zebra. That's what we learned from Cyrus.
And check, metanephrine and normetanephrine, either in plasma or urine in your dogs. Sus suspect of having pheochromocytoma What we've learned from Billy Billy showed us that hyper Odo is a top differential in differential diagnosis, hypertension and hypokalemia, especially if they are concurrent and for diagnosis, we need to have a decreased potassium within an appropriate aldosterone. Aldosterone may be in the reference range and still inappropriate.
So also, interpret this sample in the same sample. So all of the practise results together and, decrease ring, despite the fact that methodology for R is very, very discussable, adenectomy is recommended in case of a unilateral mass. Don't forget.
And the medical treatment in cases that, it's difficult to go to surgery or there is some contraindications. We may use oral potassium prolactin in the M lodipine with a good prognosis in around 2.5 years for survival Time of medical treatment in three years with surgery.
And in most of the cases, prolactin is the paramount medication. So we don't necessarily need in all of them oral, potassium or even amlodipine according to whether there is severe hypokalemia or severe hypertension, respectively. OK, so I'd like to thank you.
Say Oh, God, as we say in Portuguese, to the Web vet for the invitation to lecture on adrenal diseases. I love adrenals, as you may have shown. And I really sorry for my language Bugs sometimes because, as you may be aware of English is not my native language.
So really sorry for it. And to show you my team. So this is me.
This is Joanna, my former resident that is now works in the hospital in the Internal Medicine Service as a senior clinician. This is, Beatrice, my current internal medicine resident. This is Patricia, my current PhD student.
She's working on adrenal glands in CATS. Which is a nice study. And this is our our my, right and left hands and arms.
My the best nurse in the world that it's my, internal medicine and nurse here in Portugal. So thank you so much to all of you if you have any questions, so please feel free to email me. And if you enjoyed the webinar please, please feel free to give me your feedback as well.
This is my email ral at FMV dot U lisboa dot PT. So please feel free to share Share your opinions about this webinar and to answer, and to ask me questions if you have any or share your cases of fear and hyper ostrem that would be a pleasure to help you the best I can. Thank you so much once again for having choosing me on the webinar vet.
And, I'm welcome for you to see you in the near future. Thank you so much.