So good afternoon, everybody, here and online. We have 70 people who are apparently listening from outside. Very much welcome to this meet a professor. This is educational. It's interactive. And therefore, I have a couple of questions. So most importantly, I don't have any conflict of interest. And here you may want to scan. So that we can do some polling. But it's even more important to have some direct interactions. So primary ALDO is very much at my heart. Probably also at your heart. I've started working scientifically on PA in 2008. And the last 14 years have been very interesting for me as a scientist, clinician scientist, and basic scientist, and mainly a clinician. And so hopefully, this will be a very good session. And I would like to encourage you to go forward to the mic and ask your questions. My first question to the room is, this is not an official poll. So it's just to know whether this is maybe an expert audience already. So who has treated more than 1,000 cases of PA? Hands up. OK, more than 100. Hands up. Oh, yeah, here they are, the real experts. More than 10. Hands up. Yes, very good. So you are already known very much. So this is the first case I would like to discuss. It's a very easy one. But I have embedded some of the background information. And I apologize for being quite selective. There is, of course, a bunch of information out. And I cannot cite every study. So if this is selective and I missed your study, I'm very sorry. And I apologize. But it's not on purpose. It's a 46-year-old female in good health. She's leaned. And she has refractory hypertension since more than 10 years. Blood pressure pills don't work with me. And here you see the office blood pressure. And also the ambulatory blood pressure monitoring confirms quite severe hypertension, also non-dipping during the night. And here are some more information. She's currently, her potassium is normal. And that's the medication what she's on. Already a mineralocorticoid receptor antagonist at low dose, I would say. And beta blocker and angiotensin II receptor blocker. So your suspicion? OK. You can just shout. PA, yes, of course. Yeah, that's a PA session. So that will be not a pheochromocytoma. You are right. OK. So you know the normal physiology. And in primary aldo, we have this renin-independent production of aldosterone, which then increases sodium retention and potassium diuresis. We get volume overload hypertension and the increased aldosterone-to-renin ratio. So the renin is relatively or absolutely suppressed. And this all goes back to Jerome Kahn, who described it in 1954 in Ann Arbor. And the therapeutic consequences of diagnosing it is quite substantial. So if we diagnose unilateral primary aldosteronism, then the adalectomy leads to cure of hypertension in a substantial percentage of patients and also cures hypokalemia. It's cost-saving. And if we diagnose a bilateral form, then we have specific antagonists, which are working quite well. And of course, we all know that this is a spectrum. This is not black and white. And there are also some early stages, low renin hypertension states. And most of the patients nowadays are normokalemic. In these severe cases with hypokalemia, they represent less than 1% of the hypertensive population, whereas the normokalemic variant is much more frequent. And this is the algorithm which we are using based on the Endocrine Society guideline from 2016. And so the first initial step is always taking the aldosterone to renin ratio. And may I ask you into the room, do you consider PA diagnosis difficult or easy? Tricky, okay. So quite some challenge. Why? If I may ask back, why is it challenging? It depends on whether they're on medications and then in their video. The medications issue with the screening, yeah. Adrenal vein sampling is not so easily available and so on. Yeah, yeah, these are all good points. So that is what currently is recommended. The spectrum of patients where we should look for a primary ALDO, this represent roughly 50% of all hypertensive, so to say. One can discuss in some of those categories whether it's really worthwhile or not. You see also some numbers over here. You can see my pointer. So the pretest probability increases with a stage of hypertension, of course. Hypokalemia is very much pointing towards primary ALDO. Adrenal incidental lomas may have 2%, but it could be also higher. Then you see that obstructive sleep apnea has a 9% prevalence. So it depends really on the category of patients, but in general, these all represent already 50%. And that it is really important to screen, I just would like to remind you why this study, which was not done in specialized centers, but in primary care centers in Torino, 1,672 patients were screened for primary ALDO steranism of those who are hypertensive in these participating centers and you can see that the outcome, the final diagnosis of primary ALDO was close to 6% and the proportion of those who had unilateral disease was 1 third, which means that 1.6% of all hypertensives in primary care might have primary ALDO steranism. And again, we see here that the prevalence increases with the degree of hypertension. So let's have a look on the reality. Here's a questionnaire sent to 250 Italian physicians and 250 German physicians, and they are treating loads of patients as an average 1,400 and 1,700 during this given period of time and they are treating, of course, a lot of hypertensive patients. And here you see now the percentage of patients who have been screened or not screened, so to say. In Italy, 93% have not been screened and in Germany, 92% have not been screened. So this is a reality. Still a very limited number of patients is screened and here's also evidence from the US. This is a huge study with 269,000 participants with treatment-resistant hypertension. And you see in the left panel the number of patients per center and always this small dark green or dark blue part of each column. So these are all the individual centers you see. That is the number of patients screened for PA. And here you see the average. It's all around 1%. And you see also over time, so starting in 2001 until 2017, the number of patients treated is increasing, but the percentage of patients with PA screened is not increasing. So it remains stable. You can even say it diminished. This line here shows the average percentage screened. So wherever we are, in Europe or in the US, screening appears to be not very popular. And I calculated it for our own country, Germany, with around 82 million population. And we know that we identify per year only 400 patients with hypokalemic PA and around 1,000 patients with normokalemic PA. But there should be, based on these 6%, there should be around 250,000 or one million, so in total 1.2 million of patients out there with primary aldosteronism. And this means that we are currently not even diagnosing 1%. It's rather one per mil in Germany. And this per year. So that means provocatively speaking that we need another 1,000 years to diagnose those patients who currently have PA. So back to our patient. This is what the baseline endocrine evaluation. But as I told you, so the aldosterone-to-renin ratio turned out to be elevated. But as I told you, and you have already mentioned that the patient was on medication which interferes, we have the aldosterone, we have the antitensin II receptor blocker, we have the beta blocker, and we have epiluronone, so three drugs which interfere. So what can we do? Well, let's first have a look on the influence of medication. That's a complicated issue, really. So we have drugs like beta blocker and central alpha agonists who may cause false positive results because they decrease renin. We have then drugs like ACE inhibitors, diuretics, angiotensin II receptor blocker, and mineralocorticoid receptor antagonists who may cause false negatives because they increase renin concentrations and aldosterone. And then we have the calcium channel blockers and alpha blockers and vasodilated taters who are rather neutral and have minimal influence. So our practice is, if you go to the mic, that would be best, probably, so that the participants can directly hear. So just to finish, we change the medication as required by the guidelines ahead of the aldosterone-to-renin ratio to verapamile and or doxazosazine and, if necessary, dehydralazine. But because there are patients where you cannot do it, we just measure the ratio. Yes, your question. Sorry, I was just gonna raise the point about the calcium channel blockers being put into one block and not differentiating the dihydropyridine versus the... Yes, you are right that the verapamile types have minimal influence whereas amlodipine and others have some substantial influence and should be avoided. So, and we have to keep in mind, aldosterone-to-renin ratio, the cutoff are very much depending on the SA used and on the units. And then there are additional influences of medications like antidepressants which reduce the ratio and increase false negative rates. And we have oral estrogens and gastrogens which increase the ratio and can increase false positive rates. Finally, it means also that confirmatory testing is necessary. We have to repeat the ratio several times because sometimes it may turn normal all of a sudden or the renin levels may turn normal. So it's not the best biomarkers which we have but it's what we currently have. And of course it would be a very good strategy to test every patient before you put them on medication. And to show you some evidence for it, this is a small not published study from Munich where we also collaborated with GPs and enrolled 210 patients into a study and they had not received any medication. And finally we found in this rather small cohort after confirmatory testing 12 patients which represent again this five to six percent of prevalence in primary care but now this time in untreated patients. And of course it's much easier to screen untreated patients than in already treated patients where you have this interfering medications. Good, so we have the aldosterone to renin ratio. We repeated it and it still was abnormal. And this algorithm shows you that we may, the question is now do we have to do confirmatory testing and there are some patients where we don't have to do it when there's hypokalemia and very high aldosterone levels. And here are some numbers from our centers how we are screening around 300 patients per year with the aldosterone to renin ratio with a suspected primary aldo. And in the large majority of cases where we have an elevated aldosterone to renin ratio we do the confirmatory testing and only few patients can be bypassed because they have such a severe phenotype. But they are out there and we should use that bypass of course to proceed directly to the next step. So my question now for you is which confirmatory testing are you using because you are here the experts. This is a question which you may answer and you can now use your iPhone and vote. Okay, oh that's interesting. So very good, thank you. So we have a majority for the saline infusion test and we have also strong fraction using 24-hour urine aldosterone which I think is not so popular in Europe but apparently quite popular because there are also some data out, very recent one which are supporting that, very good. So I don't have data on the 24-hour urine sensitivity and specificity but this is because it was not analyzed in this manuscript which was a meta-analysis of established confirmatory testing by Vincent Wu and he came up with in this analysis for the sodium infusion test with a sensitivity of 85 and the specificity of 87%. For the captopril test, 87% and 84% and for the flutocortisone suppression test which nobody apparently is doing here in this audience, it was higher, 87% and 95% but this is a complicated procedure, in-house requires a lot of supervision and measurements and not so easy to perform. Good, so these I think are the preferred tests but of course 24-hour urine assessment with sodium loading is also a very good one. We have been comparing captopril test and sodium infusion test in terms of side effects and there it's clear that the captopril test, the captopril challenge is definitely less frequently causing hypertensive episodes and hypertension crisis. However, there is of course some patients who are very sensitive to captopril challenge and may have a hypotensive episode. So we choose often the test depending on the degree of hypertension, very hypertensive patients we use the captopril test because we think it's more safe. And this can be seen here on this screening sheet or our numbers in our center where we perform around 200 sodium infusion tests per year and 176 captopril tests. Actually we sometimes do both tests in a patient to make really sure that our diagnosis is correct. Good, so our patient underwent a sodium infusion test and was switched to verapamil and doxorazosin and here you see the results. Cortisol is decreasing during the four hours test. Renin is suppressed during the test and these are the aldosterone levels. So this means that the patient has an abnormal test result and this looks very suspicious of primary aldosterone. Do you agree with that? Yes, I see nodding, wonderful. Okay, so we have done a confirmatory testing and now the question is what is behind this. I remember you, I remind you it's a normal calemic patient with, if we go back, the aldosterone levels are between 125. This was the baseline screening and now at baseline 332. So it's medium to high but not extremely high and the question is what would we expect? So we have subtypes of primary aldo. We may have aldosterone producing adenoma. We have this bilateral hyperplasia. We can rarely have this macronodular bilateral disease and of course we can also have familial hyperaldosteronism, also very rare and so in prevalences we have in hypocalemic cases 70% unilateral disease whereas these two entities here at the bottom are very, very rare but in the normal calemic variant of course we have much more of the bilateral disease. Good, so imaging is best done with CT although MRI is also a good choice and can be preferable in young patients and to reduce radiation but the CT scan allows nowadays better identification especially in very slim patients. MRI may be difficult to visualize the adrenal glands. So you may find normal looking adrenals, unilateral tumors and the sensitivity for unilateral disease is, as you know, not very high especially also the specificity because you may have adrenal incident alomas and often you have a situation like these adrenals where you really don't know is this here a central nodule. It's definitely smaller than one centimeter but it's not normal looking and then you don't know what it is. And in our patient we had an MRI which was already performed by an outside endocrinologist and we have here right-sided adrenal nodule of 1.5 centimeter and leukotypical. Good, so we have done adrenal imaging and now we can consider next step, which would be adrenal vein sampling, as you know. And here are the criteria where we might skip adrenal vein sampling, young patients, unilateral adenoma, and normal looking contralateral adrenal, and a strong biochemical phenotype. These are the characteristic where you can really avoid adrenal vein sampling with a very good outcome. All the other patients, like others, have to undergo adrenal vein sampling. And now the question, although I have already answered it in a way, should we do? But there are, of course, always option. So my question to you is now, would you do AV sampling in this patient, yes or not? A, yes. No. B, I would proceed to surgery. C, no, I would prefer additional imaging. Maybe you have something very fancy in your institution, some hot pet scanning or so. Or D, no, I would use MRI therapy anyway in all patients. So let's see what you are voting for. Okay. Okay. Okay, so this looks quite clear. May I ask you, who is having AVS in the same institution? Hands up. Okay, who would have to transfer the patients to an institution where AVS is available? This is similar, yes. And who has no AVS available? Which is also, yes, okay, good. Good, so this is an AVS-driven audience. The radiologists will love it. AVS is very different from country to country in terms of reimbursement. So how much is it in Germany? It's around 2,000 euros, all inclusive. But I heard numbers for the US, which are rather in the area of $20,000. No? Who knows how much it costs here in the US? Okay. They don't want us to know, okay, good. Okay. Good, so yeah, here's some, it's endorsed by the guidelines. It's costly and technically demanding. There's this study a couple of years ago in 2016 published by the group from the Netherlands around Jack Lenders that CT-based decision making is non-inferior. There has been a lot of criticism. It achieved 80% remission, whereas in AVS-based decision making it was 89%. So there was a trend towards a better outcome with AVS, but it was not significant. And in a multi-centric study organized by Tracy Williams and our institution with a couple of collaborators here in the audience, we also saw that in a very selected cohort that those patients who received CT or MRI-based decision making had an inferior outcome. So 80% were biochemically in remission, based on imaging alone, whereas 93% had remission after AVS and imaging. So in summary, you can do your decisions on CT. Yes, you can do, but there's a larger rate of failure. And I think you have to acknowledge this to the patient. So because it has already been mentioned that AVS is a demanding procedure, I agree. I told you that 2008 was the start year when we started to improve our algorithm. So we were doing very few AVS before and had a low success rate, around 54%. And since then, the number of procedures per year has been increasing and increasing, and I think in 2020, we even did 137 AVS. So this was the highest number, but in 2021, we had more than 150. And the success rate is always around 90%, sometimes a little bit below. We have four radiologists who are dedicated to it. And I'm just mentioning it that I believe that this difficult access to AVS, it's also depending on us. If we would lobby for our patients, say we really need it, like we needed petroleum sinus sampling for Cushing's, nobody is debating it, that we have that. But if we would lobby for our patients, we would have, we would generate better access to this technology. At least in Germany, starting from 2008, many more centers are now doing AVS. It has become quite popular. So I think that's a good perspective in general, but I know that still it's very limited in many cases. Okay, so our lady underwent AVS, and you know, you calculate this, you first do the selectivity index. We are using non-ACTH stimulated, I'm not going into detail, but we are using non-ACTH stimulated bilateral simultaneous AVS, and use selectivity index of greater than two, which was met here, compared to the peripheral vein. And then, of course, you calculate the aldosterone to cortisol ratio, and that showed a strong gradient to the right side, where this nodule was sitting. So that appears to be a clear-cut case, and also, which is nice, you have this contralateral suppression. You have here, in the peripheral vein, you have a cortisol-corrected aldosterone of around 10, and here in the left adrenal vein, you have clearly a lower gradient. So this seems to be a clear-cut case. So we have done adrenal vein sampling, and just to finish our statistics, so in the year 2020, we had these 300 cases which were screened. We did these 137 adrenal vein samplings, and we had 42 cases of unilateral disease, and 95 cases who were then bilateral disease, which were treated with mineralocorticoid receptor antagonists. Adrenal surgery is very easy in expert hands. There's very, very low morbidity, so infections rate extremely low, no mortality. We had no single case of mortality in our 300 patients during the last 12 years or 14 years. Sometimes, in severe cases with severe hypokalemia, you may have afterwards hyperkalemia, especially in patients who have renal insufficiency, and if you carefully look, you will also detect some intermittent adrenal insufficiency, so low stimulated cortisol levels, sometimes requiring glucocorticoid replacement therapy. So after surgery, of course, you have to look whether you have been doing surgery on the right side. This is done following an international consensus, which is called PASO. You are assessing the clinical outcome, which is very much deciding whether you have been diagnosing PA very early on or very late in life, and you, of course, assess the biochemical outcome. So back to Our Lady. You remember 10 years of resistant hypertension. I would like to have a vote from you. What if the patient would not have surgery so far, and she would ask, please tell me, what can I expect in terms of outcome? Will my blood pressure normalize, and will I need further drugs or not? What would you answer? So what would you guess is the remission rate, which means normal blood pressure, no drugs against hypertension? Please vote here. Okay. How good? Okay. So quite optimistic here. The optimists are, I love this audience. You are very positive. But I have to tell you, it really depends. And so on average, those who were a little bit more pessimistic would have been correct. So this is the clinical success in a large study around 700 patients, and you can see that complete remission of hypertension is achieved in this large, multi-centric international study in 37%. Partial, which means improvement, is the majority of patients. And there are also some patients who do not have a real improvement in hypertension. More importantly, but complete biochemical remission, this was a series of patients who all underwent AVS, was very high, 94%, and only a very, very few patients did not go into remission. Those who go not into remission probably have bilateral disease or unfortunately had surgery on the wrong side. But now, it's not only about age and sex in the patient. We have a female patient, middle-aged, 46-year-olds, but 10 years of hypertension. There's also some geographic issue. Look at this. This is surgical outcome by blood pressure in the different centers which participated in this study. And green means complete remission and red means no major change. So if you can choose, you wouldn't go to Munich, actually, to treat, let your PA treat it. Instead, you would go to Australia, to Michael Stovasser, who has brilliant data. It's quite interesting, and that in Brisbane, really, the patients are younger and have a less long history of hypertension compared to the Munich and Nijmegen cases where we had an average of 14 years until the diagnosis of PA. At the same time, these are the data for the biochemical outcome, and I told you that it was a rather homogeneous series. AVS was done in all patients, but using different criteria. But nicely, you can see that the overall biochemical cure was more or less with small differences, similar in all the centers. And you can see that some centers only had CT available and that they had a little bit higher missing or partial remission rate. Good. The earlier the better you diagnose PA, the better will be the clinical outcome. And if you use AVS, you can say 90% of the patients, even 94%, will be in biochemical remission. Is PA a binary disease? Yes and no. Unilateral, bilateral? No. André Lacroix is shaking the head. No. We have to admit it is not. It is a spectrum. And probably we are using AVS to identify the very lateralized cases. But true unilateral, whether really true unilateral PA exists so that no aldosterone is produced on the other side in case of suppressed renin, that's really questionable. And evidence for that comes from many, many studies now. I cannot acknowledge all of them, but we have been focusing on those patients who did have absent or partial absent biochemical remission because we thought this is a cohort of patients where we can really get information on histopathology which might represent also the histopathology or the other side of the adrenal. So we have been doing this histaldo consensus with five very dedicated histopathologists a couple of years ago. I think it was before the pandemic in 2019 that it took some time to finalize it. And I would like to share this information because you may have overlooked this manuscript, but I think it's a good one because I think that we should really use this histopathology classification to classify primary aldosteronism. So what was done, we had a large number of samples adrenals from surgically treated patients for primary aldosteronism. They had then standardized nomenclature was developed for main histopathological features. And based on that recommendation for the histopathology was developed. And in general it was categorized into classical and non-classical histopathology. So what is this meaning? Here are the classical on the left side. This is solitary aldosterone producing adenoma. You see here this strong brown staining which means it's staining for CYP11B2, the aldosterone synthase. And if you have such an adrenal then you can call it a solitary aldosterone producing adenoma. But often you may also find those nodules who are not positive and then it's an incident adenoma. So this is classical. And then you see dominant aldosterone producing nodules which are smaller than one centimeter. It's the size which decides on it, but this is also classical. These are of course hard to detect by CT. And then we have the non-classicals which is multiple aldosterone producing nodules, MAPN. They have been termed APCCs in the past. And I would like to acknowledge Bill Raney's groundbreaking work in this area. He's sitting in the audience here. And we have also these cases, aldosterone producing diffuse hyperplasia where you have a strong diffuse uptake of CYP11B2 immunohistochemistry. And in terms of outcomes and follow-up study where we analyzed 60 resected adrenals, we detected that 75% of these patients diagnosed in Munich had the classical histopathology and 25% had the non-classical. And those patients who have the non-classical histopathology have not so good outcome in terms of biochemical outcome. So more or less all the patients who had this classical unilateral aldosterone producing adenoma or nodule were biochemically cured whereas those patients who have a non-classical histopathology, there's a certain fraction who apparently have bilateral disease. Although AVS indicated a unilateral production, but you have to assume that this not-so-good biochemical outcome indicates that this was a lateralized bilateral adrenal hyperplasia. And also we saw that in the non-classical patients, this is strong evidence for our assumption that the aldosterone concentration or the aldosterone-to-cortisol ratio in the contralateral adrenal was much higher than in the classical cases. Good. Question to that? If not, I proceed. I have 13 minutes left. Sorry. So mineralocorticoid antagonist treatment is the gold standard for those patients who do not undergo surgery. It's excellent efficacy, low number of side effects. In males, higher doses are not well tolerated. Starting dose should be low. Increase in dose slowly after four to eight weeks because of the long half-life and the metabolites have to be built. Uptitration according to serum, potassium, and plasmarin in concentration. Eplerinone is a less potent but working alternative. There are three randomized trials out, all of them not perfect. This was the first one showing that Eplerinone is equally effective but at higher doses, so you have to use it at a double or three times higher dose than spironolactone. If you compare surgery versus mineralocorticoid antagonist therapy, quality of life appears to be lower in those treated with mineralocorticoid antagonists. So the surgical patients are the dotted lines and you see that the solid lines have a smaller area, which indicates lower quality of life in the SF-12 or SF-36 in all dimensions. And here's a study listing all the benefits of the two treatments, adrelectomy or MRI therapy, and you can see that most studies are in favor of adrelectomy in terms of all these outcomes, cardiovascular outcomes, and so on. Some are equivalent, but no study favors MRI, MRI aid therapy. And there's also now very convincing evidence from several studies, including this big study that the cardiovascular comorbidities are higher in patients with mineralocorticoid antagonist treatment compared to those who underwent surgery. It's quite impressive here. This is the line of essential hypertensives or primary hypertensives, and the same is also shown in cardiovascular events and also in mortality. Adrelectomy appears to be the better choice, and especially with the mineralocorticoid receptor antagonist treated patients, those who have still suppressed renin concentrations, you know that, have a diverse outcome compared to those who have measurable and stimulated renin concentrations during mineralocorticoid receptor treatment. Good. Our patient underwent adrelectomy. She had a CYP11B2 positive adenoma, so classical histopathology, and that was performed. And then the question is next step. Is there anything what we should do in such a patient? Something missing? Genetic markers. You could do it, but it's not a standard. Renin levels. Yeah, very good. Outcome. Postoperative outcome assessment, of course. And that was done here. The patient had, as you can see, something which we very often observe, that the plasma renin concentration are still suppressed. It takes months, even years, that the renin levels come back. But the aldosterone was very low. We, in this case, did a saline infusion test, and that suppressed the renin concentration very easily. So although the initial aldosterone to renin ratio were elevated, it's clearly remission of hypertension. And remission of primary aldosteronism. Blood pressure is normal, but... So very, very good outcome in such a patient. Good. So PASO assessment is essential. Here are some summaries. I'm going over that because we have still five minutes left and to discuss some more cases, which I would very shortly mention. This is a 55-year-old patient with grade 2 hypertension on three antihypertensive drugs. And she had an elevated aldosterone to renin ratio, and she underwent a CAPTOPIL challenging test. So we have here cortisol levels, aldosterone levels, renin concentrations. At baseline, 60 and 120 minutes. This is the cortisol. These are the aldosterone levels. And these are the suppressed renin concentration. This is a positive test for PA. I assume that you are not so familiar with CAPTOPIL challenge testing, but this is clearly a case. However, because this patient participated in a study protocol, we considered to have that the patient has confirmed PA, but we measured it also with LC-MS. That was the whole purpose of the study. And that resulted into some shocking and very provocative data. Aldosterone using LC-MS was extremely low and suppressed easily following CAPTOPIL challenging. So what is this? PA? No. This patient falls into a category which you have to be aware of. There's an inaccuracy of automated immunoassays. This paper came out this year, led by Graham Eisenhofer, and it shows that with automated aldosterone assessments, this is either the liaison by Diaserine or the ISIS, you measure higher aldosterone levels than with LC-MS, substantially higher. And especially in those patients, this is here, in those patients who have low aldosterone levels, you may have strong discrepancies. Why is that? Well, this discrepancy between immunoassays and LC-MS levels goes away when you extract the samples. So there are interfering proteins, probably heterophilic antibodies, which interferes with these automated assays. And you have to be very careful when you use these automated assays, and you have to make sure that you are, it does not appear to be a problem with immunoassays in general, it's these automated, which cause this problem. Have you been heard of that? Hands up. Heartland Green, who still suppresses myocardial prolapse. Yes. So the patient has low renin hypertension. What is the purpose of measuring cortisol during the test? We always measure cortisol to demonstrate that the patient is not stressed. If you have a stressed patient with an increased cortisol, you also may have an increased aldosterone. Okay? Therefore, during saline infusion and captor pill test, we always do that. Okay. Good, this was patient one. We have still some minutes left. I think it's an important message. You always have to make sure that, which assays you are using. And in some countries like the US, LCM is very popular anyway, but in Europe, it's not. So the 90% of all patients still get immunoassay-based diagnosis, and there, this can be a major problem. So here's a completely different patient. I need your full attention during the last couple of minutes. 39-year-old patient with recurrent hypertensive crisis. You see a very high blood pressure, and potassium is very low. But plasma renin concentration is 108. Aldosterone is upper normal range, 232 picograms per milliliter. She has some co-morbidities, and she's started on drugs to treat her. So here you see a repeat lab test. Plasma renin, 96. Aldosterone, 196. No evidence for pheochromocytoma. Baseline cortisol and ACTH are normal. So clearly not some sort of ectopic Cushing syndrome or something like that. She also had duplex sonography of the renal arteries. No evidence of stenosis. MRI of the abdomen. No evidence of an adrenal tumor. What does this patient have? Angioscan. You don't trust the duplex sonography. Well, this is America or Canada versus Europe. In Europe, the duplex sonography is world-class, really, and much better than MRI. But we have been doing it here. It was normal. No evidence of renal artery stenosis. So, any other idea? Reninoma. So who ever had a patient with a reninoma? Hands up. Oh, gosh, so many. This is the first patient I have been looking out for a reninoma for 30 years. Never saw one. And this was the first patient. So, I couldn't believe it. And since then, we have diagnosed two more. Yes. This is very recent. Three years ago. So, you're right. This is a reninoma, but a very small one. So, we did another re-demonstration of the MRI images. And then, it's difficult to see here. On the right lower kidney pole, this is the kidney here, you see a very small nodule. Less than one centimeter. And the surgeons didn't believe it and didn't want to do surgery. So, we did, in this case, renal sampling for renin. Showing elevated renin concentrations in all those areas. But, in number five, lower right kidney pole, we have this gradient. Demonstrating that this is renin producing small adenoma and the patient got surgery. And after surgery, renin was normal. Potassium was normal. Blood pressure was normal. Everything returned to normal. So, one has really to look out, watch out for those patients. Yeah. We shouldn't overlook those. Okay. You want to have another patient? Or would you like to have Q&As? Okay. I see more support for another patient. This is a 53-year-old male with, of course, hypertension, spontaneous hypokalemia, quite severe. Despite a lot of oral potassium and also spironolactone therapy. So, there must be quite some drive of aldosterone. So, refractory hypertension since five years. Extremely high aldosterone. Completely suppressed renin. And despite spironolactone, low dose, 50 milligrams was not so much. And that was before the guideline actually. So, we did here confirmatory testing and you can really discuss whether this is needed in such a patient. And it confirmed that aldosterone remained high. And then we did a CT on this patient. And both adrenals are of completely normal appearance. And the only thing what the report mentions is a two-centimeter measuring nodule adjacent to the renal helix. So, any ideas for that? Normal-looking adrenals. Small nodule besides. Hm? Again, I couldn't hear it. Ectopic. Ah, Irina, okay. Yeah, you are the expert. So, we did adrenal vein sampling. But with no result, to be honest. So, we have here the classical AVS finding of double down sign, so to say. So, on both sides, the aldosterone to cortisol ratio is lower than in the periphery. Can you see it? We had two attempts. Both were successful. So, cortisol was higher than in the periphery. More than, clearly more than two times. So, the selectivity index was met and positive. But aldosterone levels low in all the samples. Not higher in the adrenal veins. Okay? Double down sign. And it's an indication that either you have been missing the adrenal vein which is supporting this tissue or it may be something else. And in this case... You're selective because the cortisol is higher than the periphery, so you're selective. You are selective, so we are in the adrenal veins. But whatever is happening, the drainage of the aldosterone producing tissue is not going through the central right and left adrenal vein. So, in this case, we used an imaging technique which was at that time available which is called Gallium Pentixa 4. It's a chemokine receptor based imaging technique for oncology imaging, especially myeloma. And it is also... This chemokine receptor 4, CXCR4, is very high in the adrenal gland, especially in the zona glomerulosa. This is a paper by Stephanie Hanna who was the first author on this study. And you can see that in this small series of patients, aldosterone-producing tumours pick up very nicely this tracer, whereas the contralateral adrenal does not. And we did also this in this case. And here you can see that we have, in this ectopic location, a strong uptake which gave us support for the diagnosis of an ectopic aldosterone-producing adenoma in an atypical situation, high SUV. And the patient underwent surgery and had a dramatic response, so had only one drug remaining, normalized blood pressure on both sides, and no longer hypokalemia. So, it was a very active aldosterone-producing adenoma in an atypical location. Okay. And afterwards, everything was good. Yeah. So, thank you very much. Time is over. You were a great audience, very positive.

primary aldosteronism

aldosterone overproduction

adrenal glands

diagnosis

treatment options

adrenal vein sampling

adrenalectomy

heterogeneity

imaging techniques