Unpacking Primary Aldosteronism: New Insights and Advances in Diagnosis

Unpacking Primary Aldosteronism: New insights and advances in diagnosis

[00:00:00] Welcome to Healthier World with Quest Diagnostics. Our goal is to prompt action from Insight as we keep you up to date on current clinical and diagnostic topics in cardiovascular, metabolic, endocrine, and wellness medicine.

[00:00:19] Approximately 120 million people in the U. S. have hypertension. That's about half of the adult U. S. population. Yet 90% of patients with hypertension. Don't know why they have it. Uh, identifying the mechanisms that can cause hypertension is not only a scientific advancement, but it's also crucial for the proper treatment of patients. Uh, recent studies suggest that up to 30% of patients are suffering from hypertension due to a condition Called primary aldosterone ism or PA,But less than 1% of the population is screened for PA. Okay. So the stats are staggering.But the bottom line. Is that a lot ofpeople have hypertension. Many people with hypertension could [00:01:00] have it because of a condition called primary aldosterone ism.

[00:01:03] And basically no in a screen for it.

[00:01:05] Today we have on our podcast,

[00:01:07] Dr. Sanjay Dixit and Dr. Marco Marcelli, board certified endocrinologists and medical directors with Quest Diagnostics. We are here today to talk about a breakthrough study that may help drive screening for a primary aldosterone aneurysm in hypertensive patients. Welcome Dr. Dixon. Welcome Dr. Marcelli. Thank you for joining me today.  

[00:01:27] Thank you. Good to be here.

[00:01:29] Thank you, Mason. Good to be here.  

[00:01:32] Let's start off today by talking about the risk that comes along with primary industrialism, this condition that we once expect it to be a rare condition, but

[00:01:40] Now we understand underlies a significant portion of hypertensive cases compared to what we originally thought. Dr. Dixit, why should we go back and screen for primary pedestrianism in hypertensive patients?  

[00:01:53] Hypertension is an important medical problem in and of itself. However, [00:02:00] hypertension caused by primary aldosteronism is important in thatThere's an association with primary aldosteronism with a whole host of cardiometabolic disorders.

[00:02:08] Heart failure, atrial fibrillation, stroke, coronary artery disease. Type 2 diabetes mellitus in greater proportion than in patients with just essential hypertension not caused by primary aldosteronism.

[00:02:23] Right. So it's not just about hypertension right? It'sthat these patients with primary aldosterone is Mr. More at risk for cardio-metabolic conditions. So for example, The odds of having a stroke are more than 2.5 times higher. If you have primary aldosterone ism compared to somebody with just essential hypertension, um, that number increases when you think about kidney dysfunction,

[00:02:46] You have two times greater odds of having my grow up. And area, if you have primary aldosterone ism compared to, again, those patients with just. essential hypertension. and that pattern continues with

[00:02:58] glycaemic control, [00:03:00] right? Increased odds of having diabetes metabolic syndrome, and even non-alcoholic fatty liver disease. So that's quite remarkable and notable clearly primary aldosterone ism is something

[00:03:10] we should have on our radar.

[00:03:11] Let's now jump into the biology of primary aldosterone. CISM by starting with the role of aldosterone in the body and the regulation of blood pressure by aldosterone in healthy person.

[00:03:24] Absolutely. In a normal, healthy individual, the rein angiotensin aldosterone system. Think of it as the body's blood pressure and fluid control system. When that person's blood pressure gets too low, for example, because of dehydration, the kidneys note this first and secrete a hormone called rein rein.

[00:03:48] Then in turn, acts on a protein in the bloodstream called angiotensinogen. and then produces angiotensin 1. Another enzyme converts angiotensin [00:04:00] 1 to angiotensin 2. Angiotensin 2 has important effects. It tightens up the blood vessels, increases blood pressure, it tells the brain to have the patient drink more fluids, which also increases blood pressure, but it also tells the adrenal glands to produce more of aldosterone, which is the topic of this podcast.

[00:04:23] So aldosterone tells the kidneys to hold onto more sodium and more water. And as you might expect, more fluid in the blood stream leads to higher blood pressure. So this whole process is intricate but really helps maintain a person's blood pressure and fluid balance.

[00:04:44] Great. So, under normal circumstances, say a person, like you said

[00:04:48] has low blood pressure. Randon is where least from the kidneys to tell the adrenal glands to produce more aldosterone. And it does multiple things, but, you know, including acting on the adrenals to release more aldosterone, which [00:05:00] then act on the kidneys, Causing the kidneys to take in more potassium for excretion in the urine, and push out more sodium and water into the bloodstream, which increases blood pressure.

[00:05:10] So ultimately when you have low blood pressure, aldosterone really is the signal for increasing that blood pressure. But then as that blood pressure returns to normal, the release of Renton is decreased. So that signal for aldosterone is no longer present. So running comes down, aldosterone comes back down and it stops calling for that increase in blood pressure, essentially. What are some clues that the system has gone awry?

[00:05:35] Well, I think we both said it, right? In a normal, healthy patient, right? Renin is responsible for the production of aldosterone. And in primary aldosteronism, aldosterone is produced without that renin stimulus.

[00:05:52] Typical lab findings in a patient with primary aldosteronism, as you might expect, would be low renin, high aldosterone, [00:06:00] and on occasion, low potassium.

[00:06:02] So low rent in high aldosterone and on occasion, low potassium. And of course,High blood pressure, which is a hallmark symptom of a patient with primary aldosterone ism. Let's take a step back and briefly define

[00:06:14] hypertension.

[00:06:16] yeah, the2017 guidelines state that blood pressure is systolic 130 or above and or diastolic 80 or above Okay. So Let's actually talk about screening methodology.

[00:06:30] this question is for Dr. Marcelli, what is the classic screening method for primary aldosterone ism.

[00:06:36] Yeah, this is an important question because, the last, uh, U. S. based, guidelines uh, published for the diagnosis of, um, primary aldosteronism. or for its treatment was in 2016 by the Endocrine Society. And so at the time it was established that the ratio of [00:07:00] aldosterone measured in nanograms per deciliter to plasmarin inactivity measured in nanograms per milliliters per hour is the ideal screening tool for primary aldosteronism.

[00:07:12] According to these guidelines, if the ratio is 30 or above, this is considered a positive screening results.

[00:07:22] Right. So the ratio of aldosterone to run in, uh, has been classically looked at as the.

[00:07:29] Ideal screening tool for primary aldosterone ism. If that ratio is above 30, that is considered a positive screening. But as we know, the guidelines

[00:07:38] have now been under scrutiny since 2016 and studies that have been published since then indicate that there may be more effective screening tools beyond using that aldosterone to run in ratio.

[00:07:49] Can you talk a little bit more about that research?

[00:07:51]

[00:07:52] So very importantly, in 2021, a meta analysis from Canada and New Zealand [00:08:00] was published. This meta analysis included 10 studies representing 1, 410 patients and it was found that the sensitivity of the aldosteron renin ratio test was less than 50 percent in three of these studies. And, uh, additional studies have been done after, uh, for instance, uh, uh, they tried to find, uh, other screening tests beside the aldosterone urine ratio.

[00:08:30] And they, used the, 24 hour urine, uh, collection where the, aldosterone secretion during the 24 hours was measured. And, uh, this actually turned out to be a more, sensitive, uh, way to diagnose primary aldosteronism. However, it consists in a 24 hour urine specimen. this is, potentially associated with a lot of things that can go wrong.

[00:08:57] Patients usually don't like this [00:09:00] test. and therefore. even, uh, other, screening, methodology have been, uh, tested. But overall, the, research suggests that while the aldosterone renin ratio is effective for detecting overt cases of primary aldosteronism with very elevated aldosterone level, it is less effective for milder forms of the condition. 

[00:09:25] Wow. Okay. So some studies are showing that the aldosterone render ratio has sensitivity less than 50%. that's pretty striking and something to keep in mind. looking at aldosterone over a 24 hour period is capturing patients with primary aldosteronism, but it carries its own issues. Right? It's not as practical in everyday use So where does that leave us?

[00:09:48] so the, type of screening test that was introduced, during the last, uh, years is to use, uh, the, plasma renin activity, when the plasma renin [00:10:00] activity level is suppressed to less than one nanograms per milliliter, per hour. This would be a positive screening test, and, uh, only patients with a plasma renin activity less than one are considered for an algorithm that measures plasma aldosterone concentration and categorizes individuals with suppressed renin accordingly.

[00:10:27] And there are three different categories. In the presence of suppressed PRA, if the plasma aldosterone concentration is greater than 15, this indicates overt primary aldosteronism. Levels between 5 and 15 suggest likely primary aldosteronism until proven otherwise, and finally, uh, level less than five nanograms per deciliter indicated that it is unlikely that the patient has primary [00:11:00] aldosteronism, and this situation suggests instead low renin hypertension. 

[00:11:06] Okay, so let me interrupt you to summarize the methodology that you're explaining now. So in recent years, we're starting to look more toward the idea of measuring plasma, ran an activity.

[00:11:17] Renon less than one nanogram per mil per hour is considered suppressed. Those patients will then go on to get a plasma aldosterone concentration run. If they have plasma aldosterone concentration greater than 15 nanograms per deciliter, They have overt primary aldosterone aneurysm. If their aldosterone levels fall between five and 15 nanograms per deciliter. they also have a positive screen for aldosterone ism,

[00:11:45] Anything less than five nanograms per deciliter of aldosterone Is considered low run and hypertension.

[00:11:51] So, how does that compare to the aldosterone running ratio?

[00:11:55] So, here at Quest, we recently had the [00:12:00] possibility to compare, uh, the aldosterone renin ratio equal to or more than 30 to the plasma renin activity lesson one screening test. We, used, almost 95, 000 patients from the Quest database who were referred by their physicians for primary aldosterone screening.

[00:12:21] So, for each one of these patients, we had a renin and we also had aldosterone. And so we compared the effectiveness of the aldosteronin ratio test with a cutoff of more than 30. And our findings revealed that 13. 2 percent of the patients screened positive according to the aldosterone renine ratio test more than 30, compared to 45.

[00:12:50] 9 patients who tested positive for plasma renine activity less than 1. When we categorized the [00:13:00] patients according to the plasma aldosterone concentration level, 30. 3 met the criteria for a positive screening with a aldosterone level. More than 15 or between five and 15, uh, the remaining 15% had had a plasma doum concentration, less than five, indicating lowin hypertension.

[00:13:25] And we also did an additional, uh, analysis of the data, and we found that 98% of the patients with a positive Aldo screening also had a suppressed plasma. activity, meaning that, uh, the plasma renin activity basically recognized everybody that was also, uh, recognized the positivity of the aldosterone renin ratio screening test.

[00:13:50] In contrast, only 30 percent of those suppressed, uh, plasma renin activity, uh, were found to have an aldosterone renin ratio more than [00:14:00] 30, indicating, therefore, that, uh, the Um, plasma renin activity test is superior to the aldosterone renin ratio more than 30 as a screening tool for primary, aldosterone.

[00:14:14]

[00:14:15] So aldosterone random ratio recognized of individuals with primary aldosterone aneurysm while suppressed Wren and identified about 30% that were positive for primary aldosterone aneurysm, and about 15%. That had a low run and hypertension, as you pointed out. Very interesting. So I can picture these two methodologies parallel in my head, the aldosterone run and ratio greater than 30 and the suppress Renton less than one followed by an aldosterone level. But. Can we put some numbers to solidify? Why the suppressed run and followed by an aldosterone works significantly better than the aldosterone random ratio.

[00:14:56] yes, for instance, uh, let's [00:15:00] consider a situation where the, plasma renin activity is 0. 8 and the aldosterone is 16. And in this case, the aldosterone renal ratio would be 20, and the patient would not be diagnosed with primary aldosteronism if we were to go by, the, guidelines of 2016.

[00:15:20] by using this, algorithm, we now have a situation where we, uh, analyze the Two parameters, renin and aldosterone independently. First of all, we need to look at the renin concentration. If it is less than one, that indicates a positive test. And therefore, now we can look independently at the aldosterone level, which is 16, which is considered very elevated. particularly in the presence of renin suppressed to less than one. biochemistry like this represents definitely a positive [00:16:00] screening for primary aldosteronism.

[00:16:02]

[00:16:03] Yes, that's a great example. And I think that that really will help, uh, our listeners make sense of these two methodologies together. So.

[00:16:11] Dr. Dixon, did you have any thoughts that you wanted to add Regarding this study.

[00:16:15] My thoughts about this study is how concordant the QUEST study data is with what's out in the literature using the plasma renin activity as a screen and then going to plasma aldosterone concentrationAbout 45 percent of those folks were, were identified, which fits perfectly with the literature where anywhere between 30 and 50 percent of patients with hypertension have primary aldosteronism using this, these screening criteria. That just speaks to the power of the Quest study and how broadly applicable this is to the adult population. population with hypertension.Yeah. I mean a sample size of almost [00:17:00] 95,000 patients. That's pretty powerful.

[00:17:02] So who should be screened for primary aldosterone aneurysm? you know, from what I'm hearing.

[00:17:07] I feel like the answer could be everybody with hypertension. But what is your perspective? Dr. Marcelli?

[00:17:13] I think that we are in front of, uh, some important cultural changes, because, uh, we now came to the realization that primary aldosteronism is not, uh, that rare disease. In fact, it could be present in up to 30 percent of the patients with hypertension.

[00:17:33] And so based on this, uh, some expert groups, these are, guidelines published in Japan and Korea by their respective endocrine societies suggest that that the field should move toward universal screening for primary aldosteronism. In other words, everybody coming in with a newly diagnosed hypertension should be screened for primary aldosteronism.

[00:17:58] Um, [00:18:00] We are not yet at this point with the U. S. Guidelines, which have not come out yet. However, I think it's, uh, logical to, screen the high risk population, uh, with severe or resistant hypertension. unexplained hypokalemia, adrenal mass, sleep apnea, atrial fibrillation. In other words, the group of patients that were described earlier by Dr.

[00:18:28] Dixit. Okay. So as you're saying, you know, there are certain individuals with. Resistant hypertension or high risk populations having primary aldosterone autism leaves them more at risk for cardio-metabolic conditions that we described previously.

[00:18:45] But as a provider, how has this shifted your thinking?

[00:18:49] so,physicians, uh, should be more aware of, uh, the existence of primal doxorhinism and the possibility of screening for the disease.   

[00:18:59] I think [00:19:00] that a cultural shift that has to happen in the, uh, months, years to come is that primary endosterone is not anymore screened at the level of the specialist, endocrinologist, nephrologist, or cardiologist, but it actually should be screened at the level of primary care physician. So the specialist is able to, consider the next steps more readily than, um, otherwise.  

[00:19:26] And, uh, the, other important takeaway is that, We as physicians should consider lowering the threshold for initiating treatment with mineralocorticoid receptor antagonists and use more, freely mineralocorticoid receptor antagonists in patients with hypertension and suppressed renin.

[00:19:49] Consider that this class of drug should be viewed as a frontline agent in patients screening positive for primary aldosteronism in contrast to the current [00:20:00] practices that recommend, mineralocorticoid receptor antagonist as fourth lining of treatment. And then another important, um, message is that, there are criteria to establish if a patient receiving mineralocorticoid receptor antagonism is actually responding to the treatment.

[00:20:21] So, in physiology. When you are blocking the mineralocorticoid receptor, the response should be an increase in plasmarinian activity. And so what we do, we monitor over time the response of the plasmarinian activity to treatment with mineralocorticoid receptor antagonist. And if the, plasmarinian activity desaturates and increases to one and above.

[00:20:49] This indicates that the patient is receiving an adequate dose of the medication and that mineralocorticoid receptor activation is [00:21:00] effectively blocked.  

[00:21:01] Oh, this is wonderful. That's really great insight. Dr. Dixon, did you have Any final thoughts to add?   

[00:21:09] The only thing I'd add is,

[00:21:10] . is endocrinologists, Marco and I were taught that, um, uh, uh, patients either had Primary aldosteronism or they did not. What we know now, since the 2010s, research done in the 2010s, is that this is more of a spectrum, and that patients can have slightly elevated levels of aldosterone in the bloodstream, still affecting blood pressure, still affecting all those other conditions that I discussed earlier.

[00:21:37] Uh, so this is a sea change and how to think about. Primary aldosteronism as well.

[00:21:43] Additionally primary care physicians, any physician that treats adults, cardiologists, nephrologists, endocrinologists, we all see patients with blood pressure that is not adequately controlled.

[00:21:54] What I like about this approach to primary aldosteronism is it helps solve a [00:22:00] problem. Getting these patients to better blood pressures is something that's eluded providers for decades. So if this helps increase the rate at which patients get adequate care for their high blood pressure and associated conditions, uh, I'm all for it.

[00:22:17] Absolutely. That's so powerful. What a fruitful discussion. Uh, Thank you so much,

[00:22:22] Dr. Dixit and Dr. Marcelli for joining me today.  

[00:22:26] Thank you for having me. Thank you very much. It was great to be here. 

[00:22:32] That's a wrap on this episode of Healthier World with Quest Diagnostics. Please follow us on your favorite podcast app, and be sure to check out Quest Diagnostics Clinical Education Center for more resources, including educational webinars and research publications. Thank you for joining us today as we work to create a healthier world, one life at a time.