Primary aldosteronism

People often have few or no symptoms. They may get occasional muscular weakness, muscle spasms, tingling sensations, or excessive urination.High blood pressure, manifestations of muscle cramps (due to hyperexcitability of neurons secondary to low blood calcium), muscle weakness (due to hypoexcitability of skeletal muscles secondary to hypokalemia), and headaches (due to low blood potassium or high blood pressure) may be seen.{{citation needed|date=August 2020}}

Secondary hyperaldosteronism is often related to decreased cardiac output, which is associated with elevated renin levels.{{Cite web |title=Hyperaldosteronism |url=https://www.lecturio.com/concepts/hyperaldosteronism/ |access-date=25 July 2021 |website=The Lecturio Medical Concept Library}}

File:Adrenal gland Conn syndrome4.jpg

The condition is due to:{{Cite book |title=Williams textbook of endocrinology. |vauthors=Kronenberg HM |publisher=Saunders/Elsevier |year=2008 |isbn=978-1-4160-2911-3 |edition=11th |location=Philadelphia}}

• Bilateral idiopathic (micronodular) adrenal hyperplasia: 66% of cases
• Adrenal adenoma (Conn's disease): 33% of cases
• Primary (unilateral) adrenal hyperplasia: 2% of cases
• Aldosterone-producing adrenocortical carcinoma: <1% of cases
• Familial Hyperaldosteronism (FH)
• Glucocorticoid-remediable aldosteronism (FH type I): <1% of cases
• FH type II (APA or IHA): <2% of cases
• Ectopic aldosterone-producing adenoma or carcinoma: < 0.1% of cases

40% of people with an adrenal aldosterone producing adenoma have somatic gain-of-function mutations in a single gene (KCNJ5).{{Cite journal |vauthors=Brown MJ |date=September 2012 |title=Platt versus Pickering: what molecular insight to primary hyperaldosteronism tells us about hypertension |journal=JRSM Cardiovascular Disease |volume=1 |issue=6 |pages=1–8 |doi=10.1258/cvd.2012.012020 |pmc=3738367 |pmid=24175075}} This gene is mutated in inherited cases of early onset primary aldosteronism and bilateral adrenal hyperplasia, albeit less frequently.{{Cite journal |display-authors=6 |vauthors=Choi M, Scholl UI, Yue P, Björklund P, Zhao B, Nelson-Williams C, Ji W, Cho Y, Patel A, Men CJ, Lolis E, Wisgerhof MV, Geller DS, Mane S, Hellman P, Westin G, Åkerström G, Wang W, Carling T, Lifton RP |date=February 2011 |title=K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension |journal=Science |volume=331 |issue=6018 |pages=768–772 |bibcode=2011Sci...331..768C |doi=10.1126/science.1198785 |pmc=3371087 |pmid=21311022}} These mutations tend to occur in young women with the adenoma in the cortisol secreting zona fasciculata. Adenomas without this mutation tend to occur in older men with resistant hypertension.{{citation needed|date=August 2020}}

Other genes commonly mutated in aldosterone producing adenomas are ATP1A1{{Cite journal |display-authors=6 |vauthors=Beuschlein F, Boulkroun S, Osswald A, Wieland T, Nielsen HN, Lichtenauer UD, Penton D, Schack VR, Amar L, Fischer E, Walther A, Tauber P, Schwarzmayr T, Diener S, Graf E, Allolio B, Samson-Couterie B, Benecke A, Quinkler M, Fallo F, Plouin PF, Mantero F, Meitinger T, Mulatero P, Jeunemaitre X, Warth R, Vilsen B, Zennaro MC, Strom TM, Reincke M |date=April 2013 |title=Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension |journal=Nature Genetics |volume=45 |issue=4 |pages=440–4, 444e1–2 |doi=10.1038/ng.2550 |pmid=23416519 |s2cid=205346722 |hdl=11577/2573243}}{{Cite journal |display-authors=6 |vauthors=Azizan EA, Poulsen H, Tuluc P, Zhou J, Clausen MV, Lieb A, Maniero C, Garg S, Bochukova EG, Zhao W, Shaikh LH, Brighton CA, Teo AE, Davenport AP, Dekkers T, Tops B, Küsters B, Ceral J, Yeo GS, Neogi SG, McFarlane I, Rosenfeld N, Marass F, Hadfield J, Margas W, Chaggar K, Solar M, Deinum J, Dolphin AC, Farooqi IS, Striessnig J, Nissen P, Brown MJ |date=September 2013 |title=Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension |journal=Nature Genetics |volume=45 |issue=9 |pages=1055–1060 |doi=10.1038/ng.2716 |pmid=23913004 |s2cid=205347424}} ATP2B3, CACNA1D, and CTNNB1.{{Cite journal |display-authors=6 |vauthors=Åkerström T, Maharjan R, Sven Willenberg H, Cupisti K, Ip J, Moser A, Stålberg P, Robinson B, Alexander Iwen K, Dralle H, Walz MK, Lehnert H, Sidhu S, Gomez-Sanchez C, Hellman P, Björklund P |date=January 2016 |title=Activating mutations in CTNNB1 in aldosterone producing adenomas |journal=Scientific Reports |volume=6 |pages=19546 |bibcode=2016NatSR...619546A |doi=10.1038/srep19546 |pmc=4728393 |pmid=26815163}}

Aldosterone has effects on most or all cells of the body but, clinically, the most important actions are in the kidney, on cells of the late distal convoluted tubule and medullary collecting duct. In the principal cells aldosterone increases activity of basolateral membrane sodium-potassium ATPase and apical epithelial sodium channels, ENaC, as well as potassium channels, ROMK. These actions increase sodium reabsorption and potassium secretion. Since more sodium is reabsorbed than potassium secreted, it also makes the lumen more electrically negative, causing chloride to follow sodium. Water then follows sodium and chloride by osmosis. In Conn syndrome, these actions cause increased extracellular sodium and fluid volume and reduced extracellular potassium. Aldosterone also acts on intercalated cells to stimulate an apical proton ATPase, causing proton secretion that acidifies urine and alkalizes extracellular fluid.{{citation needed|date=August 2020}}

In summary, hyperaldosteronism causes hypernatremia, hypokalemia, and metabolic alkalosis.

Finer notes on aldosterone include the fact that it stimulates sodium-potassium ATPase in muscle cells, increasing intracellular potassium and also increases sodium reabsorption all along the intestine and nephron, possibly due to widespread stimulation of sodium-potassium ATPase. Finally, epithelial cells of sweat gland ducts and distal colon surface respond exactly the same as the principal cells of the nephron. These responses are important in climate adaptation and as a cause of constipation with elevated aldosterone{{citation needed|date=August 2020}}.

The sodium retention leads to plasma volume expansion and elevated blood pressure. The increased blood pressure will lead to increased glomerular filtration rate and cause a decrease in renin released from the granular cells of the juxtaglomerular apparatus in the kidney decreasing sodium reabsorption and returning sodium renal excretion to near normal levels allowing sodium to 'escape' the effect of mineralocorticoids (also known as aldosterone escape mechanism in primary hyperaldosteronism also contributed to by increased ANP level). If there is primary hyperaldosteronism, the decreased renin (and subsequent decreased angiotensin II) will not lead to a decrease in aldosterone levels (a very helpful clinical tool in diagnosis of primary hyperaldosteronism).

Screening may be considered in people with high blood pressure presenting with low blood potassium, high blood pressure that is difficult to treat, other family members with the same condition, or a mass on the adrenal gland.

Measuring aldosterone alone is not considered adequate to diagnose primary hyperaldosteronism. Rather, both renin and aldosterone are measured, and a resultant aldosterone-to-renin ratio (ARR) is used for case detection.{{Cite journal |vauthors=Tiu SC, Choi CH, Shek CC, Ng YW, Chan FK, Ng CM, Kong AP |date=January 2005 |title=The use of aldosterone-renin ratio as a diagnostic test for primary hyperaldosteronism and its test characteristics under different conditions of blood sampling |journal=The Journal of Clinical Endocrinology and Metabolism |volume=90 |issue=1 |pages=72–78 |doi=10.1210/jc.2004-1149 |pmid=15483077 |doi-access=free}}{{Cite web |title=Renin/Aldosterone Protocol |url=http://www.ubht.nhs.uk/pathology/ChemicalPathology/TestProtocols/16Renin.html |archive-url=https://archive.today/20070813115254/http://www.ubht.nhs.uk/pathology/ChemicalPathology/TestProtocols/16Renin.html |archive-date=2007-08-13 |website=United Bristol Healthcare NHS Trust}} A high aldosterone-to-renin ratio suggests the presence of primary hyperaldosteronism. The diagnosis is made by performing a saline suppression test, ambulatory salt loading test, or fludrocortisone suppression test.{{Cite journal |display-authors=6 |vauthors=Funder JW, Carey RM, Fardella C, Gomez-Sanchez CE, Mantero F, Stowasser M, Young WF, Montori VM |date=September 2008 |title=Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline |journal=The Journal of Clinical Endocrinology and Metabolism |volume=93 |issue=9 |pages=3266–3281 |doi=10.1210/jc.2008-0104 |pmid=18552288 |doi-access=free}}

Measuring sodium and potassium concentrations simultaneously in serum and urine specimens has been suggested for screening purposes. Calculating the serum sodium over urinary sodium to serum potassium over urinary potassium (SUSPUP) and the (serum sodium to urinary sodium to (serum potassium)² (SUSPPUP) ratios delivers calculated structure parameters of the RAAS, which may be used as a static function test.{{Cite journal |vauthors=Willenberg HS, Kolentini C, Quinkler M, Cupisti K, Krausch M, Schott M, Scherbaum WA |date=January 2009 |title=The serum sodium to urinary sodium to (serum potassium)2 to urinary potassium (SUSPPUP) ratio in patients with primary aldosteronism |journal=European Journal of Clinical Investigation |volume=39 |issue=1 |pages=43–50 |doi=10.1111/j.1365-2362.2008.02060.x |pmid=19067735 |s2cid=25616329 |doi-access=free}}{{Cite journal |vauthors=Yin GS, Zhang SL, Yan L, Li F, Qi YQ, Chen ZC, Cheng H |date=April 2010 |title=[New index of using serum sodium and potassium and urine sodium and potassium jointly in screening primary aldosteronism in hypertensive patients] |journal=Zhonghua Yi Xue Za Zhi |volume=90 |issue=14 |pages=962–966 |pmid=20646645}} Its results have to be confirmed by calculating the ARR.{{citation needed|date=October 2021}}

If primary hyperaldosteronism is confirmed biochemically, CT scanning or other cross-sectional imaging can confirm the presence of an adrenal abnormality, possibly an adrenal cortical adenoma (aldosteronoma), adrenal carcinoma, bilateral adrenal hyperplasia, or other less common changes. Imaging findings may ultimately lead to other necessary diagnostic studies, such as adrenal venous sampling, to clarify the cause. It is not uncommon for adults to have bilateral sources of aldosterone hypersecretion in the presence of a nonfunctioning adrenal cortical adenoma, making adrenal venous sampling (AVS) mandatory in cases where surgery is being considered. For cases where AVS is unable to provide lateralisation of the source/sources of aldosterone hypersecretion, radionuclide imaging such as NP-59 scintigraphy,{{Cite journal |last=Fischer |first=Matan |last2=Rosenbach |first2=Eyal Alan |last3=Glaser |first3=Benjamin |last4=Stokar |first4=Joshua |date=2023-02-24 |title=131I-Iodo-cholesterol scintigraphy for primary aldosteronism lateralization in a patient with polycystic kidney disease |url=https://www.aaceclinicalcasereports.com/article/S2376-0605(23)00010-X/fulltext |journal=AACE Clinical Case Reports |language=English |volume=9 |issue=3 |pages=97–98 |doi=10.1016/j.aace.2023.02.006 |issn=2376-0605 |pmc=10213608 |pmid=37251975 |s2cid=257212197}} or PET/CT with ¹¹C-Metomidate is an option. Since ¹¹C-Metomidate is unspecific for CYP11B1/CYP11B2 the patient needs pre-treatment with dexamethasone to downregulate the expression of CYP11B1.{{Cite journal |vauthors=Chen Cardenas SM, Santhanam P |date=December 2020 |title=¹¹C-metomidate PET in the diagnosis of adrenal masses and primary aldosteronism: a review of the literature |journal=Endocrine |volume=70 |issue=3 |pages=479–487 |doi=10.1007/s12020-020-02474-3 |pmid=32886316 |s2cid=221479027}}{{Cite journal |display-authors=6 |vauthors=O'Shea PM, O'Donoghue D, Bashari W, Senanayake R, Joyce MB, Powlson AS, Browne D, O'Sullivan GJ, Cheow H, Mendichovszky I, Quill D, Lowery A, Lappin D, Gurnell M, Dennedy MC |date=May 2019 |title=¹¹ C-Metomidate PET/CT is a useful adjunct for lateralization of primary aldosteronism in routine clinical practice |url=https://www.repository.cam.ac.uk/handle/1810/291185 |journal=Clinical Endocrinology |volume=90 |issue=5 |pages=670–679 |doi=10.1111/cen.13942 |pmid=30721535 |s2cid=73450281}}{{Cite journal |vauthors=Zhou Y, Wang D, Jiang L, Ran F, Chen S, Zhou P, Wang P |date=December 2020 |title=Diagnostic accuracy of adrenal imaging for subtype diagnosis in primary aldosteronism: systematic review and meta-analysis |journal=BMJ Open |volume=10 |issue=12 |pages=e038489 |doi=10.1136/bmjopen-2020-038489 |pmc=7780716 |pmid=33384386}}

The diagnosis is best accomplished by an appropriately-trained subspecialist, though primary care providers are critical in recognizing clinical features of primary aldosteronism and obtaining the first blood tests for case detection.{{citation needed|date=August 2020}}

Some people only use Conn's syndrome for when it occurs due to an adrenal adenoma (a type of benign tumor).{{Cite book |title=Robbins and Cotran pathologic basis of disease |vauthors=Cotran RS, Kumar V, Fausto N, Abbas A, Robbins SL |publisher=Elsevier Saunders |year=2005 |isbn=978-0-7216-0187-8 |location=St. Louis, Mo |page=1210}} In practice, however, the terms are often used interchangeably, regardless of the underlying physiology.

Other causes of treatment-resistant hypertension include renal artery stenosis, secondary hyperaldosteronism, pheochromocytoma, deoxycorticosterone- or renin-secreting tumors, and kidney ischemia. Excess consumption of licorice can inhibit 11β-hydroxysteroid dehydrogenase and cause similar symptoms as PA. Chrétien syndrome, Gitelman syndrome, and Liddle syndrome can cause secondary aldosteronism or pseudohyperaldosteronism.

The treatment for hyperaldosteronism depends on the underlying cause. In people with a single benign tumor (adenoma), surgical removal (adrenalectomy) may be curative. This is usually performed laparoscopically, through several very small incisions. For people with hyperplasia of both glands, successful treatment is often achieved with spironolactone or eplerenone, drugs that block the aldosterone receptor. With its antiandrogen effect, spironolactone drug therapy may have a range of side effects in males and females, including gynecomastia and irregular menses. These symptoms occur less frequently with eplerenone drug therapy.{{Cite web |title=Inspra (eplerenone) [prescribing information] |url=http://labeling.pfizer.com/ShowLabeling.aspx?id=599 |url-status=live |archive-url=https://web.archive.org/web/20110808054425/http://labeling.pfizer.com/ShowLabeling.aspx?id=599 |archive-date=2011-08-08 |access-date=2011-07-17}}

In the absence of treatment, individuals with hyperaldosteronism often have poorly controlled high blood pressure, which may be associated with increased rates of stroke, heart disease, and kidney failure. With appropriate treatment, the prognosis is considered good.{{Cite web |title=Hyperaldosteronism (Conn's Syndrome) |url=http://www.cumc.columbia.edu/dept/cs/pat/adrenal/hyperaldosteronism.html |archive-url=https://web.archive.org/web/20110526183416/http://www.cumc.columbia.edu/dept/cs/pat/adrenal/hyperaldosteronism.html |archive-date=2011-05-26 |website=Columbia Adrenal Center}}

Esaxerenone, the first non-steroidal mineralocorticoid blocker, was approved in 2019 in Japan to treat essential hypertension. Finerenone, a drug belonging to the same class, reached phase 3 clinical trial in 2020, but is not yet considered for hypertension. More importantly, next-generation Aldosterone Synthase Inhibitors have entered the research pipeline with CIN-107 undergoing Phase 2 clinical trial as of 2021{{Cite web |title=Spark-PA – Spark-PA is a clinical research study exploring an investigational study drug that may help people with primary aldosteronism (PA) lower their blood pressure. |url=https://spark-pa.com/ |url-status=dead |archive-url=https://web.archive.org/web/20210802021422/https://spark-pa.com/ |archive-date=2021-08-02 |access-date=2021-03-05 |language=en-US}}

In the past, the prevalence of primary aldosteronism was considered to be less than 1% of patients with hypertension. More recent studies have reported much higher prevalence of primary aldosteronism, up-to 12.7% in primary care and to 29.8% in referral centers.{{Cite journal |display-authors=6 |vauthors=Käyser SC, Dekkers T, Groenewoud HJ, van der Wilt GJ, Carel Bakx J, van der Wel MC, Hermus AR, Lenders JW, Deinum J |date=July 2016 |title=Study Heterogeneity and Estimation of Prevalence of Primary Aldosteronism: A Systematic Review and Meta-Regression Analysis |journal=The Journal of Clinical Endocrinology and Metabolism |volume=101 |issue=7 |pages=2826–2835 |doi=10.1210/jc.2016-1472 |pmid=27172433 |s2cid=13922901 |doi-access=free}} Very low rates of compliance with screening guidelines lead to the underdiagnoses of primary aldosteronism.{{Cite journal |display-authors=6 |vauthors=Hundemer GL, Imsirovic H, Vaidya A, Yozamp N, Goupil R, Madore F, Agharazii M, Knoll G, Sood MM |date=January 2022 |title=Screening Rates for Primary Aldosteronism Among Individuals With Hypertension Plus Hypokalemia: A Population-Based Retrospective Cohort Study |journal=Hypertension |volume=79 |issue=1 |pages=178–186 |doi=10.1161/HYPERTENSIONAHA.121.18118 |pmc=8664996 |pmid=34657442}}{{Cite journal |vauthors=Brown JM, Siddiqui M, Calhoun DA, Carey RM, Hopkins PN, Williams GH, Vaidya A |date=July 2020 |title=The Unrecognized Prevalence of Primary Aldosteronism: A Cross-sectional Study |journal=Annals of Internal Medicine |volume=173 |issue=1 |pages=10–20 |doi=10.7326/M20-0065 |pmc=7459427 |pmid=32449886}}

The Primary Aldosteronism Foundation{{Cite web |title=Welcome to the Primary Aldosteronism Foundation |url=https://www.primaryaldosteronism.org/ |access-date=2021-03-05 |language=en-US}} is a patient-driven initiative committed to creating the paradigm shift that will lead to optimum diagnosis and treatment of primary aldosteronism by raising awareness, fostering research, and providing support to patients and healthcare professionals worldwide.{{citation needed|date=October 2021}}

Conn's syndrome is named after Jerome W. Conn (1907–1994), the American endocrinologist who first described the condition at the University of Michigan in 1955.

{{Reflist}}

• {{Cite journal |display-authors=6 |vauthors=Funder JW, Carey RM, Mantero F, Murad MH, Reincke M, Shibata H, Stowasser M, Young WF |date=May 2016 |title=The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline |journal=The Journal of Clinical Endocrinology and Metabolism |volume=101 |issue=5 |pages=1889–1916 |doi=10.1210/jc.2015-4061 |pmid=26934393 |doi-access=free}}

{{Medical resources

| DiseasesDB = 3073

| ICD10 = {{ICD10|E|26|0|e|20}}

| ICD9 = {{ICD9|255.1}}

| ICDO =

| OMIM =

| MedlinePlus = 000330

| eMedicineSubj = med

| eMedicineTopic = 432

| MeshID = D006929

}}

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