Hyperaldosteronism occurs due to the excess production of aldosterone from the adrenal gland. Hyperaldosteronism can initially present as essential and refractory hypertension and can often go undiagnosed. This disorder can be of primary or secondary origin, both presenting similarly but differentiated by a set of lab values and diagnostic studies. Treatment is specific to the individual causes of hyperaldosteronism.
Its primary or secondary origin can differentiate hyperaldosteronism.
Primary hyperaldosteronism is due to the excess production of the adrenal gland, more specifically the zona glomerulosa. This can present more commonly as a primary tumor in the gland known as Conn syndrome or bilateral hyperplasia. Rarer forms are unilateral adrenal hyperplasia, ectopic aldosterone-secreting tumors, aldosterone-producing adrenocortical carcinomas, and familial hyperaldosteronism type 1.
Secondary hyperaldosteronism occurs due to excess activation of the renin-angiotensin-aldosterone system (RAAS). This activation can take the form of a renin-producing tumor, renal artery stenosis, or edematous disorders like left ventricular heart failure, cor pulmonale, or cirrhosis with ascites.
Primary hyperaldosteronism is the culprit of less than 1% of hypertensive patients. Although a higher prevalence has been considered, studies have shown an overestimation of cases. Secondary hyperaldosteronism is diagnosed even less often than primary. Both present more frequently in women.
Primary hyperaldosteronism occurs due to the excess production of the adrenal gland. The most common cause in two-thirds of the patients occurs due to idiopathic bilateral adrenal hyperplasia. In one-third of patients, a tumor in the zona glomerulosa, known as Conn syndrome, can directly cause an increase in aldosterone. The clinical picture of these patients can range from asymptomatic to hypertension with hypokalemia.
Secondary hyperaldosteronism occurs due to the excess stimulation of the RAAS. Renal artery stenosis (either in the form of atherosclerosis or fibromuscular dysplasia) causes decreased blood flow through the kidneys, stimulating a false sense of hypovolemia and activating aldosterone secretion. In left-sided heart failure and cor pulmonale, a decrease in cardiac output causes aldosterone stimulation. Cirrhosis with ascites patients will produce decreased circulating fluid volume, resulting in less perfusion through the kidneys and causing an increase in aldosterone. Less common is a renin-producing tumor in the juxtaglomerular cells. Like primary, secondary hyperaldosteronism can present with a wide clinical range.
While histopathology is not a common diagnostic tool for hyperaldosteronism, studies have found a correlation between the immunohistochemical staining of CYP-11B2 in aldosterone-producing adenomas. This is primarily used to differentiate the variable types of adenomas such as unilateral micronodules, subtype classifications of adrenal adenomas, multiple aldosterone-producing cell clusters, and aldosterone-producing adenomas.
Patients often can present asymptomatically, but this varies with the severity of hyperaldosteronism. First-occurrence and resistant hypertension are the most common presenting symptoms for these patients, and the sequelae of fatigue, headache, polyuria, and polydipsia commonly occur with it. Metabolic alkalosis is frequently observed in these patients as they are susceptible to the same mechanism that occurs in contraction alkalosis.
Concurrently, hypokalemia historically has been found in a majority of cases, but recent studies have shown a less than 40% correlation. Mild hypernatremia and hypomagnesemia also are found in these patients.
More rarely, muscle weakness and spasms occur due to the hypokalemia of the disorder. Numbness and paroxysmal paralysis also have been reported.
Laboratory findings are typically consistent with hypokalemia, mild hypernatremia, and mild hypomagnesemia.
Plasma renin concentration (PRC) and plasma renin activity (PRA) are initial laboratory measurements ordered when hyperaldosteronism is suspected. In primary hyperaldosteronism, the PRC and PRA will be decreased (less than 1 ng/mL/hour and undetectable, respectively) as the increased aldosterone originates from the zona glomerulosa itself and not an extrinsic pathway. In secondary hyperaldosteronism, the PRC and PRA will be increased, as renin is the mediator for its hyperaldosteronism effect. These levels are measured in the morning after patients have been out of bed for more than two hours and sitting for at least 5 minutes.
Plasma aldosterone concentration (PAC) to PRA ratio is used to confirm a suspicion of primary hyperaldosteronism. Specific criteria vary from institution to institution, but studies support an elevated PAC/PRA (greater than 30) and PAC (greater than 20 ng/dL) levels with a sensitivity and specificity of 90%. However, a PAC/PRA ratio of greater than 20 and PAC greater than 15 ng/dL have been reported to be sufficient. In secondary hyperaldosteronism, both PRA and PRC are increased, but the PAC/PRA is less than 10.
Twenty-four-hour urine collection is controversial in hyperaldosteronism, but it is used to detect inappropriate potassium wasting (greater than 30 mEq/day). This is primarily used to rule out extrarenal losses and diuretic abuse for explanations of hypokalemia with insignificant to mild aldosterone increases.
Aldosterone suppression testing is typically necessary for confirmation and is achieved with sodium loading and consequent aldosterone measurement. This can be performed with oral sodium loading over 3 days (5000 mg total in diet or 90 mEq of sodium as a tablet) and a urine aldosterone excretion measurement of greater than 12 mcg/day to confirm hyperaldosteronism. Another method is a two-liter intravenous isotonic saline infusion over 4 hours. With the saline infusion, PAC levels greater than 10 ng/dL are consistent with hyperaldosteronism; however, saline infusion has a false negative rate of 30%.
Radiological imaging such as CT scan can be used to differentiate adenomas from bilateral hyperplasia, but studies have found that CT cannot differentiate the two reliably.
Adrenal vein sampling is used to differentiate unilateral from bilateral pathology if a CT scan is not diagnostic. An incongruence in levels (usually a four-fold increase on the side of the adenoma) indicates unilateral origin, whereas equivalent levels indicate bilateral origin.
Surgery is the treatment of choice in primary hyperaldosteronism cases where a unilateral lesion is the source of disease. A laparoscopic adrenalectomy is preferred over open adrenalectomy due to fewer complications and a shorter hospital stay. Complete adrenalectomy is preferred over partial adrenalectomy due to greater efficacy and resolution of symptoms. For nonsurgical candidates, mineralocorticoid receptor antagonists (MRA) were preferred as a medical therapy.
For bilateral hyperplasia in primary hyperaldosteronism, MRAs are the treatment of choice. Either spironolactone or eplerenone is used, depending on the adverse effect profile exhibited in the patient. A combination of medical therapy, sodium restriction (less than 100 mEq/day), alcohol avoidance, smoking cessation, aerobic exercise, and maintenance of ideal body weight were shown to produce the best results. According to the 2016 Endocrine Society Guidelines, the spironolactone starting dose is 12.5 to 25 mg daily and titrated upward every 2 weeks. Eplerenone is started at 50 mg daily and titrated upward. The clinical course ultimately dictates increase and frequency in dosage.
For secondary hyperaldosteronism, the treatment of the underlying disease will lead to resolution of the symptoms. Salt restriction also is recommended for better efficiency.
Similar presentations have been observed in essential hypertension, Liddle syndrome, syndrome of apparent mineralocorticoid excess, congenital adrenal hyperplasia, primary glucocorticoid resistance, and ectopic adrenocorticotropic hormone (ACTH) syndrome.
Essential hypertension presents with a normal PAC/PRA ratio. Liddle syndrome will have low aldosterone levels and will normally present in childhood. Syndrome of apparent mineralocorticoid excess will present with low aldosterone levels, high urinary free cortisol levels, hereditary implications, and/or a history of excessive licorice consumption. Congenital adrenal hyperplasia will have a family history of 11-beta-hydroxylase or 17-alpha-hydroxylase deficiency and low aldosterone levels. Primary glucocorticoid resistance will have low aldosterone levels, an elevated ACTH and cortisol, and a family history of this syndrome. Ectopic ACTH syndrome will have elevated ACTH that cannot be suppressed with high-dose dexamethasone, and these patients will have an underlying tumor.
Few studies have been performed on the mortality rates of either form of hyperaldosteronism, but 10-year-survival rates have been reported between 90% to 95% in patients who are treated. The most common morbidity associated with this disorder is cardiovascular. Cardiovascular mortality is increased in these patients, but all-cause mortality is not significantly different.
The most common complication and comorbidity associated with these patients is the increased risk of cardiovascular mortality. This is associated with excessive aldosterone secretion and can present as atrial fibrillation, left ventricular hypertrophy, myocardial infarction, and stroke.
Salt restriction (less than 100 mEq/day), alcohol cessation, smoking cessation, maintenance of ideal body weight, and aerobic exercise are all beneficial in the postoperative and posttreatment care.
Endocrinologists and nutritionists can better manage these patients long-term. Surgery is indicated for a subset of this disorder.
|Prevalence of primary hyperaldosteronism in resistant hypertension: a retrospective observational study., Douma S,Petidis K,Doumas M,Papaefthimiou P,Triantafyllou A,Kartali N,Papadopoulos N,Vogiatzis K,Zamboulis C,, Lancet (London, England), 2008 Jun 7 [PubMed PMID: 18539224]|
|Histopathological diagnosis of primary aldosteronism using CYP11B2 immunohistochemistry., Nanba K,Tsuiki M,Sawai K,Mukai K,Nishimoto K,Usui T,Tagami T,Okuno H,Yamamoto T,Shimatsu A,Katabami T,Okumura A,Kawa G,Tanabe A,Naruse M,, The Journal of clinical endocrinology and metabolism, 2013 Apr [PubMed PMID: 23443813]|
|Laboratory investigation of primary aldosteronism., Stowasser M,Taylor PJ,Pimenta E,Ahmed AH,Gordon RD,, The Clinical biochemist. Reviews, 2010 May [PubMed PMID: 20498828]|
|Laparoscopic adrenalectomy is superior to an open approach to treat primary hyperaldosteronism., Duncan JL 3rd,Fuhrman GM,Bolton JS,Bowen JD,Richardson WS,, The American surgeon, 2000 Oct [PubMed PMID: 11261619]|
|Differential diagnosis in primary aldosteronism., Opocher G,Rocco S,Carpenè G,Mantero F,, The Journal of steroid biochemistry and molecular biology, 1993 Apr [PubMed PMID: 8481351]|
|Observational study mortality in treated primary aldosteronism: the German Conn's registry., Reincke M,Fischer E,Gerum S,Merkle K,Schulz S,Pallauf A,Quinkler M,Hanslik G,Lang K,Hahner S,Allolio B,Meisinger C,Holle R,Beuschlein F,Bidlingmaier M,Endres S,, Hypertension (Dallas, Tex. : 1979), 2012 Sep [PubMed PMID: 22824982]|
|Distinction between hyperaldosteronism due to bilateral hyperplasia and unilateral aldosteronoma: reliability of CT., Doppman JL,Gill JR Jr,Miller DL,Chang R,Gupta R,Friedman TC,Choyke PL,Feuerstein IM,Dwyer AJ,Jicha DL,, Radiology, 1992 Sep [PubMed PMID: 1509049]|
|Resistant Hypertension in Adults With Type 1 or 2 Diabetes: A Structured Diagnostic Approach., McFarlane PA,, Canadian journal of diabetes, 2018 Apr [PubMed PMID: 29602405]|
|Update in adrenal venous sampling for primary aldosteronism., Rossi GP,, Current opinion in endocrinology, diabetes, and obesity, 2018 Mar 7 [PubMed PMID: 29521660]|
|Anomalous adrenal vein anatomy complicating the evaluation of primary hyperaldosteronism., Ford KM,Smolinski S,Perez Lozada JC,, Radiology case reports, 2018 Feb [PubMed PMID: 29487649]|