Primary aldosteronism

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Primary aldosteronism
Other namesPrimary hyperaldosteronism, Conn's syndrome
Aldosterone-2D-skeletal.svg
Aldosterone
Specialty Endocrinology
Symptoms High blood pressure, poor vision, headaches, muscular weakness, muscle spasms [1] [2]
Complications Stroke, myocardial infarction, kidney failure, abnormal heart rhythms [3] [4]
Usual onset30 to 50 years old [5]
Causes Enlargement of both adrenal glands, adrenal adenoma, adrenal cancer, familial hyperaldosteronism [6] [1]
Diagnostic method Blood test for aldosterone-to-renin ratio [1]
TreatmentSurgery, spironolactone, eplerenone, low salt diet [1]
Frequency10% of people with high blood pressure [1]

Primary aldosteronism (PA), also known as primary hyperaldosteronism, refers to the excess production of the hormone aldosterone from the adrenal glands, resulting in low renin levels and high blood pressure. [1] This abnormality is caused by hyperplasia or tumors. About 35% of the cases are caused by a single aldosterone-secreting adenoma, a condition known as Conn's syndrome. [7] [8]

Contents

Many patients experience fatigue, potassium deficiency and high blood pressure which may cause poor vision, confusion or headaches. [1] [2] Symptoms may also include: muscular aches and weakness, muscle spasms, low back and flank pain from the kidneys, trembling, tingling sensations, dizziness/vertigo, nocturia and excessive urination. [1] Complications include cardiovascular disease such as stroke, myocardial infarction, kidney failure and abnormal heart rhythms. [3] [4]

Primary hyperaldosteronism has a number of causes. About 33% of cases are due to an adrenal adenoma that produces aldosterone, and 66% of cases are due to an enlargement of both adrenal glands. [1] Other uncommon causes include adrenal cancer and an inherited disorder called familial hyperaldosteronism. [6] PA is under diagnosed; the Endocrine Society recommends screening people with high blood pressure who are at increased risk, [9] while others recommend screening all people with high blood pressure for the disease. [3] Screening is usually done by measuring the aldosterone-to-renin ratio in the blood (ARR) whilst off interfering medications and a serum potassium over 4, with further testing used to confirm positive results. [1] While low blood potassium is classically described in primary hyperaldosteronism, this is only present in about a quarter of people. [1] To determine the underlying cause, medical imaging is carried out. [1]

Some cases may be cured by removing the adenoma by surgery after localization with adrenal venous sampling (AVS). [1] [10] A single adrenal gland may also be removed in cases where only one is enlarged. [4] In cases due to enlargement of both glands, treatment is typically with medications known as aldosterone antagonists such as spironolactone or eplerenone. [1] Other medications for high blood pressure and a low salt diet, e.g. DASH diet, may also be needed. [1] [4] Some people with familial hyperaldosteronism may be treated with the steroid dexamethasone. [1]

Primary aldosteronism is present in about 10% of people with high blood pressure. [1] It occurs more often in women than men. [5] Often, it begins in those between 30 and 50 years of age. [5] Conn's syndrome is named after Jerome W. Conn (1907–1994), an American endocrinologist who first described adenomas as a cause of the condition in 1955. [11] [12]

Signs and symptoms

People often have few or no symptoms. [1] They may get occasional muscular weakness, muscle spasms, tingling sensations, or excessive urination. [1] 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 ]

Secondary hyperaldosteronism is often related to decreased cardiac output, which is associated with elevated renin levels. [13]

Causes

Two slices of an adrenal gland with a cortical adenoma, from a person with Conn's syndrome Adrenal gland Conn syndrome4.jpg
Two slices of an adrenal gland with a cortical adenoma, from a person with Conn's syndrome

The condition is due to: [14]

Genetics

40% of people with an adrenal aldosterone producing adenoma have somatic gain-of-function mutations in a single gene (KCNJ5). [15] This gene is mutated in inherited cases of early onset primary aldosteronism and bilateral adrenal hyperplasia, albeit less frequently. [16] 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 ]

Other genes commonly mutated in aldosterone producing adenomas are ATP1A1 [17] [18] ATP2B3, [17] CACNA1D, [18] and CTNNB1. [19]

Pathophysiology

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 ]

In summary, hyperaldosteronism causes hypernatremia, hypokalemia, and metabolic alkalosis. [13]

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 ].

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). [13]

Diagnosis

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. [1]

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. [20] [21] 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. [22]

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. [23] [24] Its results have to be confirmed by calculating the ARR.[ citation needed ]

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. [22] [10] For cases where AVS is unable to provide lateralisation of the source/sources of aldosterone hypersecretion, radionuclide imaging such as NP-59 scintigraphy, [25] 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. [26] [27] [28]

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 ]

Classification

Some people only use Conn's syndrome for when it occurs due to an adrenal adenoma (a type of benign tumor). [29] In practice, however, the terms are often used interchangeably, regardless of the underlying physiology. [1]

Differential diagnosis

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. [9]

Treatment

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. [30]

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. [31]

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 [32]

Epidemiology

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. [33] Very low rates of compliance with screening guidelines lead to the underdiagnoses of primary aldosteronism. [34] [35]

Society and culture

The Primary Aldosteronism Foundation [36] 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 ]

Eponym

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. [11]

Related Research Articles

<span class="mw-page-title-main">Adrenal gland</span> Endocrine gland

The adrenal glands are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer cortex which produces steroid hormones and an inner medulla. The adrenal cortex itself is divided into three main zones: the zona glomerulosa, the zona fasciculata and the zona reticularis.

<span class="mw-page-title-main">Aldosterone</span> Mineralocorticoid steroid hormone

Aldosterone is the main mineralocorticoid steroid hormone produced by the zona glomerulosa of the adrenal cortex in the adrenal gland. It is essential for sodium conservation in the kidney, salivary glands, sweat glands, and colon. It plays a central role in the homeostatic regulation of blood pressure, plasma sodium (Na+), and potassium (K+) levels. It does so primarily by acting on the mineralocorticoid receptors in the distal tubules and collecting ducts of the nephron. It influences the reabsorption of sodium and excretion of potassium (from and into the tubular fluids, respectively) of the kidney, thereby indirectly influencing water retention or loss, blood pressure, and blood volume. When dysregulated, aldosterone is pathogenic and contributes to the development and progression of cardiovascular and kidney disease. Aldosterone has exactly the opposite function of the atrial natriuretic hormone secreted by the heart.

<span class="mw-page-title-main">Mineralocorticoid</span> Group of corticosteroids

Mineralocorticoids are a class of corticosteroids, which in turn are a class of steroid hormones. Mineralocorticoids are produced in the adrenal cortex and influence salt and water balances. The primary mineralocorticoid is aldosterone.

<span class="mw-page-title-main">Adrenal insufficiency</span> Medical condition

Adrenal insufficiency is a condition in which the adrenal glands do not produce adequate amounts of steroid hormones. The adrenal glands—also referred to as the adrenal cortex—normally secrete glucocorticoids, mineralocorticoids, and androgens. These hormones are important in regulating blood pressure, electrolytes, and metabolism as a whole. Deficiency of these hormones leads to symptoms ranging from abdominal pain, vomiting, muscle weakness and fatigue, low blood pressure, depression, mood and personality changes to organ failure and shock. Adrenal crisis may occur if a person having adrenal insufficiency experiences stresses, such as an accident, injury, surgery, or severe infection; this is a life-threatening medical condition resulting from severe deficiency of cortisol in the body. Death may quickly follow.

Congenital adrenal hyperplasia due to 17α-hydroxylase deficiency is an uncommon form of congenital adrenal hyperplasia (CAH) resulting from a mutation in the gene CYP17A1, which produces the enzyme 17α-hydroxylase. It causes decreased synthesis of cortisol and sex hormones, with resulting increase in mineralocorticoid production. Thus, common symptoms include mild cortisol deficiency, ambiguous genitalia in men or amenorrhea at puberty in women, and hypokalemic hypertension. However, partial (incomplete) deficiency often has inconsistent symptoms between patients, and affected women may be asymptomatic except for infertility.

<span class="mw-page-title-main">Adrenocortical carcinoma</span> Medical condition

Adrenocortical carcinoma (ACC) is an aggressive cancer originating in the cortex of the adrenal gland.

<span class="mw-page-title-main">Hypoaldosteronism</span> Medical condition

Hypoaldosteronism is an endocrinological disorder characterized by decreased levels of the hormone aldosterone. Similarly, isolated hypoaldosteronism is the condition of having lowered aldosterone without corresponding changes in cortisol.

<span class="mw-page-title-main">Zona glomerulosa</span> Part of the adrenal gland

The zona glomerulosa of the adrenal gland is the most superficial layer of the adrenal cortex, lying directly beneath the renal capsule. Its cells are ovoid and arranged in clusters or arches.

Secondary hypertension is a type of hypertension which by definition is caused by an identifiable underlying primary cause. It is much less common than the other type, called essential hypertension, affecting only 5-10% of hypertensive patients. It has many different causes including endocrine diseases, kidney diseases, and tumors. It also can be a side effect of many medications.

<span class="mw-page-title-main">Hyperaldosteronism</span> Hormonal disorder

Hyperaldosteronism is a medical condition wherein too much aldosterone is produced by the adrenal glands, which can lead to lowered levels of potassium in the blood (hypokalemia) and increased hydrogen ion excretion (alkalosis).

<span class="mw-page-title-main">Apparent mineralocorticoid excess syndrome</span> Medical condition

Apparent mineralocorticoid excess is an autosomal recessive disorder causing hypertension, hypernatremia and hypokalemia. It results from mutations in the HSD11B2 gene, which encodes the kidney isozyme of 11β-hydroxysteroid dehydrogenase type 2. In an unaffected individual, this isozyme inactivates circulating cortisol to the less active metabolite cortisone. The inactivating mutation leads to elevated local concentrations of cortisol in the aldosterone sensitive tissues like the kidney. Cortisol at high concentrations can cross-react and activate the mineralocorticoid receptor due to the non-selectivity of the receptor, leading to aldosterone-like effects in the kidney. This is what causes the hypokalemia, hypertension, and hypernatremia associated with the syndrome. Patients often present with severe hypertension and end-organ changes associated with it like left ventricular hypertrophy, retinal, renal and neurological vascular changes along with growth retardation and failure to thrive. In serum both aldosterone and renin levels are low.

<span class="mw-page-title-main">Mineralocorticoid receptor antagonist</span> Drug class

A mineralocorticoid receptor antagonist or aldosterone antagonist, is a diuretic drug which antagonizes the action of aldosterone at mineralocorticoid receptors. This group of drugs is often used as adjunctive therapy, in combination with other drugs, for the management of chronic heart failure. Spironolactone, the first member of the class, is also used in the management of hyperaldosteronism and female hirsutism. Most antimineralocorticoids, including spironolactone, are steroidal spirolactones. Finerenone is a nonsteroidal antimineralocorticoid.

<span class="mw-page-title-main">Liddle's syndrome</span> Medical condition

Liddle's syndrome, also called Liddle syndrome, is a genetic disorder inherited in an autosomal dominant manner that is characterized by early, and frequently severe, high blood pressure associated with low plasma renin activity, metabolic alkalosis, low blood potassium, and normal to low levels of aldosterone. Liddle syndrome involves abnormal kidney function, with excess reabsorption of sodium and loss of potassium from the renal tubule, and is treated with a combination of low sodium diet and potassium-sparing diuretics. It is extremely rare, with fewer than 30 pedigrees or isolated cases having been reported worldwide as of 2008.

Pseudohyperaldosteronism is a medical condition which mimics the effects of elevated aldosterone (hyperaldosteronism) by presenting with high blood pressure (hypertension), low blood potassium levels (hypokalemia), metabolic alkalosis, and low levels of plasma renin activity (PRA). However, unlike hyperaldosteronism, this conditions exhibits low or normal levels of aldosterone in the blood. Causes include genetic disorders, acquired conditions, metabolic disorders, and dietary imbalances including excessive consumption of licorice. Confirmatory diagnosis depends on the specific root cause and may involve blood tests, urine tests, or genetic testing; however, all forms of this condition exhibit abnormally low concentrations of both plasma renin activity (PRA) and plasma aldosterone concentration (PAC) which differentiates this group of conditions from other forms of secondary hypertension. Treatment is tailored to the specific cause and focuses on symptom control, blood pressure management, and avoidance of triggers.

<span class="mw-page-title-main">Adrenocortical adenoma</span> Medical condition

An adrenocortical adenoma or adrenal adenoma is commonly described as a benign neoplasm emerging from the cells that comprise the adrenal cortex. Like most adenomas, the adrenocortical adenoma is considered a benign tumor since the majority of them are non-functioning and asymptomatic. Adrenocortical adenomas are classified as ACTH-independent disorders, and are commonly associated with conditions linked to hyperadrenalism such as Cushing's syndrome (hypercortisolism) or Conn's syndrome (hyperaldosteronism), which is also known as primary aldosteronism. In addition, recent case reports further support the affiliation of adrenocortical adenomas with hyperandrogenism or florid hyperandrogenism which can cause hyperandrogenic hirsutism in females. "Cushing's syndrome" differs from the "Cushing's disease" even though both conditions are induced by hypercortisolism. The term "Cushing's disease" refers specifically to "secondary hypercortisolism" classified as "ACTH-dependent Cushing's syndrome" caused by pituitary adenomas. In contrast, "Cushing's syndrome" refers specifically to "primary hypercortisolism" classified as "ACTH-independent Cushing's syndrome" caused by adrenocortical adenomas.

The ACTH test is a medical test usually requested and interpreted by endocrinologists to assess the functioning of the adrenal glands' stress response by measuring the adrenal response to adrenocorticotropic hormone or another corticotropic agent such as tetracosactide or alsactide (Synchrodyn). ACTH is a hormone produced in the anterior pituitary gland that stimulates the adrenal glands to release cortisol, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and aldosterone.

Glucocorticoid remediable aldosteronism also describable as aldosterone synthase hyperactivity, is an autosomal dominant disorder in which the increase in aldosterone secretion produced by ACTH is no longer transient.

Feline hyperaldosteronism is a disease in cats. The symptoms are caused by abnormally high concentrations of the hormone aldosterone, which is secreted by the adrenal gland. The high concentrations of aldosterone may be due directly to a disorder of the adrenal gland, or due to something outside of the adrenal gland causing it to secrete excessive aldosterone.

SUSPUP (serum sodium to urinary sodium to serum potassium to urinary potassium) and SUSPPUP (serum sodium to urinary sodium to (serum potassium)2 to urinary potassium) are calculated structure parameters of the renin–angiotensin-aldosterone system (RAAS). They have been developed to support screening for primary or secondary aldosteronism.

<span class="mw-page-title-main">18-Oxocortisol</span> Chemical compound

18-Oxocortisol is an endogenous steroid, a metabolite of cortisol.

References

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