Pseudohyperaldosteronism (also pseudoaldosteronism) is a medical condition which mimics the effects of elevated aldosterone (

hyperaldosteronism 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). This cause of min ...

) by presenting with high

blood pressure Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "blood pressure" r ...

(

hypertension Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...

), low blood potassium levels (

hypokalemia Hypokalemia is a low level of potassium (K+) in the blood serum. Mild low potassium does not typically cause symptoms. Symptoms may include feeling tired, leg cramps, weakness, and constipation. Low potassium also increases the risk of an abno ...

metabolic alkalosis Metabolic alkalosis is a metabolic condition in which the pH of tissue is elevated beyond the normal range (7.35–7.45). This is the result of decreased hydrogen ion concentration, leading to increased bicarbonate, or alternatively a direct res ...

, and low levels of

plasma renin activity Plasma renin activity (PRA), also known as the renin (active) assay or random plasma renin, is a measure of the activity of the plasma enzyme renin, which plays a major role in the body's regulation of blood pressure, thirst, and urine output. Me ...

(PRA). However, unlike hyperaldosteronism, this conditions exhibits low or normal levels of aldosterone in the blood. Causes include genetic disorders (e.g.

Apparent mineralocorticoid excess syndrome Apparent mineralocorticoid excess is an autosomal recessive disorder causing hypertension (high blood pressure), hypernatremia (increased blood sodium concentration) and hypokalemia (decreased blood potassium concentration). It results from mutat ...

Liddle's syndrome 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 alkalo ...

, and types of

Congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders characterized by impaired cortisol synthesis. It results from the deficiency of one of the five enzymes required for the synthesis of cortisol in the adrenal cortex. ...

), acquired conditions (e.g.

Cushing's syndrome Cushing's syndrome is a collection of signs and symptoms due to prolonged exposure to glucocorticoids such as cortisol. Signs and symptoms may include high blood pressure, abdominal obesity but with thin arms and legs, reddish stretch marks, a ...

and

mineralocorticoid 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 (electrolyte balance and fluid balance). The primary mi ...

-producing adrenal tumors), metabolic disorders, and dietary imbalances including excessive consumption of

licorice Liquorice (British English) or licorice (American English) ( ; also ) is the common name of ''Glycyrrhiza glabra'', a flowering plant of the bean family Fabaceae, from the root of which a sweet, aromatic flavouring can be extracted. The liq ...

. 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 Secondary hypertension (or, less commonly, inessential 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, ...

. Treatment is tailored to the specific cause and focuses on symptom control, blood pressure management, and avoidance of triggers.

Presentation

The presentation of pseudohyperaldosteronism varies depending on the cause. The genetic conditions such as Liddle's syndrome and Congenital adrenal hyperplasia present in childhood or earlier in life than the acquired causes which can present at any age. Adult patients present with clinical history of resistant hypertension despite typical medical therapy and lifestyle changes. Hypertension may be

asymptomatic In medicine, any disease is classified asymptomatic if a patient tests as carrier for a disease or infection but experiences no symptoms. Whenever a medical condition fails to show noticeable symptoms after a diagnosis it might be considered asy ...

or may lead to symptoms such as headache, dizziness, vision changes, or kidney disease. Symptoms of hypokalemia include fatigue, muscular weakness, and increased urine production.

Causes

This condition has several known causes including genetic disorders, acquired conditions, metabolic derangements, and dietary imbalances. All causes mimic the effects of elevated aldosterone without raising aldosterone levels but achieve this through varying mechanisms.

Genetic forms

Genetic disorders that lead to this condition include Liddle's syndrome, Apparent mineralocorticoid excess (AME), and two types of Congenital adrenal hyperplasia (CAH). * Liddle's syndrome is

autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

disorder affecting epithelial sodium channels (

ENaC The epithelial sodium channel (ENaC), (also known as amiloride-sensitive sodium channel) is a membrane-bound ion channel that is selectively permeable to sodium ions (). It is assembled as a heterotrimer composed of three homologous subunits α ...

) in the distal tubules of the kidneys. In this disorder, a gain of function mutation decreases ENaC degradation leading to increased renal absorption of sodium and water. * Apparent mineralocorticoid excess genetic forms include

autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

disorders with mutations lowering the activity of the enzyme 11-beta-hydroxysteroid dehydrogenase type 2 (11-β-HSD2). These mutations limit the ability of 11-β-HSD2 to transform active cortisol to the less active

cortisone Cortisone is a pregnene (21-carbon) steroid hormone. It is a naturally-occurring corticosteroid metabolite that is also used as a pharmaceutical prodrug; it is not synthesized in the adrenal glands. Cortisol is converted by the action of the enz ...

. Excess cortisol is then able to bind and activate mineralocorticoid receptors due to receptor cross-reactivity leading to aldosterone-like effects. * Congenital Adrenal Hyperplasia is an autosomal recessive disorder with multiple types, two of which lead to pseudohyperaldosteronism. Deficiency of 11-beta-hydroxylase blocks the conversion of

11-deoxycorticosterone 11-Deoxycorticosterone (DOC), or simply deoxycorticosterone, also known as 21-hydroxyprogesterone, as well as desoxycortone (INN), deoxycortone, and cortexone, is a steroid hormone produced by the adrenal gland that possesses mineralocorticoid ac ...

(DOC) to

corticosterone Corticosterone, also known as 17-deoxycortisol and 11β,21-dihydroxyprogesterone, is a 21-carbon steroid hormone of the corticosteroid type produced in the cortex of the adrenal glands. It is of minor importance in humans, except in the very rare ...

leading to an excess of DOC which acts as a mineralocorticoid similar to aldosterone. Deficiency of 17-alpha-hydroxylase blocks the conversion of

pregnenolone Pregnenolone (P5), or pregn-5-en-3β-ol-20-one, is an endogenous steroid and precursor/ metabolic intermediate in the biosynthesis of most of the steroid hormones, including the progestogens, androgens, estrogens, glucocorticoids, and mineraloc ...

and

progesterone Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the m ...

to their 17-a-hydroxy forms leading to increased mineralocorticoid production.

Acquired forms

Some causes of pseudohyperaldosteronism can be acquired throughout life with examples including

adrenal tumor An adrenal tumor or adrenal mass is any benign or malignant neoplasms of the adrenal gland, several of which are notable for their tendency to overproduce endocrine hormones. Adrenal cancer is the presence of malignant adrenal tumors, and includes ...

s and

Ectopic ACTH syndrome Small-cell carcinoma is a type of highly malignant cancer that most commonly arises within the lung, although it can occasionally arise in other body sites, such as the cervix, prostate, and gastrointestinal tract. Compared to non-small-cell lung ...

. * Adrenal tumor subtypes include adrenal adenomas that produce 11-deoxycorticosterone (DOC) leading to increased mineralocorticoid activity without elevated aldosterone. * Ectopic ACTH syndrome describes conditions leading to excess production of

adrenocorticotropic hormone Adrenocorticotropic hormone (ACTH; also adrenocorticotropin, corticotropin) is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important c ...

(ACTH) subsequently leading to mineralocorticoid production. This can arise in ectopic forms of Cushing's syndrome associated with small-cell lung cancers and other ACTH-producing tumors. The excess ACTH can saturate the 11-β-HSD2 enzyme leading to decreased conversion of cortisol to cortisone and increased mineralocorticoid effects.

Metabolic and dietary forms

Metabolic causes include conditions of

glucocorticoid Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebr ...

resistance and from mineralocorticoid excess which can occur following high-dose corticosteroid therapy. Dietary causes include overconsumption of licorice-containing products.

Glycyrrhetinic acid Enoxolone (INN, BAN; also known as glycyrrhetinic acid or glycyrrhetic acid) is a pentacyclic triterpenoid derivative of the beta-amyrin type obtained from the hydrolysis of glycyrrhizic acid, which was obtained from the herb liquorice. It is u ...

in licorice inhibits the 11-β-HSD2 enzyme resulting in inappropriate stimulation of the

mineralocorticoid receptor The mineralocorticoid receptor (or MR, MLR, MCR), also known as the aldosterone receptor or nuclear receptor subfamily 3, group C, member 2, (NR3C2) is a protein that in humans is encoded by the ''NR3C2'' gene that is located on chromosome 4q31 ...

by cortisol leading to aldosterone-like effects.

Diagnosis

In patients with hypertension, diagnostic clues pointing to pseudohyperaldosteronism can be found on routine labwork. These include low serum potassium (hypokalemia), elevated serum sodium (

hypernatremia Hypernatremia, also spelled hypernatraemia, is a high concentration of sodium in the blood. Early symptoms may include a strong feeling of thirst, weakness, nausea, and loss of appetite. Severe symptoms include confusion, muscle twitching, and b ...

), and elevated serum

bicarbonate In inorganic chemistry, bicarbonate (IUPAC-recommended nomenclature: hydrogencarbonate) is an intermediate form in the deprotonation of carbonic acid. It is a polyatomic anion with the chemical formula . Bicarbonate serves a crucial biochemic ...

(metabolic alkalosis). Urine studies may show elevated urine potassium ( kaliuresis). To further differentiate between hyperaldosteronism and pseudohyperaldosteronism, studies including plasma renin activity (PRA) and plasma aldosterone concentration (PAC) can be obtained. Pseudohyperaldosteronism will exhibit low levels of both PRA and PAC while hyperaldosteronism will demonstrate elevated PAC. Confirmatory tests to diagnose the specific forms of pseudohyperaldosteronism vary depending on the cause. The genetic conditions such as Liddle's syndrome and CAH can be confirmed with genetic tests for the affected genes. CAH can also be confirmed by analyzing enzyme levels following ACTH stimulation testing. AME can be diagnosed with a 24 hour urine collection exhibiting an increased ratio of urinary cortisol to urinary cortisone.

Treatment

Specific treatment of pseudohyperaldosteronism depends on the inciting cause. General management focuses on countering the effects of excess mineralocorticoid activity to achieve adequate blood pressure control and avoid end-organ damage and cardiovascular mortality. In some cases, specific antihypertensive medications may be recommended. In Liddle's syndrome, ENaC-binding potassium-sparing diuretics (e.g.

amiloride Amiloride, sold under the trade name Midamor among others, is a medication typically used with other medications to treat high blood pressure or swelling due to heart failure or cirrhosis of the liver. Amiloride is classified as a potassium-spar ...

triamterene Triamterene (trade name Dyrenium among others) is a potassium-sparing diuretic often used in combination with thiazide diuretics for the treatment of high blood pressure or swelling. The combination with hydrochlorothiazide, is known as hydroch ...

) are used to counter the excess ENaC activity. In AME, the mineralocorticoid receptor-binding potassium-sparing diuretics (e.g.

spironolactone Spironolactone, sold under the brand name Aldactone among others, is a medication that is primarily used to treat fluid build-up due to heart failure, liver scarring, or kidney disease. It is also used in the treatment of high blood pressure ...

eplerenone Eplerenone, sold under the brand name Inspra, is an aldosterone antagonist type of potassium-sparing diuretic that is used to treat chronic heart failure and high blood pressure, particularly for patients with resistant hypertension due to ele ...

) are used to limit aldosterone receptor activity. Other medications such as glucocorticoids are added in AME and CAH to inhibit ACTH and further cortisol production. Lifestyle changes such as a low sodium diet are also used for managing hypertension, and cessation of licorice intake is recommended in cases of licorice overconsumption.

References

External links

{{Medical resources , DiseasesDB = 7471 , ICD10 = I15.1 , ICD9 = , ICDO = , OMIM = 177200 , MedlinePlus = , eMedicineSubj = , eMedicineTopic = , MeshID = D056929 , Orphanet = 526 Hypertension