Hyperaldosteronism

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Hyperaldosteronism Main page
Patient Information
Overview
Classification 1- Primary hyperaldosteronism 2- Secondary hyperaldosteronism 3- Pseudohyperaldosteronism causes (low renin)
Differentiating diagonsis
History and symptoms

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mehrian Jafarizade, M.D [2]

This page contains general information about hyperaldosteronism. For more information on specific types, please visit the pages on primary hyperaldosteronism and secondary hyperaldosteronism.

Synonyms and keywords: Aldosteronism

Overview

Hyperaldosteronism is a clinical scenario of mineralocorticoid excess with resistant hypertension, hypokalemia, and metabolic alkalosis due to increased hydrogen ion excretion. Aldosteronism may be classified into three types, primary hyperaldosteronism (Conn's syndrome), secondary hyperaldosteronism, and pseudohyperaldosteronism. Primary hyperaldosteronism can caused by aldosterone-secreting adenoma, bilateral hyperplasia of the adrenal glands, and ectopic secretion of aldosterone from ovaries and kidneys. Primary hyperaldosteronism features overproduction of aldosterone despite suppressed plasma renin activity (PRA). The resulting Na+ retention produces hypertension, and elevated K+ excretion may cause hypokalemia.

Classification

Aldosteronism and mineralocorticoid excess may be classified into three types, primary hyperaldosteronism (conn's syndrome), secondary hyperaldosteronism, and pseudohyperaldosteronism. The different types of mineralocorticoid excess are described in the below table:

Primary hyperaldosteronism (conn's syndrome)

Primary hyperaldosteronism	Category	Diseases
	Adrenal causes	Aldosterone-secreting adrenal adenoma
		Idiopathic hyperaldosteronism Bilateral hyperplasia of the adrenal gland
	Extra-adrenal causes	Ectopic secretion of aldosterone From the ovaries and kidneys
	Familial hyperaldosteronism	Familial hyperaldosteronism type I Glucocorticoid-remediable aldosteronism [GRA]
		Familial hyperaldosteronism II Familial occurrence of aldosterone-secreting adrenal adenoma or bilateral idiopathic hyperplasia or both
		Familial hyperaldosteronism type III Associated with the germline mutation in the KCNJ5 potassium channel)
	Other	Pure aldosterone-producing adrenocortical carcinomas
		Unilateral adrenal hyperplasia

Secondary hyperaldosteronism

	Category	Diseases
Secondary hyperaldosteronism	Genetic mutation	Bartter and Gitelman syndromes (hyperplasia of the juxtaglomerular apparatus, the source of renin in the kidney)
	Endocrine causes	Cushing syndrome The main pathogenetic mechanism is linked to the excess of cortisol which saturates 11-HSD2 activity, This allows cortisol to bind mineralocorticoid receptor
		Ectopic ACTH production (Secondary to carcinomas such as lung cancer)
	Renovascular	Kidney transplant
		Renin-secreting juxtaglomerular cell tumors
		Scleroderma renal crisis
		Malignant hypertension
	Tumors	Reninoma
	Intravascular hypovolemia	Heart failure Hepatic cirrhosis Nephrotic syndrome

Pseudohyperaldosteronism causes (low renin):

Pseudohyperaldosteronism causes	Disease	Etiology	Clinical features	Labratory				Treatment
				Elevated mineralocorticoid	Renin	Aldosterone	Other
Endogenous causes	17 alpha-hydroxylase deficiency	Mutations in the CYP17A1 gene	Ambiguous genitalia in male Hypertension Primary amenorrhea Absence of secondary sexual characteristics Minimal body hair	Deoxycorticosterone (DOC)	↓	↓	Cortisol ↓	Corticosteroids
	11β-hydroxylase deficiency	Mutations in the CYP11B1 gene	Ambiguous genitalia in female Hypertension and hypokalemia Virilization				Cortisol ↓
	Apparent mineralocorticoid excess syndrome (AME)	Genetic or acquired defect of 11-HSD gene Cortisone decreases and cortisol accumulates and binds to aldosterone receptors	Severe juvenile hypertension Hypercalciuria, nephrocalcinosis, polyuria (due to hypokalemia-induced nephrogenic diabetes insipidus) Renal failure	Cortisol has mineralocorticoid effects	↓	↓	Urinary free cortisone ↓↓	Dexamethasone and/or mineralocorticoid blockers
	Liddle’s syndrome (Pseudohyperaldosteronism type 1)	Mutation of the epithelial sodium channels (ENaC) gene in the distal renal tubules	Hypertension Hypokalemia	No extra mineralocorticoid presents, and mutations in Na channels mimic aldosterone mechanism	↓	↓	Cortisol ↓	Amiloride or triamterene
	Cushing’s syndrome	The main pathogenetic mechanism is linked to the excess of cortisol which saturates 11-HSD2 activity, This allows cortisol to bind mineralocorticoid receptor	Rapid weight gain, particularly of the trunk and face with limbs sparing (central obesity) Proximal muscle weakness A round face often referred to as a "moon face" Excess sweating Headache	Cortisol has mineralocorticoid effects	↓	↓ if excess cortisol saturates 11-HSD2 enzyme activity ↑ in direct activation of renin angiotensin system activation by glucocorticoids	Urinary free cortisol markedly ↑↑	Pasireotide, Cabergoline, Ketoconazole, and Metyrapone Adrenalectomy
	Insensitivity to glucocorticoids (Chrousos syndrome)	Mutations in glucocorticoid receptor (GR) gene	Hypertension Adrenal hyperandrogenism	Deoxycorticosterone (DOC)	↓	↓	Cortisol	Dexamethasone
	Cortisol-secreting adrenocortical carcinoma	Multifactorial	Rapid weight gain, particularly of the trunk and face with limbs sparing (central obesity) Proximal muscle weakness A round face often referred to as a "moon face" Excess sweating Headache	Cortisol has mineralocorticoid effects	↓	↓ if excess cortisol saturates 11-HSD2 enzyme activity ↑ in direct activation of renin angiotensin system activation by glucocorticoids	Urinary free cortisol markedly ↑↑	Surgery
	Geller’s syndrome	Mutation of mineralocorticoid (MR) receptor that alters its specificity and allows progesterone to bind MR	Severe hypertension particularly during pregnancy	Progesterone has mineralocorticoid effects	↓	↓	-	mineralocorticoid blockers
	Gordon’s syndrome (Pseudohypoaldosteronism type 2)	Mutations of at least four genes have been identified, including WNK1 and WNK4	Hypertension Hyperkalemia Normal renal function	No excess mineralocorticoid; an increased activity of the thiazide-sensitive Na–Cl co-transporter in the distal tubule	↓	Normal	Hyperkalemia	thiazide diuretics and/or dietary sodium restriction
Exogenous causes	Corticosteroids with mineralocorticoid activity	Fludrocortisone or fluoroprednisolone can mimic the action of aldosterone,	Hypertension Hypokalemia	Medications such as fludrocortisone	↓	↓	-	Change the treatment
	Licorice ingestion	Glycyrrhetinic acid that binds mineralocorticoid receptor and blocks 11-HSD2 at the level of classical target tissues of aldosterone	Hypertension Hypokalemia	-	↓	↓	Urinary free cortisol Moderate ↑	Discontinue licorice
	Grapefruit	High assumption of naringenin, a component of grapefruit, can also block 11-HSD	Hypertension	-	↓	↓	-	Discontinue grapefruit
	Estrogens	Estrogens can retain sodium and water by different mechanisms, causing: Increased blood pressure values and suppressing the renin aldosterone system, on the other side inducing secondary hyperaldosteronism due to the stimulation of the synthesis of angiotensinogen	Hypertension Headache Edema Weight gain	-	↓	↓	-	Discontinue estrogens

Other less common causes of pseudohyperaldosteronism are:

• Sclerosis of juxtaglomerular apparatus (diabetic microangiopathy and/or of the elderly)

• Low-renin essential hypertension

• B-Adrenergic agonists

• Partial/total nephrectomy or removal of renal tissue

• Autonomic dysfunction

Differentiating Diagnosis

Hyperaldosteronism should be differentiated from other diseases causing hypertension and hypokalemia for example:

• Renal artery stenosis
• Cushing's syndrome
• Congenital adrenal hyperplasia (CAH)
  • 17 alpha hydroxylase deficiency
  • 11 beta hydroxylase deficiency
• Liddle's syndrome
• Diuretic use
• Licorice ingestion
• Renin-secreting tumors

Hypertension and Hypokalemia

Plasma renin activity

Normal or High (Plasma Renin/Aldosterone ratio <10

Suppressed (Plasma Renin/Aldosterone ratio >20

*Renin-secreting tumors *Diuretic use *Renovascular hypertension *Coarctation of aorta *Malignant phase hypertension

Urinary aldosterone

Elevated

Normal

Low

Conn's syndrome (Primary aldosteronism)

Profound K+ depletion

• 17 alpha hydroxylase deficiency • 11 beta hydroxylase deficiency • Liddle's syndrome • Licorice ingestion • Deoxycortisone producing tumor

Add Mineralocrticoid antagonist for 8 weeks

BP response

No BP response

• Deoxycorticosterone excess( Tumor, 17 alpha hydroxylase and 11 beta hydroxylase deficiency) • Licorice ingestion •Glucocorticoid resistance

Liddle's syndrome)

History and symptoms

History

Hyperaldosteronism may be suspected in the following scenarios:

• Patients with a history of spontaneous or unprovoked hypokalemia along with hypertension.
• Patients who develop severe and/or persistent hypokalemia while on low to moderate doses of potassium-wasting diuretics.
• Patients with a history of treatment-refractory/-resistant hypertension (HTN).

Patients with profound hypokalemia report fatigue, muscle weakness, cramping, headaches, and palpitations. They can also have polydipsia and polyuria from hypokalemia-induced nephrogenic diabetes insipidus. Long-standing HTN may lead to cardiac, retinal, renal, and neurologic problems, with all the associated symptoms and signs. Patients with primary hyperaldosteronism may have subclinical systolic dysfunction, more bradycardia, higher blood pressure and vascular resistance values than those with the secondary hyperaldosteronism. Plasma renin activity has been found to be lower in primary than in secondary hyperaldosteronism.

Common Symptoms

Common symptoms of Hyperaldosteronism include:

Hypertension related symptoms

• Headaches
• Facial flushing
• Weakness
• Visual impairment
• Impaired consciousness
• Seizures (hypertensive encephalopathy)

Hypokalemia related symptoms

• Constipation
• Polyuria and polydipsia (because of impaired renal concentrating ability)
• Weakness

Less Common Symptoms

Less common symptoms of hyperaldosteronism include:

• Paralysis
• Palpitations
• Ileus

References

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