Hypoaldosteronism is defined as decreased levels of the hormone aldosterone or a resistance of the target tissue to the actions of aldosterone. There are several causes for decreased levels of aldosterone, including kidney disorders, adrenal insufficiency, congenital adrenal hyperplasia, and medications such as ACE inhibitors, angiotensin receptor blockers, NSAIDs and calcineurin inhibitors. Mutation in the mineralocorticoid receptor gene (NR3C2) may lead to resistance to the actions of the aldosterone. Hypoaldosteronism results in hyperkalemia, which can be a serious medical condition. Hyponatremia is unusual in isolated aldosterone deficiency as under normal conditions cortisol inhibits antidiuretic hormone secretion. In patients with adrenal insufficiency as a cause of hypoaldosteronism, decrease in cortisol, aldosterone, and androgen levels may lead to hyponatremia. Hypoaldosteronism may be classified into two categories depending on the level of plasma renin and depending on the level of aldosterone. The most common cause of hypoaldosteronism is diabetic nephropathy, acute glomerulonephritis, tuberculosis, hemorrhage, infarction, sarcoidosis, AIDS, CMV, and Addison’s disease. Less common causes of hypoaldosteronism include sarcoidosis, amyloidosis, fungal infections, AIDS complications, and hemochromatosis.Hypoaldosteronism must be differentiated from other diseases that cause hypotension and muscle weakness. Common risk factors in the development of hypoaldosteronism include diabetes mellitus, sickle cell anemia, HIV, graves’ disease, hypoparathyroidism, hypopituitarism, myasthenia gravis, and pernicious anemia. If left untreated, hypoaldosteronism may lead to hyperkalemia and severe muscle weakness. Common complications of hypoaldosteronism include hyperkalemia, metabolic acidosis, hypotension, hypovolemia and hyponatremia. Prognosis of hypoaldosteronism is generally good for patients who receive treatment.

Hypoaldosteronism was first described by an American physician Hudson JB in the year 1956. Later on, in the year 1964, physicians Viser and Ulick gave a description on isolated and congenital hypoaldosteronism respectively.

Hypoaldosteronism may be classified on the basis of plasma renin levels into hyporeninemic hypoaldosteronism and hyperreninemic hypoaldosteronism. Hypoaldosteronism can also be classified on the basis of plasma aldosterone levels into aldosterone deficiency and aldosterone resistance.

Hypoaldosteronism is defined as decreased levels of the hormone aldosterone or a resistance of the target tissue to the actions of aldosterone. Hypoaldosteronism from decreased production is seen in conditions such as congenital isolated hypoaldosteronism, primary adrenal insufficiency, diabetic nephropathy, critical illness, and drugs such as ACE inhibitors, NSAIDs and calcineurin inhibitors. Resistance of the target tissue to the actions of aldosterone is seen with mineralocorticoid receptor defects (seen in pseudohypoaldosteronism) and with drugs such as potassium-sparing diuretics and trimethoprim. Hypoaldosteronism results in reduced reabsorption of sodium in the principal cells of cortical collecting tubules (CCT). This leads to decreased excretion of potassium (hyperkalemia) and mild non-anion gap metabolic acidosis. On gross pathology, adrenal glands may be irregularly shrunken or hyperplastic.

The common causes of hypoaldosteronism include diabetic nephropathy, acute glomerulonephritis, tuberculosis, hemorrhage, infarction, sarcoidosis, AIDS, CMV infection, and Addison’s disease. Less common causes of hypoaldosteronism include sarcoidosis, amyloidosis, fungal infections, AIDS complications, and hemochromatosis.

Hypoaldosteronism must be differentiated from other diseases that cause hypotension and muscle weakness such as Addison’s disease, myopathies, celiac disease, Peutz-Jeghers syndrome, anorexia nervosa, syndrome of inappropriate anti-diuretic hormone (SIADH), neurofibromatosis, porphyria cutanea tarda, salt-depletion nephritis and bronchogenic carcinoma. In addition, measurement of plasma renin activity (PRA), serum aldosterone, and serum cortisol is used to differentiate among various subtypes of hypoaldosteronism.

In hospitalized patients, the incidence of hypoaldosteronism is 3000 per 100,000 individuals. The prevalence of hypoaldosteronism in United states is estimated to be 200,000 cases. Hypoaldosteronism is most commonly seen in middle-aged and older individuals. Both men and women are affected equally. Hypoaldosteronism is more prevalent in African-American, Native Americans, and Hispanics.

Common risk factors in the development of hypoaldosteronism include diabetes mellitus, sickle cell anemia, HIV, graves’ disease, hypoparathyroidism, hypopituitarism myasthenia gravis, and pernicious anemia. Other less common risk factors include multiple myeloma, SLE-associated renal disease and Wolmans disease.

There is insufficient evidence to recommend routine screening for hypoaldosteronism.

If left untreated, hypoaldosteronism leads to hyperkalemia which can alter the function of cardiac conduction pathways. Depending upon the severity of hypoaldosteronism, hyperkalemia can be a life threatening condition. When serum potassium rises above ≥ 9 mEq/L, hyperkalemia may lead to ventricular fibrillation, PEA and even cardiac arrest. Common complications of hypoaldosteronism include hyperkalemia, metabolic acidosis, hypotension, hypovolemia and hyponatremia. Depending on the extent of the hyperkalemia and underlying renal or adrenal condition at the time of diagnosis, the prognosis of hypoaldosteronism may vary. Prognosis of hypoaldosteronism is generally good for patients who receive treatment.

There is no established criteria for the diagnosis of hypoaldosteronism. However, a positive history of hypotension, muscle weakness and fatigue should raise suspicion for hypoaldosteronism. These patients should first be tested for serum potassium levels, plasma renin activity (PRA), serum aldosterone, and serum cortisol. Asymptomatic hypoaldosteronism can also be discovered on routine laboratory evaluations.

Hypoaldosteronism often has a gradual onset. Patients of hypoaldosteronism should be enquired about the use of drugs that can alter aldosterone production or function. These drugs include ACE inhibitors, angiotensin receptor blockers and NSAIDs. The most common symptoms of hypoaldosteronism include fatigue, muscle weakness, and low blood pressure. Other less common symptoms of hypoaldosteronism include hyperpigmentation, gastrointestinal disturbances, and abdominal pain.

Patients with hypoaldosteronism usually appear fatigued. Physical examination of patients with hypoaldosteronism is usually unremarkable, unless there is severe hyperkalemia. Increased level of serum potassium level may present with muscle tenderness, hyporeflexia/areflexia and cardiac arrhythmias. The physical exam may also represent findings of underlying condition such as chronic kidney disease or diabetic nephropathy.

Laboratory findings consistent with the diagnosis of hypoaldosteronism include hyperkalemia and mild non-anion gap metabolic acidosis. Other lab findings include hyponatremia, decreased aldosterone level, and variable amounts of plasma renin activity (depends upon the underlying condition).

In hypoaldosteronism there are no specific ECG findings. However, hypoaldosteronism predisposes to hyperkalemia (decreased renal excretion) and occasional hyponatremia (from decreased renal absorption). Hyperkalemia leads to depression of SA node and conduction pathways such as AV node and His-Purkinje system causing bradycardia and conduction blocks. On the other hand, severe hyponatremia may present with ST segment elevation mimicking acute myocardial infarction.

There are no x-ray findings associated with hypoaldosteronism.

There are no specific findings of hypoaldosteronism on ultrasound. However, ultrasound may be helpful in the diagnosis of hypoaldosteronism from disorders of renal or adrenal glands. Chronic kidney disease is an important cause of hypoaldosteronism and on ultrasound presents with reduced renal length, reduced renal cortical thickness, and with poor visibility of the renal pyramids and the renal sinus. Hypoaldosteronism from adrenal insufficiency may present with irregularly shrunken adrenal glands, adrenal nodules, and signs of calcium deposits.

There are no CT scan findings associated with hypoaldosteronism. A CT scan is not routinely done for the diagnosis of hypoaldosteronism.

There are no specific MRI findings associated with hypoaldosteronism.

There are no other imaging findings associated with hypoaldosteronism.

There are no other diagnostic studies associated with hypoaldosteronism.

The mainstay of treatment for hypoaldosteronism depends upon the level of plasma potassium. Prompt ECG is advised in all patients suspected of hypoaldosteronism as hyperkalemia may lead to cardiac conduction defects and life threatening arrhythmias. Patients with no ECG changes and moderate hyperkalemia (6.5–7.5 mmol/l) require only monitoring. Patients with severe hyperkalemia (>7.5 mmol/l) are treated with emergency measures for hyperkalemia (calcium, insulin, β₂ agonist or cation resins) and fludrocortisone. Depending upon the volume status, patients may be treated with either 0.9% normal saline (hypovolemia) or furosemide (hypervolemic).

Surgical intervention is not recommended for the management of hypoaldosteronism.

There are no established measures for the primary prevention of hypoaldosteronism.

Effective measures for the secondary prevention of hypoaldosteronism include liberal salt intake of 4gm/day (to increase plasma sodium concentration), decreasing potassium intake and avoidance of drugs that affects renin angiotensin aldosterone system (RAAS) such as ACE inhibitors, ARBs, potassium sparing diuretics and β-Adrenergic receptor blockers.

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Hypoaldosteronism was first described by an American physician Hudson JB in the year 1956. Later on, in the year 1964, physicians Viser and Ulick gave a description on isolated and congenital hypoaldosteronism respectively.

The following timeline provides a brief history in the discovery of adrenal glands and hypoaldosteronism.^[1][2][3][4]

• In 1563, Bartholomeus Eustachius an anatomy professor at the Collegio della Sapienza in Rome was the first to give a description of the adrenal glands in his publication “glandulae renibus incumbentes”
• In 1586, Piccolomini was the first to name the glands as suprarenals.
• In 1651, Highmore was the first to suggest that the suprarenals act to absorb exudates from the large vessels.
• In 1656, Thomas Wharton was the first to describe the concept of the neuroendocrine function of the adrenal medulla.
• In 1805, Cuvier was the first to give a detailed description of medulla and cortex of adrenal glands.
• In 1852, Albert von Kölliker was the first to give a detailed microscopic description of the adrenal glands.
• In 1855, Thomas Addison was the first to identify and describe the condition “Addison’s disease” in his paper “On the Constitutional and Local Effects of Disease of the Suprarenal Capsules”.
• In 1856, Charles Brown-Séquard provided experimental proof of the vital role of the adrenals by performing adrenalectomies (the removal of adrenals) from several animal species.
• In 1956, Hudson James, an American physician was the first to give a detailed description of hyporeninemic hypoaldosteronism and its pathophysiology.
• In 1964, Viser and Cost were the first to give a detailed description on isolated hypoaldosteronism.
• In 1964, Ulick was the first to give a detailed description on congenital hypoaldosteronism.

Hypoaldosteronism may be classified on the basis of plasma renin levels into hyporeninemic hypoaldosteronism and hyperreninemic hypoaldosteronism. Hypoaldosteronism can also be classified on the basis of plasma aldosterone levels into aldosterone deficiency and aldosterone resistance.

Hypoaldosteronism may be classified on the basis of plasma renin levels into hyporeninemic hypoaldosteronism and hyperreninemic hypoaldosteronism. Hypoaldosteronism can also be classified on the basis of plasma aldosterone levels into aldosterone deficiency and aldosterone resistance.^[1][2][3][4]

Hypoaldosteronism can be classified on the basis of plasma renin activity into hyporeninemic or hyperreninemic hypoaldosteronism.

Hypoaldosteronism

Hyporeninemic Hypoaldosteronism

Hyperreninemic Hypoaldosteronism

• Renal insufficiency • Diabetic nephropathy • Sickle cell disease

• Addison’s disease • Any severe illness such as malignancy or sepsis

Hypoaldosteronism can also be classified on the basis of level of aldosterone.

Hypoaldosteronism

Aldosterone deficiency

Aldosterone resistance

• Renal insufficiency • Adrenal insufficiency • Diabetic nephropathy • Sickle cell disease • Critical illness • Congenital isolated hypoaldosteronism • Drugs such as ACEi, ARBs and Heparin

• Pseudohypoaldosteronism type 1 • Aldosterone antagonists • Epithelial sodium channel blockers • Calcineurin inhibitors

Hypoaldosteronism is defined as decreased levels of the hormone aldosterone or a resistance of the target tissue to the actions of aldosterone. Hypoaldosteronism from decreased production is seen in conditions such as congenital isolated hypoaldosteronism, primary adrenal insufficiency, diabetic nephropathy, critical illness, and drugs such as ACE inhibitors, NSAIDs and calcineurin inhibitors. Resistance of the target tissue to the actions of aldosterone is seen with mineralocorticoid receptor defects (seen in pseudohypoaldosteronism) and with drugs such as potassium-sparing diuretics and trimethoprim. Hypoaldosteronism results in reduced reabsorption of sodium in the principal cells of cortical collecting tubules (CCT). This leads to decreased excretion of potassium (hyperkalemia) and mild non-anion gap metabolic acidosis. On gross pathology, adrenal glands may be irregularly shrunken or hyperplastic.

• The juxtaglomerular apparatus of the macula densa primarily senses the concentration of plasma sodium and renal perfusion pressure.^[1][2]
  • In response to low plasma sodium concentration or decreased renal perfusion pressure, the juxtaglomerular apparatus secretes renin.
  • On secretion, renin cleaves angiotensinogen (produced by liver) to angiotensin I.
  • Angiotensin-converting enzyme produced in the lungs further cleaves angiotensin I to angiotensin II.
  • The main site of activity for angiotensin II is zona glomerulosa of adrenal cortex, where angiotensin II stimulates aldosterone synthase which converts deoxycorticosterone to aldosterone.

• The renin-angiotensin-aldosterone axis is a tightly controlled feedback mechanism which regulates sodium and blood pressure in our body.^[3]
  • Low plasma sodium, decreased perfusion pressure and hyperkalemia stimulates aldosterone secretion.
  • Hypokalemia suppresses aldosterone secretion.

• Aldosterone is synthesized at a rate of approximately 100 to 150 ug/day.

• Hypoaldosteronism is defined as decreased levels of the hormone aldosterone or a resistance of the target tissue to the actions of aldosterone. Hypoaldosteronism can be due to:^[4]
  • Aldosterone deficiency: The deficiency in aldosterone can be due to congenital isolated hypoaldosteronism, primary adrenal insufficiency, diabetic nephropathy, critical illness, and drugs such as ACE inhibitors, NSAID and calcineurin inhibitors.
  • Aldosterone resistance: In aldosterone resistance, the level of aldosterone is normal but there is decreased response of the target tissue to the actions of aldosterone. Aldosterone resistance is seen with mineralocorticoid receptor defects (seen in pseudohypoaldosteronism) and with drugs such as potassium-sparing diuretics and trimethoprim.

• Hypoaldosteronism results in reduced reabsorption of sodium in the principal cells of cortical collecting tubules (CCT). This leads to decreased excretion of potassium and mild non-anion gap metabolic acidosis.

• Hyporeninemic hypoaldosteronism is most commonly seen in patients with mild to moderate renal insufficiency and diabetic nephropathy:^[5][6][7]
  • In patients of renal insufficiency, atrophy of the juxtaglomerular apparatus (JGA) leads to decreased sensing of plasma sodium concentration and renal perfusion pressure.
  • With progression of the renal disease and atrophy of the juxtaglomerular apparatus (JGA) there may be inadequate renin production and release.
  • A decrease in renin production and release leads to decreased angiotensin production, which eventually causes hypoaldosteronism .
  • Renal insufficiency may also cause decreased response of the principal cells in the cortical collecting tubule to aldosterone.

• Hyperreninemic hypoaldosteronism also known as secondary isolated hypoaldosteronism is seen in patients with severe illness such as sepsis, malignancy, heart failure, adrenal dysfunction and liver cirrhosis.^[8][9][10]
  • During these stress inducing conditions, increased levels of ACTH and cortisol are seen.
  • Under normal conditions, continuous ACTH secretion for greater than 96 hours leads to suppression of aldosterone synthase activity.
  • Chronically ill patients with prolonged ACTH secretion (>96 hours) have impaired aldosterone synthase activity and decreased levels of aldosterone.
  • In response, the kidneys via its neurohormonal regulation leads to increased levels of renin and hence the term hyperreninemic hypoaldosteronism.
  • In addition, cytokine release from chronic illness or increased levels of atrial natriuretic peptide (in patients with heart failure) also have an inhibitory effect on the zona glomerulosa of adrenal cortex.
• Hyperreninemic hypoaldosteronism is also seen in patients with adrenal dysfunction such as Addison’s disease.
  • Primary adrenal insufficiency or Addison’s disease can be due to adrenal dysgenesis, impaired steroidogenesis, and adrenal destruction.
  • In patients of primary adrenal insufficiency, the adrenal glands does not produce sufficient cortisol and aldosterone.
  • The decrease in level of aldosterone leads to decreased absorption of sodium in the kidneys and increased retention of potassium. This in turn activates the juxtaglomerular apparatus (JGA) of the kidneys, which secretes renin in an attempt to normalise plasma sodium concentration and perfusion pressure. However, due to adrenal dysfunction the zona glomerulosa of adrenal cortex is unable to produce aldosterone and presents with hyperreninemic hypoaldosteronism.

• In isolated hypoaldosteronism, there is selective deficiency of aldosterone with normal cortisol production. Isolated hypoaldosteronism may result from dysfunction of zona glomerulosa or aldosterone synthase deficiency. ^[11]
  • Aldosterone synthase is an enzyme involved in the synthesis of aldosterone. Patients with aldosterone synthase enzyme deficiency (type I and type II) results in defective conversion of deoxycorticosterone to aldosterone and subsequently abnormal levels of aldosterone.
  • Certain drugs such as heparin and nitric oxide have a direct suppressive effect on the zona glomerulosa of adrenal cortex which may lead to decrease production of aldosterone.

Postadrenalectomy hypoaldosteronism is seen in patients with Conn syndrome who undergo surgery for tumor removal:^{[12][13][14][15][16][17][18]}

• Conn syndrome is most often unilateral and leads to excessive production of aldosterone from the affected adrenal gland.
• Excessive production of aldosterone causes hypertension and suppression of renin angiotensin aldosterone system (RAAS).
• Patients with Conn syndrome who are treated with spironolactone and later undergo surgery for tumor removal may develop hypoaldosteronism.
• Patients with Conn syndrome have increased levels of aldosterone and decreased plasma renin activity (from suppressed RAAS) which leads to chronic suppression of contralateral zona glomerulosa.
• On surgical removal of aldosterone producing tumor, there is sudden decline in circulating aldosterone which leads to hypoaldosteronism.

Mineralocorticoid resistance is characterized by a decrease in response to the hormone aldosterone. In mineralocorticoid resistance the level of aldosterone may be normal or supranormal. It is due to this reason mineralocorticoid resistance is also known as pseudohypoaldosteronism. Mineralocorticoid resistance can be further categorized into:^[19][20][21]

• Pseudohypoaldosteronism Type I:
  • The decrease in response to aldosterone is due to heterozygous or homozygous inactivating mutations in the mineralocorticoid receptor. These patients are also resistant to mineralocorticoid therapy.
• Pseudohypoaldosteronism Type II:
  • This is an extremely rare disorder. It is speculated that these patients have mutations in the genes encoding proteins of the serine threonine kinase family (WKNK1 or WNK4 kinases). Pseudohypoaldosteronism Type II is characterized by low or low-normal plasma renin activity and aldosterone concentrations, leading to hyperkalemia and metabolic acidosis with normal renal function. Pseudohypoaldosteronism type II is also known as Gordon’s syndrome.
• Pseudohypoaldosteronism Type III:
  • This condition presents with transient mineralocorticoid resistance. Pseudohypoaldosteronism type III is seen in patients with underlying renal conditions with decreased glomerular filtration rate. The exact cause is unknown but is thought to be related to increased levels of TGF-β.

• Genes involved in the pathogenesis of hypoaldosteronism include mutation in CYP11B2 gene and NR3C2 gene.^[22][23][24]
• CYP11B2 gene is located on chromosome 8q24.
  • Mutation in CYP11B2 gene is transmitted in autosomal recessive pattern.
  • The CYP11B2 gene encodes for the enzyme aldosterone synthase (previously known as corticosterone methyloxidase).
  • Aldosterone synthase catalyses the conversion of 11-deoxycorticosterone to aldosterone. The following flowchart depicts the various steps carried out by the enzyme aldosterone synthase:

11 Deoxycorticosterone

Corticosterone

18 Hydroxycorticosterone

Aldosterone

• Mutations in CYP11B2 can lead to:
  • Type 1 aldosterone synthase deficiency: Patients have normal to decreased levels of 18-hydroxycorticosterone and undetectable levels of aldosterone.
  • Type 2 aldosterone synthase deficiency: Patients have increased levels of 18-hydroxycorticosterone and normal to decreased levels of aldosterone.
  • Aldosterone synthase is a member of the cytochrome P450 family of enzymes.

• The other gene associated with hypoaldosteronism is NR3C2 gene.
  • NR3C2 gene is located on chromosome 4q31.1-31.2; which is the long (q) arm of chromosome 4 at position 31.1-31.2
  • NR3C2 gene encodes for mineralocorticoid receptor.
  • Mutation in NR3C2 gene can be transmitted in autosomal recessive or autosomal dominant pattern.
  • Mutated NR3C2 gene leads to defective mineralocorticoid receptor and presents with resistance to the actions of aldosterone.

• Sickle cell disease
• Analgesic nephropathy
• Lead nephropathy
• Chronic pyelonephritis
• Obstructive nephropathy
• Diabetes and renal insufficiency
• Nonsteroidal anti-inflammatory drugs
• Calcineurin inhibitors
• Vitiligo
• Premature ovarian failure
• Pernicious anemia
• Myasthenia gravis
• Chronic candidiasis
• Sjögren syndrome
• Chronic active hepatitis
• Hypothyroidism
• Graves hyperthyroidism
• Adrenoleukodystrophy

• On gross pathology, adrenal glands in hypoaldosteronism can either be:
  • Irregularly shrunken, or
  • Hyperplastic

• On microscopic histopathological analysis, adrenal gland can be divided into adrenal cortex and adrenal medulla.
• Adrenal cortex can be further categorized into:
  • Zona glomerulosa (produces aldosterone)
  • Zona fasciculata (produces cortisol)
  • Zona reticularis (produces androgens)

The most common cause of hypoaldosteronism is diabetic nephropathy. Other common causes are acute glomerulonephritis, tuberculosis, hemorrhage, infarction, sarcoidosis, AIDS, CMV, and Addison’s disease. Less common causes of hypoaldosteronism include sarcoidosis, amyloidosis, fungal infections, AIDS complications, and hemochromatosis.

Life-threatening causes of hypoaldosteronism include:^[1]

• Adrenal infarction
• Bilateral adrenal hemorrhage (caused by trauma, anticoagulant therapy, or coagulation disorders).
• Cancerous destruction of the adrenal gland, secondary to infiltrative or metastatic disease.
• Tubercular and fungal destruction of adrenal glands.

Common causes of hypoaldosteronism include:^[2]

• Diabetic nephropathy
• Acute glomerulonephritis
• Any cause of renal insufficiency
• Autoimmune/Idiopathic
• Tuberculosis
• AIDS
• CMV
• Hemorrhage into adrenal glands
• Adrenal gland Infarction
• Sarcoidosis

Less common causes of hypoaldosteronism include:

• Amyloidosis
• Fungal infections
• Hemochromatosis
• Polyglandular endocrine syndromes
• Adrenoleukodystrophy
• Adrenomyelodystrophy

Other less common causes of hypoaldosteronism include drugs such as:^{[3][4][5][6][7]}

Decreased renin release	Inhibition of aldosterone synthase	Decreased production of aldosterone	Decreased effect of aldosterone	Drugs that impair adrenal function	Direct inhibition of zona glomerulosa	Dopaminergic agonists
Acebutolol Atenolol Bisoprolol Carvedilol Flufenamic acid Indomethacin Naproxen	Cyclosporine Tacrolimus  Heparin Benidipine Azelnidipine Cilnidipine Efonidipine	Captopril Enalapril Fosinopril Lisinopril Moexipril	Amiloride Eplerenone Spironolactone Triamterene	Aminoglutethimide Metyrapone Mitotane Trilostane	Heparin sodium Nitric oxide	Bromocriptine Metoclopramide Cabergoline

Hypoaldosteronism must be differentiated from other diseases that cause hypotension and muscle weakness such as Addison’s disease, salt-depletion nephritis, myopathies, celiac disease, Peutz-Jeghers syndrome, anorexia nervosa, syndrome of inappropriate anti-diuretic hormone (SIADH), neurofibromatosis, porphyria cutanea tarda, and bronchogenic carcinoma. In addition, measurement of plasma renin activity (PRA), serum aldosterone, and serum cortisol is used to differentiate among various subtypes of hypoaldosteronism.

• Various subtypes of hypoaldosteronism can be differentiated on the basis of plasma renin activity (PRA), serum aldosterone, and serum cortisol. These tests are performed after maintaining an upright position for three hours. Under normal conditions, maintaining an upright position for long duration activates the neuro-hormonal regulation by the kidneys which leads to increased renin and aldosterone release.
• The following table distinguishes among various subtypes of hypoaldosteronism:

Disorder	Plasma Renin Activity	Plasma Aldosterone	Plasma Cortisol
Hyporeninemic hypoaldosteronism	Low	Low	Normal
Hypereninemic hypoaldosteronism	Increased	Low	Normal/↓
Primary adrenal insufficiency	High	Low	Low
Pseudohypoaldosteronism type I	High	High	Normal
Pseudohypoaldosteronism type II	Normal/↓	Normal/↓	Normal

• Hypoaldosteronism must be differentiated from other diseases that cause hypotension and muscle weakness such as Addison’s disease, myopathies, celiac disease, Peutz-Jeghers syndrome, anorexia nervosa, syndrome of inappropriate anti-diuretic hormone (SIADH), neurofibromatosis, porphyria cutanea tarda, salt-depletion nephritis and bronchogenic carcinoma.^{[1][2][3][4][5]}

Disease	Differentiating symptoms							Differentiating laboratory findings			Gold standard test
	Hypotension	Abdominal pain	Anorexia/ weight loss	Muscle weakness	Hypoglycemia	Skin pigmentation	Other symptoms	Hyponatremia	Cortisol levels	Other labs
Hypoaldosteronism	+	–	+/-	+	–	+/-	Muscle tenderness	+/-	Normal	—
Addison’s disease	+	+	+	+	+	+	N/A	+	Low	—	ACTH stimulation test
Salt-depletion nephritis	+	Flank pain	–	–	–	–	Fever Dysuria Pyuria Oliguria	+	Elevated	<15:1 BUN:CR	—
Myopathies (polymyositis, hereditary myopathies)	–	–	–	+	–	Heliotrope rash and Gottron’s sign	Muscle tenderness	–	Normal	N/A	Muscle biopsy
Anorexia nervosa	+	–	+	+	+	–	Distorted body image Oligomenorrhea	–	Elevated	N/A	Psychiatric condition
Celiac disease	–	+	+	–	–	Dermatitis herpetiformis	Greasy stools Increased fecal fat	–	Normal	N/A	Abnormal small bowel biopsy
Syndrome of inappropriate anti-diuretic hormone (SIADH)	–	–	–	–	–	–	N/A	+	Normal	Decreased osmolality Euvolemia Sodium in urine typically >20 mEq/L	Water deprivation test
Neurofibromatosis	–	–	+	+	–	Axillary- and inguinal-area freckling	Occasional development of peripheral sarcomas May have overgrowth of subcutaneous tissues	–	–	N/A	Biopsy of skin tissue
Peutz-Jeghers syndrome	N/A	+	N/A	N/A	N/A	+	Melanotic hyperpigmentation of the skin and mucous membranes	–	Normal	N/A	Colonic imaging showing the small intestinal polyps
Porphyria cutanea tarda	–	+	–	–	–	Blisters on sun-exposed sites	Associated liver disease (usually hepatitis C) Hypertrichosis	–	Normal or elevated	High level of porphyrins in the urine
Bronchogenic carcinoma	–	–	+	+/-	–	+	Cough Dyspnea Hemoptysis	–	Elevated	Increased ACTH and Hypokalemia	Cytological or histological evidence of lung cancer in sputum, pleural fluid, or tissue

In hospitalized patients the incidence of hypoaldosteronism is 3000 per 100,000 individuals. The prevalence rate of hypoaldosteronism in United states is estimated to be 200,000 cases. Hypoaldosteronism is most commonly seen in middle-aged and older individuals. Both men and women are affected equally. Hypoaldosteronism is more prevalent in African-American, Native Americans, and Hispanics.

The epidemiology and demographics of hypoaldosteronism is given below:^[1][2][3]

• The incidence of hypoaldosteronism in hospitalized patient is approximately 3000 per 100,000 individuals.

• The prevalence of hypoaldosteronism is approximately 667 per 100,000 individuals.
• The prevalence of hypoaldosteronism is estimated to be 200,000 cases in the United States.

• Hypoaldosteronism is most commonly seen in middle-aged and older individuals.
• Elderly patients on multiple drug therapy (polypharmacy) have an increased incidence of drug induced hypoaldosteronism.
• In younger patients, hypoaldosteronism is seen in patients with underlying diabetes mellitus type I or sickle cell disease.

• Hypoaldosteronism is more prevalent in African-American, Native Americans, and Hispanics.

• Hypoaldosteronism affects both men and women equally.

Common risk factors in the development of hypoaldosteronism include diabetes mellitus, sickle cell anemia, HIV, graves’ disease, hypoparathyroidism, hypopituitarism, myasthenia gravis, and pernicious anemia. Other less common risk factors include multiple myeloma, SLE-associated renal disease and Wolmans disease.

Common risk factors in the development of hypoaldosteronism include:^[1][2][3]

• Diabetes mellitus
• Sickle cell anemia
• HIV
• Graves’ disease
• Hypoparathyroidism
• Hypopituitarism
• Myasthenia gravis
• Pernicious anemia
• Vitiligo

Less common risk factors in the development of hypoaldosteronism include:^[4][5]

• Multiple myeloma
• SLE-associated renal disease.
• Wolman’s disease

There is insufficient evidence to recommend routine screening for hypoaldosteronism.

There is insufficient evidence to recommend routine screening for hypoaldosteronism.

If left untreated, hypoaldosteronism leads to hyperkalemia which can alter the function of cardiac conduction pathways. Depending upon the severity of hypoaldosteronism, hyperkalemia can be a life threatening condition. When serum potassium rises above ≥ 9 mEq/L, hyperkalemia may lead to ventricular fibrillation, PEA and even cardiac arrest. Common complications of hypoaldosteronism include hyperkalemia, metabolic acidosis, hypotension, hypovolemia and hyponatremia. Depending on the extent of the hyperkalemia and underlying renal or adrenal condition at the time of diagnosis, the prognosis of hypoaldosteronism may vary. Prognosis of hypoaldosteronism is generally good for patients who receive treatment.

• If left untreated, hypoaldosteronism can progress to hyperkalemia and hyponatremia with hypovolemia or hypervolemia.^[1][2][3]
• Hyperkalemia is an acute life threatening condition since it can alter the electrical activity of the heart and lead to life threatening arrhythmias.
• Patients with severe hyperkalemia (>7.5 mmol/l) may present with bundle branch blocks or fascicular blocks.
• When serum potassium level ≥ 9 mEq/L, hyperkalemia may lead to ventricular fibrillation, PEA and even cardiac arrest.
• Hyponatremia is unusual in isolated hypoaldosteronism since under normal conditions cortisol leads to suppression of ADH. However, patients of adrenal insufficiency have decreased cortisol and aldosterone which may progress to hyponatremia.
• Aldosterone deficiency leads to decreased sodium and water absorption which predisposes to hypovolemia. However, patients with underlying conditions such as kidney disease or heart condition may be hypervolemic.

• Common complications of hypoaldosteronism include:^[4]
  • Hyperkalemia
  • Hypotension
  • Hypovolemia
  • Metabolic acidosis
  • Hyponatremia

• Depending on the extent of the hyperkalemia and underlying renal or adrenal condition at the time of diagnosis, the prognosis of hypoaldosteronism may vary.^[4][5][6]

• Prognosis is generally good for patients of hypoaldosteronism who receive treatment.
• Untreated patients risk having hyperkalemia which is associated with cardiac arrhythmias that can be fatal.
• Patient having underlying renal insufficiency or diabetic nephropathy generally progresses to end stage stage renal disease. Drugs such as ACE inhibitor and angiotensin receptor blockers which are the mainstay of treatment with diabetes and renal dysfunction are avoided in hypoaldosteronism since these may lead to hyperkalemia.