What causes hyponatremia (low sodium levels)?

From the Guidelines

Hyponatremia is primarily caused by an imbalance of sodium in the body, often resulting from conditions such as heart failure, liver cirrhosis, syndrome of inappropriate antidiuretic hormone secretion (SIADH), and kidney disease, as well as certain medications and excessive water intake. The causes of hyponatremia can be broadly categorized into three main types: hypovolemic, euvolemic, and hypervolemic hyponatremia. Hypovolemic hyponatremia is typically caused by excessive sodium loss, often due to diuretic use, vomiting, or diarrhea, whereas hypervolemic hyponatremia is associated with conditions like heart failure and liver cirrhosis, where there is an excess of total body water relative to sodium 1.

Key Causes of Hyponatremia

• Excessive water intake (polydipsia)
• Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
• Heart failure
• Liver cirrhosis
• Kidney disease
• Adrenal insufficiency
• Hypothyroidism
• Certain medications, including thiazide diuretics, antidepressants (particularly SSRIs), antipsychotics, anticonvulsants, and NSAIDs

Mechanisms and Clinical Context

The underlying mechanism of hyponatremia typically involves either water retention (dilutional hyponatremia) or sodium loss (depletional hyponatremia), with the body's inability to excrete excess water or maintain sodium levels disrupting the critical balance needed for proper cellular function and nerve signal transmission. In clinical practice, identifying the cause of hyponatremia is crucial for effective management, as treatment strategies vary significantly depending on the underlying etiology 1.

Management Considerations

For hypervolemic hyponatremia, which is commonly seen in patients with cirrhosis and heart failure, the management involves inducing a negative water balance to normalize the increased total body water, thereby improving serum sodium concentration. While fluid restriction has been a standard approach, its efficacy is limited, and newer pharmacological agents like vaptans, which block the V2-receptors of AVP, have shown promise in improving serum sodium levels in these patients 1. The use of vaptans, such as tolvaptan, has been approved for the management of severe hypervolemic hyponatremia and offers a pathophysiologically-oriented treatment approach by improving solute-free water excretion. However, their use requires careful monitoring to avoid complications like hypernatremia, dehydration, and renal impairment.

From the FDA Drug Label

In two double-blind, placebo-controlled, multi-center studies (SALT-1 and SALT-2), a total of 424 patients with euvolemic or hypervolemic hyponatremia (serum sodium <135 mEq/L) resulting from a variety of underlying causes (heart failure, liver cirrhosis, syndrome of inappropriate antidiuretic hormone [SIADH] and others)

The causes of hyponatremia include:

• Heart failure
• Liver cirrhosis
• Syndrome of inappropriate antidiuretic hormone (SIADH)
• Other causes 2

From the Research

Causes of Hyponatremia

• Hyponatremia can be caused by excessive renal retention of water relative to sodium due to reduced solute-free water clearance, often as a result of increased release of arginine vasopressin 3.
• Defective water excretion, usually because of elevated serum vasopressin levels, or excessive fluid intake can also lead to hypotonic hyponatremia 4.
• Thiazide-induced hyponatremia is a common cause of decreased sodium levels in elderly individuals, particularly in those with certain risk factors such as heart failure, liver disease, or malignancy 5, 6.
• The combined use of thiazide diuretics and selective serotonin reuptake inhibitors (SSRIs) can also lead to severe hyponatremia due to a synergistic effect in impairment of renal free water clearance 7.

Mechanisms of Hyponatremia

• Thiazide diuretics can impair diluting ability by inhibiting sodium and chloride transport, stimulating vasopressin release, reducing glomerular filtration, and enhancing proximal water reabsorption 6.
• SSRIs can cause hyponatremia through the syndrome of inappropriate antidiuretic hormone secretion (SIADH) 7.
• Increased release of arginine vasopressin can lead to excessive water retention and hyponatremia 3.

Risk Factors for Hyponatremia

• Certain medications, such as thiazide diuretics and SSRIs, can increase the risk of hyponatremia 5, 6, 7.
• Underlying medical conditions, such as heart failure, liver disease, or malignancy, can also increase the risk of hyponatremia 5.
• Elderly individuals, particularly those with risk factors, are more susceptible to thiazide-induced hyponatremia 5, 6.