Can Proton Pump Inhibitors (PPIs) cause hyponatremia?

Proton Pump Inhibitors Can Cause Hyponatremia

Yes, proton pump inhibitors (PPIs) can cause hyponatremia, primarily through syndrome of inappropriate antidiuretic hormone secretion (SIADH) mechanisms, with the highest risk occurring during the first weeks of treatment. 1

Mechanisms of PPI-Induced Hyponatremia

• PPIs can directly affect renal water handling, leading to SIADH, which results in inappropriate water retention and consequent dilutional hyponatremia 1
• Increased gastric pH from PPI use promotes intestinal microbial changes that may contribute to systemic inflammation affecting water homeostasis 1
• Impaired absorption of micronutrients due to PPI therapy may play a secondary role in electrolyte disturbances, including sodium balance 1

Evidence Supporting PPI-Hyponatremia Association

• A study of elderly patients (>65 years) found that 31.3% of those treated with PPIs for more than one year developed moderate hyponatremia ([120-134] mEq/L) compared to only 9.3% in the control group, with an odds ratio of 4.4 2
• Case reports document both omeprazole and pantoprazole causing hyponatremia in the same patient, suggesting this may be a class effect of PPIs rather than specific to one medication 3
• Symptomatic severe hyponatremia due to SIADH has been reported with pantoprazole use, with sodium levels normalizing after discontinuation 4

Risk Factors and Clinical Considerations

• Elderly patients appear to be at higher risk for PPI-induced hyponatremia 2, 3
• In patients with cirrhosis, PPIs can exacerbate pre-existing hyponatremia, potentially worsening hepatic encephalopathy 1
• The relationship between hyponatremia and PPI dose has not been found to be significant in some studies (R²=0.05, p=0.74) 2

Monitoring and Management

• Monitoring of serum sodium is advisable when initiating PPI therapy, particularly in high-risk patients such as the elderly 1
• When PPI-induced hyponatremia is diagnosed, discontinuation of the medication typically leads to normalization of sodium levels 3, 4
• If reflux treatment is still needed, consider switching to H2-receptor antagonists (like ranitidine) rather than another PPI 3
• If another PPI must be used, close monitoring of serum sodium is essential as cross-reactivity may occur 3

Clinical Significance

• Hyponatremia is the most common electrolyte abnormality in hospitalized patients and can lead to serious complications if not properly managed 5, 6
• Even mild hyponatremia is associated with adverse outcomes including impaired cognition, falls, fractures, and increased mortality 5
• PPI-induced hyponatremia may be underrecognized in clinical practice as PPIs are not always considered among common causes of hyponatremia 5, 6

Caveats and Pitfalls

• Always consider PPI use when evaluating unexplained hyponatremia, especially in elderly patients 2, 5
• Avoid assuming that switching to another PPI will resolve the issue, as cross-reactivity between different PPIs has been documented 3
• The American Gastroenterological Association does not currently recommend routine screening for electrolyte abnormalities in all patients taking PPIs, but individual risk assessment is warranted 7
• Meticulous medication history is essential when evaluating hyponatremia, as many commonly prescribed medications can contribute to low sodium levels 5