Causes of Hypochloremia
Hypochloremia is primarily caused by renal or extra-renal losses of chloride, with key etiologies including Bartter syndrome, diuretic use, gastrointestinal losses, and metabolic alkalosis. 1
Renal Causes
- Salt-losing tubulopathies - Bartter syndrome (BS) is characterized by impaired salt reabsorption in the thick ascending limb of the loop of Henle, leading to renal tubular salt wasting with hypochloremic metabolic alkalosis 1
- Diuretic therapy - Loop diuretics and thiazides can cause hypochloremia through increased urinary chloride excretion 1
- Diuretic resistance - Hypochloremia itself can contribute to diuretic resistance, creating a vicious cycle where decreased intraluminal chloride gradient reduces diuretic efficacy 1
- Post-hypercapnic states - After correction of respiratory acidosis, renal compensation may lead to chloride wasting 1
Gastrointestinal Causes
- Protracted vomiting - Leads to loss of hydrochloric acid from the stomach, causing hypochloremic metabolic alkalosis 2
- Congenital chloridorrhea - A rare autosomal recessive disease caused by SLC26A3 gene mutations, characterized by profound diarrhea with high chloride concentration in stool 3
- Gastric outlet obstruction - Can cause severe hypochloremia through persistent vomiting, as seen in cases of malignancy affecting the gastric outlet 2
- Intestinal fistulas or drainage - External drainage of intestinal contents can lead to significant chloride losses 4
Metabolic Causes
- Metabolic alkalosis - Hypochloremia and metabolic alkalosis often coexist in a bidirectional relationship, where each condition can exacerbate the other 1
- Hyperaldosteronism - Causes increased renal sodium reabsorption with concomitant chloride loss 1
- Excessive bicarbonate administration - Can lead to chloride dilution and metabolic alkalosis 4
Heart Failure-Related Causes
- Neurohormonal activation - In heart failure, activation of the renin-angiotensin-aldosterone system (RAAS) can lead to chloride depletion 1, 5
- Diuretic therapy - Commonly used in heart failure management, can cause hypochloremia 5
- Decreased chloride delivery to macula densa - Triggers renin release, exacerbating RAAS activation and worsening sodium retention 1
Fluid Management-Related Causes
- Excessive administration of hypotonic fluids - Can dilute serum chloride concentration 1
- Water excess relative to chloride - When water losses are less than sodium and chloride losses 6
Clinical Pearls
- Hypochloremia is often accompanied by hypokalemia and metabolic alkalosis, forming a triad of electrolyte abnormalities 1
- Serum chloride correlates with plasma renin concentration, suggesting its role in neurohormonal activation 5
- Patients with hypochloremia may exhibit paradoxical renal wasting of chloride despite overall depletion 5
- In heart failure patients, hypochloremia is associated with poor diuretic response (odds ratio 7.3) 5
- Chloride supplementation may improve diuretic response in selected patients with heart failure and hypochloremia 7
Diagnostic Approach
- Evaluate for renal versus extra-renal causes by measuring urinary chloride excretion 4
- Assess acid-base status to determine if hypochloremia is associated with metabolic alkalosis 1, 4
- Consider fractional excretion of chloride or urinary sodium/chloride ratio to distinguish renal from extrarenal salt losses 1
- In patients with Bartter syndrome, fractional chloride excretion is usually elevated (>0.5%) despite hypochloremia 1