Chloride

Physiology

Chloride is the major extracellular anion, found together with sodium. Chloride is important for osmolality and acid-base balance. Because chloride is found in a 1:1 ratio with sodium (although is slightly lower than sodium in plasma), changes in chloride should always be interpreted with sodium. Changes in free water and the gain or loss of chloride and sodium are the major mechanisms for a change in chloride concentration.

  • A loss or gain of free water and/or a loss or gain of electrolyte-rich fluids will change sodium and chloride concentrations proportionally. For example, a secretory diarrhea results in excessive loss of sodium and chloride with respect to free water (“gain of free water”) in intestinal secretions combined with water retention secondary to stimulation of antidiuretic hormone (ADH) from hypovolemia (due to loss of fluid with diarrhea).
  • A selective loss or gain of chloride in excess of sodium will result in disproportional changes in sodium and chloride and indicates that there is an acid-base disturbance. This is because chloride acts essentially as an “acid”. By Stewart’s acid-base principles, chloride is a strong anion, an independent variable. So if chloride is gained or lost in excess of sodium, it indicates a metabolic acidosis (“gain” of an acid) or alkalosis (“loss of an acid”), respectively.

To determine if a change in chloride is due to free water or an acid-base disturbance, we need to correct the chloride, i.e. modify the results to take into account changes in sodium (which reflects free water). This can be done in two ways and requires a reference interval for both electrolytes (i.e. this cannot be done for those species in which reference intervals are not available):

  • Eyeballing results: Assess the degree of change in sodium with respect to the limits of the reference interval for sodium, i.e. degree of change = measured sodium minus appropriate reference limit (if decreased, use the lower limit of the interval; if increased, use the upper limit of the interval). Then assess the degree of change in chloride with respect to the reference interval limits for chloride (measured chloride minus appropriate reference limit) and determine if it is roughly similar to the change in chloride (remember, that chloride is normally found in slightly lower concentrations than sodium in plasma, so the degree of change does not have to be exactly equal; it is quite rare to have such clear-cut changes with biological data).  See the example below.
    • A chemistry panel reveals a sodium of 139 mEq/L (reference interval, 142-150 mEq/L). The chloride is 80 mEq/L (reference interval, 105-118 mEq/L). Eyeballing the results, the degree of change (or decrease) in sodium from the lower limit of the reference interval is -3 mEq/L (139-142 mEq/L). The degree of decrease in chloride is -25 mEq/L. The change in chloride is far greater than the change in sodium (-25 versus -3 mEq/L) indicating a disproportionate decrease in chloride with respect to sodium. Since a decreased chloride indicates loss of an acid, this result indicates a metabolic alkalosis (alkalosis = loss of acid and/or gain of base). Thus, this change should be accompanied by evidence of a metabolic alkalosis (high bicarbonate) as long as a mixed acid base disturbance is not concurrently present (which would affect bicarbonate concentrations). The low sodium in this example also indicates a concurrent loss of electrolyte-rich fluid but also gain of free water. In this case, the dog was vomiting resulting in loss of HCl in gastric secretions with some concurrent loss of sodium (but far less than chloride) and ADH-mediated retention of water and drinking resulting in dilution of sodium concentrations.
  • Correcting the chloride: Instead of eyeballing results, the chloride concentration can be “corrected” for changes in free water (or the sodium concentration) using the following formula:

Corrected Cl– = (normal Na+/measured Na+) x measured Cl–
where, normal Na+ is the midpoint of the sodium reference interval

The corrected chloride is then interpreted based on the provided chloride reference interval. Using the same example above:

    • The normal sodium is 146 mEq/L (142 + 150/2). The corrected chloride is 84 mEq/L (146/139 x 80 mEq/L, which is still far below the reference interval (105-118 mEq/L), indicating a corrected hypochloridemia or a loss of chloride in excess of sodium with the same interpretation as above.

Note, that small disproportional changes (decreases or increases) in chloride with respect to sodium should not be over-interpreted as indicating an acid-base disturbance. All laboratory data should always be interpreted with respect to the patient and if there is no evidence of an acid-base disturbance or no disease process that could result in an acid-base abnormality, then you should not give the animal one based on laboratory data alone.

Methodology

Serum or plasma concentrations of these major electrolytes can be measured by ion-specific electrodes or flame photometry. Measurement of electrolytes by ion-specific electrodes is called potentiometry. There are two types of potentiometry: direct and indirect. Direct potentiometry is utilized by blood gas machines and does not involve sample dilution. Indirect potentiometry is utilized by automated chemistry analyzers, such as the ones used at Cornell University, and involves sample dilution before analysis. This distinction is important because endogenous interferents such as lipemia may falsely decrease electrolyte concentrations with indirect, but not direct, potentiometry.

Technique used at Cornell

Direct (blood gas machine) or indirect (chemistry analyzer) potentiometry.

Procedure

With this technique, an electrode containing an internal electrolyte solution is immersed in the patient sample, which is separated from the internal solution by a membrane that can detect the electromotive force (EMF) generated by the ions in both solutions. This EMF is determined by the difference in concentration of the test ion in the test solution and internal filling solution (test ion at fixed concentration). The EMF is predicted by the Nernst equation (see Techniques for more details on the method). For testing purposes with the chemistry analyzer, the sample is diluted 1:32 before analysis (indirect potentiometry).

Units of measurement

Chloride concentration is measured in mEq/L (conventional units), mg/dL (conventional units), or mmol/L (SI units). The unit conversion formulas are shown below:

mEq/L x 1 = mmol/L
mg/dL ÷ 3.55 = mmol/L

Sample considerations

Sample type

Serum, plasma, or urine

Anticoagulant

Heparin or EDTA

Stability

The Cl– concentration in human plasma or serum is stable for several days when separated from red blood cells and stored at 2 – 8°C. Samples of urine should be stored at 4°C.

Interferences

  • Lipemia: Lipemia will falsely decrease chloride concentrations measured with indirect potentiometry (chemistry analyzer) but not direct (blood gas) potentiometry. Since indirect potentiometry is the main method used to determine electrolyte concentrations on chemistry panels, lipemia may affect our chloride results to a similar extent as sodium.
  • Hemolysis and Icterus: No effect.

Test interpretation

Normal corrected chloride

The corrected chloride is within the chloride reference interval. This indicates the chloride changes are due to changes in free water and primary causes of hypo- or hypernatremia should be pursued (refer to sodium for causes).

High corrected chloride (hyperchloridemia)

  • Artifact
    • Anticonvulsant medication: The ion-selective electrode used to measure chloride is, unfortunately, not specific for chloride. It also detects other anions, such as bromide, and measures them as “chloride”. Thus, chloride concentrations measured by potentiometry (direct or indirect) will be falsely increased in animals on bromide medication for seizures. In these settings, we measure chloride using flame photometry, which provides more accurate chloride measurements. We have noticed a similar artifact in dogs on zonisamide therapy for seizures.
  • Iatrogenic
    • Drug administration: Administration of Cl-containing fluids (hypertonic saline, ammonium chloride).
  • Pathophysiologic causes
    • Primary normal anion gap (hyperchloremic) metabolic acidosis (associated with loss of bicarbonate with retention of chloride by the kidney): Renal failure, proximal and distal renal tubular acidosis. 
    • Compensatory metabolic acidosis (associated with loss of bicarbonate with retention of chloride by the kidney): The kidney excretes bicarbonate and retains chloride as a compensatory response to a primary respiratory alkalosis (hypocapnea or hyperventilation).

Low corrected chloride (hypochloremia)

A low corrected chloride is associated with a chloride-responsive (or chloride-depleted) metabolic alkalosis (chloride behaves as an acid), whether a primary acid-base disturbance or a compensatory response to a primary respiratory acid-base disturbance. Bicarbonate concentrations are expected to be increased with a normal anion gap. However, the disease state that results in a primary metabolic alkalosis (e.g. vomiting, abomasal outflow obstruction) frequently also produces a lactic acidosis (due to hypovolemia), hence bicarbonate concentrations may not be increased as expected and the anion gap may be high (reflecting accumulation of lactic acid, an unmeasured anion). The bicarbonate concentration and pH will be affected in opposite directions by a primary metabolic alkalosis and primary metabolic acidosis; the dominating disturbance will determine the final result. For example, if acidosis is dominating, the pH may be acidic and bicarbonate will be decreased (below the reference interval) or the pH and bicarbonate may be closer towards the lower end of interval (if the pH and bicarbonate results are within  reference intervals). The reverse would be the case if the metabolic alkalosis is dominating.

  • Iatrogenic
    • Drug administration: Administration of sodium-rich fluids, diuretics (loop diuretics – these inhibit the Na-K-2Cl carrier in the loop of Henle, hence two chloride ions are lost per one sodium; thiazide diuretics inhibit the NaCl cotransporter in the early distal tubule; although this is expected to result in proportional losses of sodium and chloride, the increased sodium delivered to the collecting tubule may be absorbed by principal cells with concurrent stimulation of acid excretion and chloride being lost with the acid, resulting in a potential disproportionate loss of chloride).
  • Pathophysiologic causes:
    • Loss of chloride in excess of sodium:
      • Gastrointestinal:
        • Loss of chloride-rich fluid: Vomiting of gastric contents in small animals, marked ptyalism and gastric reflux in horses, large colon or cecal diarrhea in horses (chloride is absorbed in the ileum and colon of horses), gastrointestinal ulcers (horses). In humans, a deficiency or abnormality in the ileal transporter for chloride results in severe chloride loss and hypokalemia (Gennari et al 2011).
        • Sequestration of chloride-rich fluid: Displaced abomasum, abomasal atony (a common finding in sick cattle), gastric rupture, gastric dilation-volvulus (dogs), ileus (horses).
      • Renal: Renal disease (especially in cattle, although losses of NaCl are usually proportional), loop diuretics (lose 2 Cl for 1 Na and 1 K in the Na-K-2Cl exchanger in the ascending limb of the loop of Henle), stimulation of the H+ATPase pump in the distal tubules (lose HCl) – the latter response is an expected and appropriate compensatory response to a primary respiratory acidosis and an expected attempted correction for a primary metabolic acidosis that is not due to renal disease.
      • Cutaneous: Excess sweating in horses (loss of KCl).
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