Chloride – Cl– 

Physiological role and pathophysiology, reference intervals and the most likely causes of abnormalities

Chloride – Cl– 

Reference interval – examples
Distribution and physiological significance of chloride
Why measure chloride ?
Chloride balance
Terms used in interpretation of chloride
Causes of hypochloremia and hyperchloremia
The value of chloride in the investigation of acid-base disturbance
Causes of ”high-AG” acidosis
Causes of ”normal-AG hyperchloremic”acidosis
Acid-base disturbances associated with abnormal chloride

Chloride (Cl–) is the major anion in the extracellular fluid and one of the most important anions in blood. The main function of Cl– is to maintain osmotic pressure, fluid balance, muscular activity, ionic neutrality in plasma, and help elucidate the cause of acid-base disturbances.

Reference interval – examples



Distribution and physiological significance of chloride

In common with sodium (Na+), most of the approximately 3200  mmol (113  g) of Cl– present in the human body is contained within the extracellular fluid. Extracellular (plasma) concentration is around 100  mmol/L, whereas intracellular-fluid concentration is closer to 2 – 5  mmol/L. As the second most abundant extracellular fluid ion after Na+, and the most abundant extracellular fluid anion, Cl– is essential for the maintenance of normal plasma osmolarity, contributing 100 of the 300 mOsmol of extracellular tonicity [137]. In combination with Na+, Cl– determines water movement between extracellular and intracellular compartments and thereby regulation of blood volume and blood pressure. Cl– is essential for maintaining the electrochemical neutrality of plasma, contributing 70 % of all negative charges in plasma, bicarbonate (HCO3–) contributing most of the remaining.

Cl– ions are secreted from parietal cells of the stomach as hydrochloric acid, a constituent of gastric juice essential for many processes involved in the digestion and absorption of food, as well as the control of bacterial growth within the gastrointestinal tract.

Cl– is present at high concentrations (~70 mmol/L) in erythrocytes compared with all other cells (2 – 5  mmol/L). This high concentration enables the movement of Cl– between plasma and erythrocytes in exchange for bicarbonate (HCO3–) [137]. This so-called ”chloride shift” is essential for the effective transport of carbon dioxide from tissues to lungs and the maintenance of normal blood pH (acid-base homeostasis).

Why measure chloride?

The clinical utility of measuring chloride concentration (cCl–) is to help elucidate the cause of acid-base disturbances, as abnormal Cl– levels alone usually signify a more serious underlying metabolic disorder, such as metabolic acidosis or alkalosis. It is also essential for the calculation of the anion gap (AG) [97] (see AG) that can be useful in the investigation of acid-base disturbance [135]. In the absence of acid-base disturbance, cCl– almost invariably parallels sodium (cNa+), so that cCl– measurement is rarely of value in routine assessment of fluid and electrolyte balance; measurement of cNa+ is sufficient and cCl– provides no additional information [136].

Chloride balance

Maintaining Cl– within normal limits principally depends on renal regulation of Cl– loss in urine. Daily dietary intake of Cl–, predominantly in the form of salt flavoring, ranges from 160 to 300 mmol (5.7 – 10.6 g) [137]. This is far in excess of what is required to replace normal obligatory physiological losses of Cl– in urine, sweat and feces, so that most of this dietary intake must be excreted in urine to remain in balance. Renal regulation of Cl– excretion, like that of sodium excretion, depends on the hormone aldosterone and the renin-angiotensin pathway. Cl– excretion is linked to HCO3– reabsorption/regeneration, an important mechanism for renal regulation of blood pH that has implication for the role of Cl– in the pathogenesis of acid-base disturbance.

Cl– balance also depends on the ability of the gastrointestinal tract to absorb almost all of the Cl– present in gastrointestinal secretions, e.g. gastric juice, pancreatic juice, bile. Vomiting and/or diarrhea can lead to Cl– depletion.

Terms used in interpretation of chloride

Decreased cCl– (i.e. <98  mmol/L) is called hypochloremia [4].

Increased cCl– (i.e. cCl– >107  mmol/L) is called hyperchloremia [4].

Causes of hypochloremia and hyperchloremia

Since cCl– almost invariably closely parallels cNa+ in both health and disease, the causes of hypochloremia are identical with the causes of hyponatremia (see Na+) and the causes of hyperchloremia are identical with the causes of hypernatremia (see Na+)

The clinical value of measuring cCl– is confined to acid-base disturbance when cCl– may not parallel cNa+.

The value of chloride in the investigation of acid-base disturbance

Measurement of cCl– is useful in the investigation of patients with unexplained metabolic acidosis because it allows the distinction between ”high-AG” metabolic acidosis and ”normal-AG” metabolic acidosis (see AG) [138]. The first, which is the more common of the two, is characterized by abnormal increase in unmeasured (non-chloride) anions derived from a causative non-volatile acid (e.g. lactic acid, keto acid). The second is characterized by an increase in measured anion (Cl–), so it is associated with hyperchloremia. In general terms, ”high-AG” metabolic acidosis is due to abnormal accumulation of an acid, such that the HCO3– buffer is consumed, and ”normal-AG, hyperchloremic” metabolic acidosis is due to primary loss of HCO3– buffer from the body, either via the gastrointestinal tract or the kidneys. The resulting decreased extracellular fluid HCO3– induces hyperchloremia to correct the anion deficit and maintain the electrochemical neutrality of extracellular fluid. This is a condition in which cCl– does not parallel cNa+; whatever the sodium concentration there is relative hyperchloremia.

Causes of ”high-AG” acidosis [86]

  • Lactic acidosis (most common cause of metabolic acidosis)
  • Diabetic ketoacidosis (DKA)
  • Alcoholic ketoacidosis
  • Starvation ketoacidosis
  • Renal failure (acute and chronic)
  • Toxins that metabolize to acids (e.g. ethylene glycol, methanol, salicylates)

 

Causes of ”normal-AG hyperchloremic” acidosis [86]

  • Renal tubule acidosis
  • Severe diarrhea
  • Drainage of pancreatic or biliary secretion
  • Bowel fistula
  • Carbonic anhydrase inhibitor drugs (e.g. acetazolamide)
  • Excessive administration of HCl or NH4Cl to correct metabolic alkalosis
  • Fluid resuscitation (e.g. saline infusion)

 

Other acid-base disturbances associated with abnormal chloride 

Hypochloremia can cause increased renal reabsorption of HCO3– and consequent metabolic alkalosis [139]. This hypochloremia is usually the result of increased loss of Cl– via the gastrointestinal tract in vomit but can be the result of renal losses, usually secondary to diuretic therapy. Symptoms of hypochloremia are due to the metabolic alkalosis that it induces.

Renal compensation for respiratory acidosis involves increased reabsorption of HCO3– in exchange for Cl–, so that chronic respiratory acidosis is associated with increased loss of Cl– in urine and consequent hypochloremia.

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Ref.: Acute care testing handbook. Radiometer Medical ApS, 2700 Brønshøj, Denmark, 2014.

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