Chloride is an essential element in the blood that plays important roles in acid and electrolyte balance, kidney and muscle function, and transport of minerals, water, and gases. Both high and low blood chloride levels can cause health issues. Keep reading to learn more about chloride, the disorders caused by changes in its concentration, and how to resolve them.
- What is Chloride (Cl-)?
- What Is the Chloride Blood Test?
- Low Chloride (Hypochloremia)
- Ways to Increase Blood Chloride
- High Chloride (Hyperchloremia)
- Ways to Decrease Blood Chloride
- Genetics of Blood Chloride Levels
- Effect of Drugs on Chloride Levels
- Limitations and Caveats
- Irregular Chloride Levels?
What is Chloride (Cl-)?
Chloride is an essential electrolyte (a mineral that conducts electricity when in water). Chloride is the body’s main anion (negatively charged electrolyte) and represents 70% of the total negative electrolytes [R, R].
- A healthy mineral concentration, acid level, and electrical balance of the body fluids
- Fluid and mineral movement between cellular compartments
- Acid production in the stomach
- Kidney function
- Muscular activity
- Blood pressure
- Transport of oxygen and carbon dioxide by red blood cells
The average adult consumes 5.8-11.8 g chloride a day from salt [R].
What Is the Chloride Blood Test?
Chloride levels are usually measured with a blood test, which is done as part of an electrolyte or metabolic panel. It can also be measured via sweat, serum, urine, and feces, in certain circumstances. The test measures the concentration of free chloride and the results are shown in milliequivalents of chloride per liter of blood (mEq/L) [R, R, R].
Normal Chloride Levels
The normal ranges for chloride levels are [R]:
- Premature babies: 95-110 mEq
- Full-term babies: 96-106 mEq
- Children and adults: 95-105 mEq
Low chloride levels (<95-100 mEq/L) are referred to as hypochloremia, while high levels (>106-110 mEq/L) are known as hyperchloremia. It is important to note that certain conditions can interfere with the analyses and result in artificially high or low chloride levels [R].
Conversely, electrolytes like iodide and bromide or drugs like salicylate can be incorrectly picked up by the electrode and register as higher chloride levels (such as in case of poisoning) [R, R, R].
Normal Electrolyte Levels
To maintain blood as an electrically neutral fluid, the concentration of positively charged electrolytes (sodium, potassium, calcium, and magnesium) must equal the concentration of negatively charged electrolytes (chloride, bicarbonate, phosphate, sulfate, and organic electrolytes) [R].
Only sodium, potassium, chloride, and bicarbonate are normally measured in blood tests. The difference between non-measured negative and positive electrolytes is called “anion gap” and is used for quality control, and to diagnose acid-base disorders, excess of antibodies in the blood (paraproteinemia), and poisoning with lithium, bromide, and iodide [R, R, R, R, R].
Normal concentrations of the main electrolytes inside the cells (left) and in blood (right). Source: [R].
Low Chloride (Hypochloremia)
Symptoms of Hypochloremia
- Irregular heart rate
- Cramps in muscles and nerves
Causes of Low Chloride Levels
1) Excessive Chloride Loss
Blood chloride levels can drop if it is excreted in excessive amounts through the kidneys or through the digestive system [R].
Through the kidneys, this is due to:
- Excessive use of diuretics [R, R]
- Genetic defects of electrolyte channels in the kidneys (e.g., Bartter’s and Gitelman syndromes) [R, R]
- High concentration of carbon dioxide in the blood with increased bicarbonate intake (respiratory acidosis) [R, R]
- Excess levels of the hormone aldosterone in blood [R]
- Adrenal hypofunction (low levels of adrenal hormones, such as cortisol) [R]
- Lung disease causing respiratory acidosis [R, R]
Through the digestive system, this is due to:
- Frequent vomiting [R]
- Abuse of laxatives [R]
- Stomach pumping [R]
- Evacuation through a surgical opening of the end of the bowel through the belly (ileostomy) [R]
- Narrowing of the opening of the stomach into the bowel [R]
- Watery diarrhea [R]
- Secretion through tumors in the bowel (McKittrick-Wheelock syndrome) [R]
2) Insufficient Chloride Intake
The recommended minimum daily intake of chloride is 2.3 g. Because the average adult consumes 5.8-11.8 g/day, chloride malnutrition is very rare [R].
A soy-based formula with very low chloride content (0-2 mEq/L) caused low blood chloride levels and metabolic alkalosis in babies (retrospective study of 13 patients). It also occurred in 4 babies with mothers with eating disorders (study of 153 babies) [R, R].
Similarly, a liquid nutritional product for individuals with severe disabilities caused chloride deficiency (retrospective study of 59 patients) [R].
Cystic tissue scarring is a hereditary syndrome that causes low blood chloride levels because it is not absorbed through the kidneys and bowel [R].
3) Excess Fluid Intake
Infusion with high volumes of low-salt fluids reduces the concentration of electrolytes (including chloride) in the blood [R].
An anorexic patient who drank large amounts of water developed low blood chloride, sodium, and potassium levels, as well as headache, vomiting, and seizures [R].
Patients with congestive heart failure retain large amounts of fluids and develop resistance to diuretics, which causes low blood chloride levels [R].
The excessive release of the antidiuretic hormone vasopressin causes an increased return of water to the blood circulation by the kidneys and thus reduces electrolyte levels [R].
4) Metabolic Alkalosis
Metabolic alkalosis (high blood pH) is a result of [R]:
- Increased bicarbonate production/intake
- Decreased bicarbonate excretion
- Loss of hydrogen ions
The loss of a positively charged electrolyte (hydrogen) and/or buildup of a negatively charged electrolyte (bicarbonate) promote the elimination of chloride to balance positive and negative charges [R, R].
Infusion or intake of high volumes of sodium bicarbonate causes blood alkalosis and may lead to chloride being exchanged for bicarbonate to maintain blood neutrality [R].
5) Electrolyte Imbalance
Because the blood concentration of positively charged electrolytes must equal that of negatively charged electrolytes, conditions that cause the loss of sodium and potassium often result in low blood chloride levels [R].
Consequences of Low Chloride Levels
1) Low Chloride Levels and Death Rate
A relationship between low blood chloride levels and increased death rate has been demonstrated in several studies:
- A cohort study of 9106 healthy individuals [R]
- A cohort study of 2699 patients with long-term heart failure [R]
- Three cohort studies of 1318, 152, and 1673 patients with heart failure [R, R, R]
- Three retrospective cohort studies of 98, 488, and 843 critically-ill patients [R, R, R]
- A cohort study of 3314 stroke patients [R]
- A retrospective cohort study of 277 patients with excessive blood pressure inside the lung vessels [R]
Similarly, low blood levels of chloride, sodium, and albumins due to malnutrition reduced the survival of HIV patients taking antiretroviral therapy (prospective cohort study of 661 African women) [R].
2) Low Chloride Levels and Kidney Function
The incidence of kidney injury increased in patients with low blood chloride levels (retrospective cohort study of 13088 patients undergoing contrast-enhanced tomography) [R].
In another study, low blood chloride was a risk factor for the development of kidney injury (retrospective cohort study of 6025 critically ill patients) [R].
Ways to Increase Blood Chloride
1) Reducing the Intake of Certain Drugs
Low blood chloride levels can be caused by drugs such as:
2) Treatment With Certain Drugs
Note: By writing this section, we are not recommending these drugs. We are simply providing information that is available in the scientific literature. Please discuss your medications with your doctor.
Low blood chloride levels and metabolic alkalosis can be treated with the following drugs:
- Carbonic anhydrase blockers [R]
- Diuretics [R]
- Corticosteroids (short-term treatments) [R]
- Arginine hydrochloride [R]
- Ammonium chloride [R]
- Lysine chloride [R]
- Potassium chloride [R]
3) Eating Chloride-Rich Foods
- Stock cubes (16%)
- Olives in brine (3%)
- Bacon (2.9%)
- Prawns (2.5%)
- Salami (2.5%)
- Blue cheese (2.3%)
- Butter (1.3%)
- Bread (0.9%)
4) Fluid Therapy Increases Blood Chloride
Chloride electrolyte losses can be replaced through infusion with 0.9% sodium chloride solution [R].
High Chloride (Hyperchloremia)
Symptoms of Hyperchloremia
- Muscle cramps
- Irregular heart rate
- Numbness or tingling
- Breathing problems
Causes of High Chloride Levels
High blood chloride can be caused by:
- Dehydration [R, R]
- Conditions that can cause fluid loss, such as fever or diarrhea [R, R]
- Too much stress, which causes high cortisol levels (adrenal hyperfunction) [R]
- Parathyroid hyperfunction (hyperparathyroidism) [R, R, R]
- Kidney disease [R, R]
- Metabolic acidosis [R, R]
- Hyperventilation causing respiratory alkalosis [R, R]
- Diabetes insipidus (a rare condition where the body produces a large amount of urine and one often feels thirsty) [R]
- Bromide intoxication [R]
- Drugs such as aspirin [R]
Dehydration increases the concentration of chloride in the body by decreasing the amount of water. In these conditions, the kidneys reduce urine production to preserve more water [R].
Dehydration can be caused by [R]:
- Insufficient water intake
- High fever
- Heat exposure
- Intense exercise
- Alcohol abuse
- Some medications (e.g., diuretics)
- Production of large amounts of diluted urine (diabetes insipidus)
- Increased urine production as a result of high salt intake
2) Excessive Salt Intake
Excessive salt intake (salty food, infusion of 0.9% salt solution during patient resuscitation, or unintentionally swallowing salty water) exceeds the capacity of the kidneys to excrete sodium and chloride, and increases water loss from urination and diarrhea, leading to a buildup of both electrolytes [R, R, R].
3) Metabolic Acidosis
Metabolic acidosis (low blood pH) occurs when the body produces excessive acids or insufficient bicarbonate. This loss of bicarbonate increases the concentration of chloride to maintain negative charges in the blood [R, R].
Alternatively, some forms of diarrhea cause the excretion of bicarbonate, which increases the retention of chloride [R].
Chloride buildup linked to metabolic acidosis also occurs in a condition in which the kidneys fail to absorb bicarbonate (proximal kidney tubular acidosis) or in patients suffering from chronic kidney failure [R, R].
Blockers of the enzyme that transforms carbon dioxide into bicarbonate (carbonic anhydrase II) also promote chloride buildup [R].
Excessive exposure to certain organic acids (e.g., toluene) can also cause high chloride [R].
4) Electrolyte Imbalances
Positive and negative charges in the blood must be balanced to remain electrically neutral. Conditions promoting the increased buildup of positive electrolytes such as sodium and potassium in the blood will lead to the excessive accumulation of chloride [R].
Consequences of High Chloride Levels
1) High Chloride Levels and Kidney Function
Several studies found a link between high blood chloride levels and increased incidence of kidney injury:
- A meta-analysis of 21 studies involving 6,253 critically ill patients [R]
- A prospective observational study on 445 critically ill patients [R]
- An open-label study on 1533 critically ill patients [R]
- Three retrospective studies on 1,221 and 250 critically ill patients [R, R]
- A retrospective cohort study and a RCT on 31,920 and 150 patients undergoing surgery [R, R]
- An observational study of 158 patients undergoing liver transplantation [R]
- A retrospective case review on 79 children with diabetic ketoacidosis [R]
- A retrospective cohort study on 240 patients with septic shock [R]
- A retrospective study on 1,267 patients with bleeding in the membrane area of the brain (subarachnoid space) [R]
However, this relationship was not seen in other studies:
- A retrospective chart review on 95 patients with septic shock [R]
- A retrospective analysis of 291 patients undergoing heart surgery [R]
- Two retrospective cohort studies of 1,298 and 189 patients undergoing surgery [R, R]
- A retrospective cohort study and a DB-RCT on 1,045 and 2,278 critically ill patients [R, R]
In an observational retrospective study on 213 patients who underwent kidney transplantation, no positive correlation could be found between high blood chloride levels in the donor and the incidence of acute kidney injury in the recipient [R].
Infusion of 0.9% salt solution reduced blood flow in the kidneys as a result of high blood chloride levels (DB-RCT on 12 healthy volunteers) [R].
2) High Chloride Levels and Death Rate
A relationship between high blood chloride levels and increased death rate of critically ill patients has been demonstrated in these studies:
- A retrospective cohort study of 1,940 patients with septic shock [R]
- Two retrospective analyses of 109,836 patients with systemic inflammatory syndrome and 890 children with septic shock [R, R]
- A cohort study of 3116 with systemic inflammatory syndrome [R]
- Two retrospective cohort studies of 31,920 and 22,851 patients undergoing surgery [R, R]
- Two cohort studies of 175 critically ill adult patients and 66 critically ill children [R, R]
- A retrospective observational study of 98 critically ill patients [R]
However, this correlation was not seen in these studies:
- A meta-analysis of 21 studies involving 6,253 critically ill patients [R]
- A DB-RCT of 2,278 patients admitted to the intensive care unit [R]
- An open-label study and a cohort study of 760 and 445 critically ill patients [R, R]
- A DB-RCT of 442 patients with septic shock [R]
3) High Chloride Levels and Blood Circulation
In two studies, patients infused with 0.9% salt required higher volumes of a neurotransmitter (catecholamine) to increase their blood pressure and support circulation than those infused with a balanced solution (RCT on 150 patients undergoing kidney transplantation and DB-RCT of 60 patients undergoing major stomach and bowel surgery) [R, R].
In a study, the infusion with a balanced solution (Ringer’s lactate) instead of 0.9% salt reduced blood loss during the operation (DB-RCT on 66 patients undergoing aortic reconstruction surgery) [R].
4) High Chloride Levels and Stomach Function
In a study (DB-RCT) on 47 elderly patients, infusion with 0.9% salt caused reduced blood flow through the stomach lining and increased nausea and vomiting when compared to balanced solutions (Hartmann’s and Hextend) [R].
In a trial (SB-RCT on 18 healthy volunteers) infusion with 0.9% salt caused a higher incidence of stomach discomfort than with a balanced solution (Ringer’s lactate) [R].
5) High Chloride Levels and Immune System
Infusion with a balanced solution induced higher circulating levels of cytokines than with 0.9% salt solution (DB-RCT on 40 patients undergoing surgery) [R].
In two cell studies, exposure to a chloride-concentrated solution reduced the activation and attachment to the inner blood vessel lining of white blood cells, suggesting that infusion with high-chloride fluids reduces the risk of septic shock [R, R].
6) High Chloride Levels and In-Hospital Complications
In a meta-analysis of 21 studies involving 6,253 critically ill patients, infusion with high-chloride fluids was associated with the requirement for longer mechanical ventilation times [R].
In two cohort studies (one on 31,920 patients undergoing surgery and one on 3,166 patients with systemic inflammatory syndrome), infusion with 0.9% salt increased the incidence of infections after the operation [R, R].
Infusion with 0.9% salt caused increased readmission rates when compared to a balanced solution (cohort study of 3,116 patients with systemic inflammatory syndrome) [R].
High blood chloride levels caused by infusion with 0.9% salt increased the length of hospital stay in two cohort studies (on 3,166 patients with systemic inflammatory syndrome and 22,851 surgical patients) [R, R].
A retrospective cohort study on 31,920 patients undergoing stomach and bowel surgery showed that patients infused with 0.9% salt were more likely to require a blood transfusion [R].
Ways to Decrease Blood Chloride
1) Staying Hydrated
If high blood chloride concentration is caused by dehydration, restore water levels by drinking abundant water, infusing balanced or chloride-free electrolyte solutions, avoiding alcohol intake [R, R, R].
2) Reducing the Intake of Certain Drugs
The following medications can cause increased blood chloride levels:
- Diuretics [R, R]
- Laxatives [R]
- Corticosteroids (short-term treatments) [R]
- Carbonic anhydrase blockers [R]
3) Treating Certain Disorders
Because they can enhance chloride (and other electrolyte) imbalances, the following disorders must be urgently resolved in patients with high blood chloride levels:
- Diabetes [R]
- Kidney failure [R]
- Liver failure [R]
- Eating disorders (if the patient is abusing laxatives) [R]
Genetics of Blood Chloride Levels
The following genetic conditions are associated with abnormal chloride levels.
1) Gordon’s Syndrome
Pseudohypoaldosteronism type II (PHAII), also known as Gordon’s syndrome, is a rare hereditary disease characterized by high blood chloride levels [R].
In the kidneys, the proteins WNK1 and WNK4 activate the electrolyte transporters Na+/Cl– cotransporter (NCC) and Na+/K+/2Cl– cotransporters 1 and 2 (NKCC1 and NKCC2), thus causing the increased intake of sodium, chloride, and potassium. Additionally, the proteins KLHL3 and CUL3 form a complex that binds to WNK4 and breaks it down, thus decreasing the absorption of these electrolytes. Mutations in all these proteins can cause Gordon’s syndrome [R, R, R, R].
2) Bartter’s Syndrome
Bartter’s syndrome is a rare inherited defect of the kidney cells in the part of the kidney that reabsorbs electrolytes (loop of Henle) and is characterized by [R]:
- Potassium wasting
- Low blood chloride levels
- Metabolic alkalosis (high blood pH)
- High blood renin levels
- High aldosterone secretion
- Normal blood pressure
- High urine prostaglandin levels
- Frequent need to drink and urinate
The syndrome is caused by mutations in the Na+/K+/2Cl– cotransporter 2 (NKCC2), as well as in the following related proteins [R]:
- ROMK (a protein that moves potassium out of the cells)
- ClC-Kb (a protein that moves chloride out of the cells)
- CaSR (a protein that detects calcium levels and uses them as a signal to activate electrolyte transporters)
3) Gitelman’s Syndrome
Gitelman’s syndrome is a hereditary disease with similar symptoms to Bartter’s (metabolic alkalosis with low potassium, low chloride, high renin, and high aldosterone levels in the blood), but due to defects in the kidney cells of a different region (distal convoluted tubule). The condition is caused by mutations in the Na+/Cl– cotransporter (NCCT) [R, R].
4) Cystic Tissue Scarring
Cystic tissue scarring is a hereditary disorder characterized by the following symptoms [R]:
- High salt concentration in sweat
- Mucus buildup
- Frequent lung diseases
- Damage in the airways
- Frequent coughing
- Pancreatic failure
- Development of diabetes
- Low bone mineral density
- Kidney failure
- Inability to grow and gain weight (in children)
- Blood clotting disorders
Regarding electrolyte balance, cystic tissue scarring causes low blood levels of chloride, sodium, and potassium, and high levels of bicarbonate [R].
5) Addison’s Disease
Addison’s disease is a rare hereditary disorder in which the glands above the kidneys are defective and produce low levels of the hormones cortisol and aldosterone. The main symptoms of this disorder are [R]:
- Generalized weakness and tiredness
- Loss of appetite
- Weight loss
- Craving for salt
- Darkening of skin areas
- Low blood pressure
- Low blood levels of sodium and chloride
- High blood levels of potassium
Addison’s disease is due to mutations in:
- AIRE (a gene causing autoimmune diseases in several organs) [R]
- ABCD1 (a protein that transports fatty acids) [R]
- DAX-1 (a protein that ensures the correct development of the kidneys and glands above them) [R].
- ALADIN (a protein of the nuclear envelope) [R]
6) Congenital Chloride Diarrhea
Congenital chloride diarrhea is a rare genetic disease characterized by the production of watery diarrhea with high chloride concentration. It causes dehydration, metabolic alkalosis, and low levels of blood chloride, sodium, and potassium. The condition is due to defects in the bowel chloride and bicarbonate transporter SLC26A3 [R, R].
7) Syndrome of Inappropriate Antidiuresis
This syndrome is characterized by reduced water elimination, continued production or action of the antidiuretic hormone vasopressin, and low blood sodium and chloride levels [R].
The disease is caused by activating mutations in the vasopressin receptor AVPR2, which leads to the excessive accumulation of water [R].
Effect of Drugs on Chloride Levels
1) Carbonic Anhydrase Blockers
Carbonic anhydrase II transforms carbon dioxide into bicarbonate. Blocking this enzyme increases chloride accumulation to compensate for the reduction of negative electrolytes. The main blockers are [R]:
- Acetazolamide (used for glaucoma, epilepsy, pressure around the brain, and altitude sickness)
- Methazolamide (used for glaucoma and pressure in the eyes)
- Ethoxzolamide (used for glaucoma, ulcers in the bowel, and as a diuretic)
- Dichlorphenamide (used for glaucoma and as a diuretic)
- Dorzolamide (used for glaucoma and pressure in the eyes)
- Brinzolamide (used for glaucoma and pressure in the eyes)
- Zonisamide (used for epilepsy and Parkinson’s disease)
Some inhibitors of the enzyme that produce prostaglandins during inflammation also inhibit carbonic anhydrase II. Among them, the main ones are [R]:
- Celecoxib (arthritis and menstruation and acute pain)
- Valdecoxib (arthritis and menstruation pain)
- Rofecoxib (arthritis and menstruation pain)
Loop diuretics are drugs acting on a certain region of kidney cells (loop of Henle), where they block the Na+/K+/2Cl– cotransporter. As a result, they reduce the reabsorption of sodium, potassium, and chloride in the kidneys. The main ones are [R]:
- Ethacrynic acid
Thiazides and thiazide-like diuretics increase water elimination by blocking the Na+/Cl– cotransporter, which prevents the absorption of sodium and chloride in the kidneys. The most common ones are [R, R]:
Potassium-sparing diuretics are drugs that increase the elimination of water, sodium, and chloride through the kidneys without causing potassium losses. The main ones are [R]:
- Aldosterone blockers like spironolactone and eplerenone: they prevent the binding of aldosterone (a hormone triggering the production of electrolyte transporters) to its receptor [R].
- Sodium channel blockers like amiloride and triamterene: they directly block sodium absorption channels, thus causing a reduced intake of sodium and chloride [R].
Aldosterone is a hormone that promotes sodium and chloride absorption. Corticosteroid drugs such as cortisone and hydrocortisone bind to the aldosterone receptor and also activate the absorption of these electrolytes [R, R].
However, the long-term use of corticosteroid drugs causes a condition called Cushing’s syndrome in which the glands above the kidneys are damaged and the production of aldosterone and other corticosteroid hormones stops. This causes the loss of sodium and chloride [R, R].
The laxative lubiprostone turns on the chloride channel ClC-2, which secretes chloride to induce the entry of sodium and water into the bowel. Similarly, a herbal laxative (anthraquinone) turns on the chloride secretion channel CFTR [R, R].
Limitations and Caveats
Although the studies were largely human studies, a large number of them were retrospective cohort studies. Because these studies look at existing data, the data may be inaccurate, incomplete, or inconsistently measured. Thus, most of the data collected is only correlational (shows a relationship between the factors) and not causal (determines a cause and effect) [R].
Irregular Chloride Levels?
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