Hyperchloremic Acidosis – Causes, Symptoms, Treatment

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Hyperchloremic Acidosis is a form of metabolic acidosis associated with a normal anion gap, a decrease in plasma bicarbonate concentration, and an increase in plasma chloride concentration[rx] (see anion gap for a fuller explanation). Although the plasma anion gap is normal, this condition is often associated with an increased urine anion gap, due to the kidney’s inability to secrete ammonia.

Normal physiological pH is 7.35 to 7.45. A decline in pH below this range is called acidosis, an increase in this range is known as alkalosis. Hyperchloremic acidosis is a disease state where acidosis (pH less than 7.35) develops with an increase in ionic chloride. Understanding the physiological pH buffering system is important. The major pH buffer system in the human body is the bicarbonate/carbon dioxide (HCO3/CO2) chemical equilibrium system.


  • H + HCO3 <– –> H2CO3 <– –> CO2 + H2O

HCO3 acts as an alkalotic substance, while CO2 functions as an acid. Therefore, an increase in HCO3 or a decrease in CO2 will make blood more alkalotic. In contrast, a decrease in HCO3 or an increase in CO2 will shift the acid-base balance towards acidic. The pulmonary system regulates CO2 levels through respiration; However, the HCO3 levels are regulated through the renal system with the help of reabsorption. Therefore, hyperchloremic metabolic acidosis is a decline in HCO3 levels in the blood.

Related Testing

When a metabolic acidosis is suspected, it is crucial to calculate the anion gap. This is defined as:

  • Serum anion gap = (Na) – [(HCO3 + Cl)]

Where Na is plasma sodium concentration, HCO3 is plasma bicarbonate concentration, and Cl represents plasma chloride concentration.

The anion gap is an estimation to determine the quantity of ionically active components within the blood that are not routinely measured. Since there are always such components that are not directly measured, we expect this value never to be equal to zero. The primary unmeasured physiologically active ion is albumen. A normal serum anion gap is measured to be 8 to 16 mEq/L. An increase in the anion gap is associated with renal failure, ketoacidosis, lactic acidosis, and ingestion of toxins, whereas a lowered bicarbonate concentration characterizes a normal anion gap acidosis.

Causes of Hyperchloremic Acidosis

The human body is very good at remaining balanced ionically under most scenarios. As a result, with loss of bicarbonate (the negatively charged ion), the negatively charged chloride (Cl) ion is displaced to the extracellular space. This leads to a narrow anion gap, an electrically neutral state without correcting the pathology that induced the acidosis. Likewise, increased Cl may displace bicarbonate intracellularly.  To determine the exact etiology of a narrow anion gap, hyperchloremic acidosis requires another test, the urine anion gap. The urine anion gap is calculated as follows:

  • Urine anion gap = (Na + K) – Cl

Where Na is urine sodium, K is urine potassium, and Cl is urine chloride. The urine anion gap provides an estimate of urinary ammonium (NH4) excretion. The normal renal response to metabolic acidosis is to increase acidic NH4 excretion renally. Therefore, a positive urine anion gap between 20 and 90 mEq/L is indicative of low or normal NH4 excretion, seen in renal causes, such as distal renal tubular acidosis. A negative urine anion gap between -20 and -50 mEq/L is indicative of increased NH4 excretion. This occurs in patients with metabolic acidosis generated by extrarenal causes, such as profuse watery diarrhea. A urine anion gap approaching 0 is indeterminate.

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Hyperchloremic metabolic acidosis is a pathological state that results from bicarbonate loss, rather than acid production or retention. Bicarbonate loss leading to hyperchloremic metabolic acidosis occurs in a variety of ways: gastrointestinal (GI) causes, renal causes, and exogenous causes. GI loss of bicarbonate occurs through severe diarrhea, pancreatic fistula, nasojejunal tube suctioning from the duodenum, and chronic laxative use. Renal sources of hyperchloremic acidosis include proximal renal tubular acidosis, distal renal tubular acidosis, and long-term use of carbonic anhydrase inhibitors.  Exogenous causes include the ingestion of acids such as ammonium chloride and hydrochloric acid and volume resuscitation with 0.9% normal saline.

Gastrointestinal causes

Normally, there is a degree of bicarbonate secreted into the intestinal lumen to allow for neutralization of the acidic environment of food from gastric emptying. Over the distance of the small intestines, this bicarbonate is reabsorbed as bile. However, in pathologies with profuse watery diarrhea, bicarbonate within the intestines is lost through the stool due to increased motility of the gut. This leads to further secretion of bicarbonate from the pancreas and intestinal mucosa, leading to net acidification of the blood from bicarbonate loss. Likewise, pancreatic fistula leads to excessive bicarbonate secretion from the pancreas into the intestines. This excess bicarbonate is ultimately lost in stools. Nasojejunal suctioning removes bicarbonate from the duodenal or jejunal space via direct suctioning of the luminal contents. The overarching theme with these pathologies is the loss of bicarbonate from the gastrointestinal spaces, which leads to an acidotic state in the blood via unopposed hydrogen in the buffering system as above.

Renal causes

Distal renal tubular acidosis (type 1) is a failure of the distal nephron to secrete hydrogen appropriately into the urine. This results in alkalotic urine and acidosis of the blood. Failure to secrete hydrogen directly correlates with the NH4 levels in urine and is able to be deduced via a positive urine anion gap as above. Proximal renal tubular acidosis (type 2) is a pathology where bicarbonate is failed to be reabsorbed appropriately. This leads to the loss of bicarbonate into the urine. The net result is acidosis of blood and alkalotic urine. Both types of renal tubular acidosis are associated with hypokalemia. Carbonic anhydrase inhibitors such as acetazolamide create a medically induced type 2 proximal renal tubular acidosis scenario by inhibiting bicarbonate reabsorption in the proximal nephron.

Exogenous causes

Many of the exogenous causes of hyperchloremic acidosis are logical evaluations. When substances such as ammonium chloride and hydrochloric acid are supplemented into the body, they react with bicarbonate in an attempt to buffer the pH. However, this will deplete bicarbonate stores leading to an acidotic state. Large volume resuscitation with 0.9% normal saline leads to an overload of chloride ions into the blood. As stated previously, chloride and bicarbonate work together to maintain an ionic balance of the cellular space. Hyperchlorhydria forces bicarbonate to move intracellularly to maintain ionic equilibrium, thus reducing the available bicarbonate for the pH buffering system leading to net acidosis.

In general, the cause of a hyperchloremic metabolic acidosis is a loss of base, either a gastrointestinal loss or a renal loss.

Gastrointestinal loss of bicarbonate (HCO
  • Severe diarrhea (vomiting will tend to cause hypochloraemic alkalosis)
  • Pancreatic fistula with loss of bicarbonate rich pancreatic fluid
  • Nasojejunal tube losses in the context of small bowel obstruction and loss of alkaline proximal small bowel secretions
  • Chronic laxative abuse
Renal causes
  • Proximal renal tubular acidosis with failure of HCO
  • Distal renal tubular acidosis with failure of H+
  • Long-term use of a carbonic anhydrase inhibitor such as acetazolamide
  • Ingestion of ammonium chloride, hydrochloric acid, or other acidifying salts
  • The treatment and recovery phases of diabetic ketoacidosis
    Volume resuscitation with 0.9% normal saline provides a chloride load, so that infusing more than 3-4L can cause acidosis
  • Hyperalimentation (i.e., total parenteral nutrition)
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Diagnosis of Hyperchloremic Acidosis

History and Physical

Patients with hyperchloremic acidosis have no effects due to the hyperchloremia necessarily. However, acidosis can have many poor health effects. A headache, lack of energy, nausea, and vomiting are common complaints, however as acidosis worsens, stupor, coma, myocardial instability, or arrest may occur. It is expected to see an increase in respiratory rate as the body attempts to decrease CO2 in compensation; however, in long-standing disease, this may lead to muscle fatigue and respiratory failure.

A physical exam may show altered mental status, tachycardia, tachypnea, accessory muscle use with respiration, neurological deficits, muscular weakness, cardiac arrhythmias, cardiac murmurs, respiratory wheezing, rales, or rhonchi.

Establishing a specific diagnosis

Laboratory diagnosis: Arterial pH is less than 7.35 (unless coupled with super-imposed respiratory alkalosis), standard base excess is less than 3 mEq/L or bicarbonate less than 22 mmol/L, albumin corrected anion gap less than 16 mEq/L.

Plasma [Cl] is usually, but not invariably elevated. [Cl] may be normal, or even low if there is hyponatremia accompanied by normal albumin concentrations. Remember that hyperchloremia without metabolic acidosis can also occur.

Normal lab values

Arterial pH less than 7.35 (unless the metabolic acidosis is coupled with an independent respiratory alkalosis), standard base excess less than -3 mEq/L or bicarbonate less than 22 mmol/L, albumin corrected anion gap less than 16 mEq/L. If these criteria are satisfied and the results are accurate, the patient has a ‘hyperchloremic’ type metabolic acidosis. The
clinical context in which this can occur varies widely.

  • Plasma chloride 100-110 mmol/L
  • Plasma sodium 135-145 mmol/L
  • Plasma albumin 33-47 g/L
  • Arterial pH 7.35-7.45
  • PaCO235-45 mm Hg
  • Arterial plasma bicarbonate 22-27 mmol/L
  • Standard base excess -3 to +3 mEq/L
  • Anion gap 5-15 mEq/L
  • Albumin corrected anion gap 5-15 mEq/L
How do I know this is what the patient has?
  • Provided the criteria are satisfied and the measurements accurate, this is the predominant acid-base abnormality. To make this diagnosis it is not necessary for hyperchloremia to be present.
Confirmatory tests
  • When the underlying cause of a non-anion gap metabolic acidosis is unclear, further investigations may be required. This is rarely necessary in intensive care practice.
  • Essentially the diagnostic sequence depends on the concentration of urinary ammonium, either de novo or after an ammonium chloride load, Urinary ammonium is reduced in RTA types 1 (distal) and 4, but present in appropriate concentrations in RTA type 2 (proximal) or with extra-renal causes of the acidosis, such as saline infusion or enteric losses. Urine ammonium can be assayed formally via a 24 hour collection or its presence detected indirectly by calculating the urinary anion gap. A negative urinary anion gap indicates the presence of significant urinary ammonium concentrations.
Three scenarios

Scenario 1. Appropriate24 hour urinary ammonium excretion (
Negativeurinary anion gap)

The plasma potassium concentration distinguishes the two main possible causes here:

  • Raised plasma potassium supports the diagnosis of Type 4 RTA. Urine pH will be less than 5.5 after an acid load. (If urinary pH >5.5, the diagnosis is more likely a hyperkalemic variant of distal RTA). Further workup then includes plasma renin and aldosterone concentrations (to diagnose mineralocorticoid deficiency or resistance), plasma free cortisol before and after synthetic ACTH (to detect hypoadrenalism), and the investigation of possible underlying nephropathy. Examples of drugs that may cause Type 4 RTA to include ACE inhibitors, heparin, potassium retaining diuretics, and beta-blockers.
  • Normal or low plasma potassium. The diagnosis is most likely to be Type 1 (distal) RTA. In this case, ammonium chloride loading or frusemide administration will fail to acidify urine pH below 5.5. Supportive features include a urine/blood PCO2gradient less than 20 mm Hg after alkali loading or frusemide. Many inherited and acquired conditions can cause distal RTA, including rheumatoid arthritis, systemic lupus erythematosus, primary biliary cirrhosis, renal transplant rejection, post-obstructive uropathy, and primary hyperparathyroidism. Drugs include amphotericin B and lithium carbonate.
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As with any illness, a detailed history and physical exam is the most important initial step in evaluation. Hyperchloremic acidosis due to gastrointestinal bicarbonate loss or medication usage is apparent easily. A complete blood count (CBC) to evaluate for an infectious cause with elevated white blood count and fluid body status with hemoglobin and hematocrit values is useful. A complete metabolic panel is important with attention to sodium, potassium, and chloride levels as these can be used to calculate the anion gap value. Arterial blood gas measurement is needed to determine pH status and to identify that the acidosis is metabolic in origin. The urinary anion gap is an essential measurement in hyperchloremic acidosis to establish the urine ammonium excretion status, as discussed above. Distal renal tubular acidosis will have urinary pH greater than 5.3 and a positive urinary anion gap. In proximal renal tubular acidosis, urinary pH is usually less than 5.3, and the urinary anion gap is variable.

Treatment of Hyperchloremic Acidosis

Patients with hyperchloremic acidosis have no effects due to the hyperchloremia necessarily. However, acidosis can have many poor health effects. A headache, lack of energy, nausea, and vomiting are common complaints. However, as acidosis worsens, stupor, coma, myocardial instability, or arrest may occur. It is expected to see an increase in respiratory rate as the body attempts to decrease CO2 in compensation; however, in long-standing disease, this may lead to muscle fatigue and respiratory failure.

In every case of hyperchloremic acidosis, the primary treatment is aimed at identifying and treating the inciting event of pathology.  If respiratory fatigue and failure occur, these patients will need to be intubated and placed on mechanical ventilation. Hyperventilation of the patient on ventilator control can help reduce the acid load. In gastrointestinal causes, it is essential to administer intravenous (IV) saline to maintain fluid load as patients will easily dehydrate from diarrhea or suctioning of the intestines. Additionally, electrolytes need to be monitored and replenished as applicable. Of specific importance is the potassium level. The acidosis is moderated by supplementing bicarbonate into the saline fluids until the underlying pathology is repaired. In renal tubular acidosis, large quantities of bicarbonate administration may be necessary. If the fluid overload is a concern, diuretics with supplemental potassium may be administered for some effect. If the acidosis is resistant to therapy, it may be necessary to utilize dialysis therapy.

As always, a variety of medications are known to induce hyperchloremic acidosis and should be avoided or used with caution.  Gastrointestinal bicarbonate loss is known to occur with calcium chloride, magnesium sulfate, and cholestyramine use. Proximal renal tubular acidosis is associated with streptozotocin, lead, mercury, arginine, valproic acid, gentamicin, ifosfamide, and outdated tetracycline usage. Distal renal tubular acidosis is associated with amphotericin B, toluene, nonsteroidal anti-inflammatory drugs, and lithium use.


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