NORMAL SERUM ANION GAP — Determination of the serum anion gap (AG) is an important step in the differential diagnosis of acid-base disorders and especially metabolic acidosis [1-5]. (See "Approach to the adult with metabolic acidosis", section on 'Physiologic interpretation of the serum anion gap'.)
The serum AG is calculated from the following formula, which represents the difference between the primary measured cation (sodium [Na]) and the primary measured anions (chlorine [Cl] and bicarbonate [HCO3]):
Serum AG = Na - (Cl + HCO3)
Some clinicians also include the serum potassium (K) in the formula; when this is done, the normal range increases by approximately 4 mEq/L:
Serum AG = (Na + K) - (Cl + HCO3)
In large population surveys, such as the National Health and Nutrition Examination Survey, the mean AG is between 11 and 12 mEq/L [6-9]. However, a wide array of instruments are used to determine Na, K, Cl, and HCO3 concentrations; therefore the reference range for the AG varies from one laboratory to another [4,6-11]. As a result of these differences, it is important to determine the normal range for electrolytes and the AG in each laboratory in order to accurately interpret the serum AG.
Albumin, which has a net negative charge, is the single largest (in mEq/L) contributor to the AG. As a result, the baseline AG must be adjusted downward in patients with hypoalbuminemia. The expected AG will fall by approximately 2.5 mEq/L for every 1 g/dL (10 g/L) reduction in the serum albumin concentration [2,12]. Thus, the value for the expected baseline AG must be interpreted with this correction factor when metabolic acidosis increases the AG. Conversely, the expected baseline value for the AG must be adjusted upward using the same correction factor in patients with hyperalbuminemia .
When the AG increases in magnitude as a result of metabolic acidosis, that increase should be compared with the magnitude of the fall in HCO3. This represents the delta AG/delta HCO3 ratio, where delta AG is the patient's value of the AG minus the normal AG, and delta HCO3 is the normal serum HCO3 (ie, 24 mEq/L) minus the patient's serum HCO3. The reciprocal relationship between these measurement changes can be affected by a number of factors including the volume of distribution of the anions and hydrogen ions, renal excretion and/or metabolism of the anions, and the accumulation of unmeasured anions unrelated to acids. In addition, the serum AG may also be increased, decreased, or even negative in a number of conditions other than metabolic acidosis. These issues are discussed separately. (See "Serum anion gap in conditions other than metabolic acidosis".)
DELTA AG/DELTA HCO3 RATIO — The serum AG is elevated in those metabolic acidoses that are due to the accumulation of any strong acid other than hydrochloric acid. The most common causes of acute, high AG acidosis are lactic acidosis and ketoacidosis. The degree to which the AG rises in relation to the fall in bicarbonate (HCO3) varies with the cause of the metabolic acidosis.
Determinants — The addition of an acid such as lactic acid (HL) to the extracellular fluid (ECF) produces the following reaction:
HL + NaHCO3 → NaL + H2CO3 → NaL + CO2 + H2O
If the extracellular space were an isolated compartment, sodium bicarbonate (NaHCO3) was the only buffering salt, and none of the lactate or hydrogen ions were lost into the urine, then the increase in serum lactate concentration (L) and the increase in serum AG would exactly match the decrease in serum HCO3 caused by buffering of hydrogen ions. These opposite changes in the serum AG and HCO3 concentration would result in a delta AG/delta HCO3 ratio of 1:1, and perfect reciprocity would exist between the increase in AG and the decrease in HCO3.
However, several important factors that influence the delta AG/delta HCO3 ratio frequently alter this 1:1 relationship:
●The buffering reaction is not limited to the ECF, and the space of distribution of hydrogen ions is different from that of lactate (or other acid anions) [4,11,13,14]. Some acid anions that remain in the body (eg, not excreted in the urine) are largely restricted to the extracellular space and thereby raise the AG. By contrast, more than 50 percent of the hydrogen ions released from the acids are buffered within the cells and in bone. The proportion of hydrogen ions that are buffered in compartments other than the extracellular space increases as the serum HCO3 falls . When hydrogen ions are buffered within cells and in bone, the serum HCO3 concentration does not fall. Thus, to the extent that this occurs, the serum AG will rise more than the HCO3 concentration will fall. This increases the delta AG/delta HCO3 ratio above 1:1. (See 'The delta AG/delta HCO3 in lactic acidosis' below.)
●The renal excretion of the acid anions and hydrogen ions can occur at different rates. To the extent that acid anions are excreted with sodium or potassium, but not with hydrogen ions or ammonium, the serum AG will decrease without a concomitant increase in the serum HCO3, and this will reduce the delta AG/delta HCO3 ratio below 1:1. This partial conversion of a high AG acidosis to a hyperchloremic (normal AG) acidosis is more common with ketoacidosis than with lactic acidosis. The lactate anion is less likely to be excreted into the urine because of markedly reduced kidney function in patients with lactic acidosis and because the lactate is reabsorbed. By contrast, kidney function usually improves rapidly during the treatment of ketoacidosis, permitting urinary excretion of beta-hydroxybutyrate and acetoacetate anions. (See 'The delta AG/delta HCO3 in ketoacidosis' below.)
Interpretation — The likely cause of a high AG metabolic acidosis is often apparent from the history, examination, and other laboratory tests (eg, lactic acidosis in patients with shock, ketoacidosis in patients with hyperglycemia and uncontrolled type 1 diabetes). However, the delta AG/delta HCO3 ratio can provide additional information in such patients:
●A delta AG/delta HCO3 ratio below 1 suggests one of the following:
•A coexisting normal (or hyperchloremic) AG metabolic acidosis (eg, due to diarrhea).
•A high AG acidosis in which both kidney function is preserved and the acid anion is readily excreted into the urine (eg, ketoacidosis, toluene ingestion, or D-lactic acidosis).
•Patients with renal tubular acidosis of early renal insufficiency can also have a delta AG/delta HCO3 ratio below 1. Such patients have a type 4 renal tubular acidosis due to impaired renal tubule acid (mainly ammonium) excretory function, in addition to the accumulation of acid anions and other unmeasured anions that results from a declining glomerular filtration rate (GFR). However, the ratio will usually increase as kidney function progressively deteriorates. (See 'The delta AG/delta HCO3 in ketoacidosis' below and 'The delta AG/delta HCO3 in other causes of high AG acidosis' below and 'The delta AG/delta HCO3 in patients with mixed metabolic disorders' below.)
●A delta AG/delta HCO3 ratio of 1:1 is consistent with an uncomplicated high AG metabolic acidosis.
●A delta AG/delta HCO3 ratio between 1 and 2 generally occurs with high AG metabolic acidosis, such as lactic acidosis, when kidney function is reduced and the acid anions are, thereby, all retained in the body. However, a ratio between 1 and 2 may also occur when metabolic alkalosis coexists with a high AG metabolic acidosis or when the baseline HCO3 level is elevated as a result of chronic respiratory acidosis.
●A delta AG/delta HCO3 ratio above 2 usually suggests that metabolic alkalosis coexists with a high AG metabolic acidosis or that the baseline HCO3 level is elevated as a result of chronic respiratory acidosis.
The delta AG/delta HCO3 in lactic acidosis — As described in the preceding section, most of the lactate anions that enter the ECF remain in this space because urinary lactate excretion is usually reduced because of hypoperfusion and kidney dysfunction and because most of the filtered lactate is reabsorbed by the renal tubules. Only a small fraction of the lactate that is generated by cellular metabolism remains in the intracellular fluid space; by contrast, more than 50 percent of the hydrogen ions that accompany the lactate are buffered in the cells and bone. The proportion of hydrogen ions buffered by cells and bone is substantially higher than 50 percent if the metabolic acidosis is severe .
The effect of the larger space of distribution of hydrogen ions compared with lactate anions and the low rate of lactate excretion is that the delta AG/delta HCO3 ratio is often greater than 1 in lactic acidosis and is usually approximately 1.6 [3,4,11,13,15,16]. Thus, within several hours, a patient with lactic acidosis and a serum HCO3 concentration of 14 mEq/L (10 mEq/L below normal) should have a serum AG of approximately 26 mEq/L (16 mEq/L above the normal AG if the baseline normal AG value was approximately 10 mEq/L). However, hydrogen ion buffering in cells and bone may take several hours to reach completion [4,15]. Thus, the ratio may initially be approximately 1:1 and then increase with time .
The delta AG/delta HCO3 in ketoacidosis — The delta AG/delta HCO3 ratio in patients with ketoacidosis averages approximately 1:1 upon presentation [13,17,18]. This is in contrast to the average ratio of 1.6 described in the preceding section in lactic acidosis. One reason for this difference is that lactic acidosis is often associated with renal hypoperfusion and increased renal tubule lactate reabsorption. By contrast, kidney function is better maintained in ketoacidosis. Preserved kidney function in patients with ketoacidosis permits urinary excretion of the sodium and potassium salts of ketoacid anions (beta-hydroxybutyrate and acetoacetate). The loss of ketoacid anion salts lowers the AG without affecting the serum HCO3 concentration. Excretion of anions offsets intracellular and bone buffering of protons, thereby reducing the delta AG/delta HCO3 ratio toward 1 [13,17,18].
The rate of ketoacid anion excretion in patients with ketoacidosis depends upon the degree to which glomerular filtration and ECF volume are maintained:
●Patients with impaired kidney function (due to underlying diabetic nephropathy and/or volume depletion) will retain a greater fraction of the ketoacid anions and have a relatively greater rise in the AG in relation to the fall in the serum HCO3 concentration, similar to that seen in hypoperfusion-induced lactic acidosis [1,17,18].
●Patients who maintain relatively normal kidney function can lose large quantities of ketoacids in the urine and may have a delta AG/delta HCO3 ratio below 1 [13,17,18]. (This generates a hyperchloremic component of metabolic acidosis.)
●During inpatient treatment of diabetic ketoacidosis, the extracellular volume is expanded and the GFR usually increases. This leads to the loss of a large amount of ketoacid anions with sodium and potassium and reduces the anion gap with an analogous increase in HCO3 concentration [17,18].
Sodium or potassium ketoacid anion salts represent what may be called "potential HCO3" since these anions can be metabolized to regenerate HCO3. When patients are treated with insulin, ketogenesis is slowed and the ketoacids ("potential HCO3"), which remain in body fluids, are metabolized to generate HCO3. If the ketoacid anions are lost in the urine (with sodium and potassium), the potential HCO3 is lost. In addition, the loss of sodium and potassium into the urine with the ketoacid anions contributes to both ECF volume depletion and potassium depletion.
Patients with salicylate intoxication develop an increased anion gap acidosis that is primarily due to increased lactic acid and ketoacid production . The urinary loss of these anions with sodium and/or potassium leads to a hyperchloremic (normal anion gap) acidosis, which is present in up to 20 percent of such patients. In addition, high salicylate concentrations can cause pseudohyperchloremia, thereby reducing the anion gap .
Thus, almost all patients with diabetic ketoacidosis who have relatively intact kidney function will develop a hyperchloremic (normal AG) metabolic acidosis during the early phase of therapy with saline volume expansion due to the urinary loss of potential HCO3 [13,17,18,21,22]. By contrast, when patients with advanced chronic kidney disease develop ketoacidosis, there will be limited or no excretion of ketoacid anions (potential HCO3) into the urine, and insulin therapy will return the serum HCO3 to values similar to those at baseline. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment", section on 'Treatment'.)
The delta AG/delta HCO3 in other causes of high AG acidosis
Methanol, ethylene glycol, and other alcohol and glycol poisoning — A number of toxic alcohols and glycols can generate a high AG metabolic acidosis. The ingested alcohols and glycols are not acids themselves and will not reduce the HCO3 concentration or increase the AG. Rather, they will increase the measured osmolality of blood and thereby generate an osmolal gap.
However, many of these compounds can be oxidized and thereby generate strong acids. As an example, methanol is sequentially metabolized by alcohol dehydrogenase and aldehyde dehydrogenase to generate acetaldehyde and then formic acid. The generated formic acid will reduce the HCO3 and reciprocally increase the AG. Initially, the delta AG/delta HCO3 will be approximately 1, and the AG increase represents the accumulated formate. However, the subsequent buffering of hydrogen ions by cells and bone will increase the HCO3 concentration, while the renal excretion of some of the formate will reduce the AG. Thus, the initial 1:1 ratio of the delta AG/delta HCO3 may be altered. Similarly, ethylene glycol is metabolized to several strong acids including oxalic acid. (See "Methanol and ethylene glycol poisoning: Pharmacology, clinical manifestations, and diagnosis".)
D-lactic acidosis and toluene inhalation — Filtered D-lactate is poorly reabsorbed by the renal tubules. Hippurate, a metabolite of toluene, is actively secreted. Thus, in D-lactic acidosis and in the acidosis of toluene inhalation (glue sniffing), efficient renal excretion of acid anions will reduce the AG without altering the HCO3 concentration. This will result in a delta AG/delta HCO3 ratio below 1 and, occasionally, a pure hyperchloremic acidosis (ie, metabolic acidosis with a normal AG). This phenomenon is especially common after toluene intoxication, and the disorder may be misdiagnosed as renal tubular acidosis.
However, a high AG acidosis will develop in patients with D-lactic acidosis or toluene intoxication if kidney function is impaired since these acid anions will then be retained and not excreted.
D-lactic acidosis — The sodium-L-lactate cotransporter in the proximal tubule is stereospecific and does not transport D-lactate. Thus, filtered D-lactate is more rapidly excreted in the urine than L-lactate. The delta AG/delta HCO3 ratio in patients with D-lactic acidosis is, therefore, often approximately 1, or less than 1, in contrast to a higher delta AG/delta HCO3 ratio that usually develops with L-lactate acidosis. The pathophysiology and etiology of D-lactic acidosis is discussed elsewhere. (See "D-lactic acidosis".)
Toluene intoxication — A hyperchloremic acidosis (with a normal AG) and marked hypokalemia often occurs in patients with toluene intoxication. Toluene is metabolized to benzoic acid and then to hippuric acid. If kidney function is normal, these anions are readily excreted into the urine as sodium and potassium salts because they are both filtered and actively secreted by the proximal tubules. Thus, most patients with toluene ingestion present with hypovolemia, hypokalemia that is often severe, and a normal AG acidosis . (See "Inhalant misuse in children and adolescents".)
Chronic kidney disease — Patients with early-stage chronic kidney disease often have greater dysfunction of tubular acid excretion (mainly due to reduced ammonium excretion) than dysfunction of acid anion excretion, and this will result in a component of hyperchloremic (normal AG) metabolic acidosis. The delta AG/delta HCO3 ratio is therefore less than 1 [24-27]. This condition is referred to as the renal tubular acidosis of early renal insufficiency. As kidney function deteriorates, a variety of acid anions and other unmeasured anions are retained, and the metabolic acidosis converts to the more typical high AG metabolic acidosis of uremia, often referred to as uremic acidosis [26-28]. (See "Pathogenesis, consequences, and treatment of metabolic acidosis in chronic kidney disease".)
The delta AG/delta HCO3 in patients with mixed metabolic disorders — Some patients have a high AG metabolic acidosis as well as a coexistent hyperchloremic (normal AG) metabolic acidosis (due, for example, to diarrhea) or a coexistent metabolic alkalosis (due, for example, to vomiting). (See "Simple and mixed acid-base disorders".)
●Patients who have both a high AG metabolic acidosis and a hyperchloremic (normal AG) metabolic acidosis typically have a delta AG/delta HCO3 ratio that is less than 1. As an example, diarrhea may generate a hyperchloremic (normal AG) metabolic acidosis as a result of the loss of sodium HCO3 and sodium salts of other organic anions such as lactate, butyrate, and citrate in the stool. However, if severe hypovolemia develops, the AG increases as a result of lactic acidosis, impaired kidney function, hyperphosphatemia, and hemoconcentration of albumin .
●Patients who have both a high AG metabolic acidosis and a condition that raises the serum HCO3 concentration (eg, metabolic alkalosis due to vomiting or diuretic use or a compensatory response to chronic respiratory acidosis) often have a delta AG/delta HCO3 ratio that is higher than expected (ie, more than 1.6:1 in lactic acidosis or more than 1:1 patients with ketoacidosis and preserved kidney function) . This occurs because metabolic alkalosis, or compensation for chronic respiratory acidosis, will increase the HCO3 concentration without altering the high AG.
POTENTIAL SOURCES OF ERROR — The utility of the delta AG/delta HCO3 ratio in patients with a high AG metabolic acidosis is dependent upon several assumptions:
●That the baseline serum AG is known or can be accurately estimated [6-11]. Evaluation of recent blood tests, if available, provides the best means of defining the baseline AG for a specific patient. In addition, the baseline AG must be adjusted downward in patients with hypoalbuminemia (by approximately 2.5 mEq/L for every 1 g/dL [10 g/L] reduction in the serum albumin concentration) [2,12]. (See 'Normal serum anion gap' above.)
●That major changes in the concentration of unmeasured cations such as potassium, calcium, magnesium, or monoclonal proteins that can affect the AG have not occurred . (See "Serum anion gap in conditions other than metabolic acidosis".)
SUMMARY AND RECOMMENDATIONS
●Assuming that the baseline serum anion gap (AG) and HCO3 concentration are known or can be accurately estimated, the delta AG/delta HCO3 ratio (ie, the ratio of the increase in AG above baseline to the decrease in HCO3 below baseline) in a high AG metabolic acidosis (eg, shock-induced lactic acidosis or diabetic ketoacidosis) can be calculated and is usually between 1 and 1.6. (See 'The delta AG/delta HCO3 in lactic acidosis' above.)
●However, a lower value (in which the delta AG is less than expected from the delta HCO3) can be seen in a number of settings:
•In ketoacidosis, D-lactic acidosis, or toluene intoxication, the accumulating organic acid anions can be excreted by the kidney as sodium and/or potassium salts. As a result, in these disorders, the delta AG/delta HCO3 ratio is often below 1, and the serum AG may be normal. (See 'D-lactic acidosis and toluene inhalation' above.)
•Patients with early-stage chronic kidney disease often have relatively well-preserved acid anion excretion but more severe dysfunction of tubular acid (ammonium) excretion. This generates a hyperchloremic metabolic acidosis and a delta AG/delta HCO3 ratio below 1. As the kidney function continues to deteriorate, anion excretion falls and the AG increases. (See 'Chronic kidney disease' above.)
●Some clinical disorders, such as severe diarrhea, can generate a combined high and normal AG acidosis. This is due to the following: a hyperchloremic acidosis resulting from the loss of HCO3 and potential HCO3 salts in the stool, an AG acidosis generated by a combination of lactic acidosis (resulting from hypovolemia and reduced tissue perfusion), an acidosis from reduced kidney function, and the effects of volume contraction on phosphate and albumin. (See 'The delta AG/delta HCO3 in patients with mixed metabolic disorders' above.)
●A higher-than-expected value (ie, delta AG/delta HCO3 ratio above 1.6 with lactic acidosis) usually reflects a mixed acid-base disorder in which a high AG acidosis coexists with a process that elevated the serum HCO3. The high HCO3 concentration may be due to a preexisting or concurrent metabolic alkalosis, as with vomiting or diuretic use, or as compensation for a chronic respiratory acidosis. (See 'The delta AG/delta HCO3 in patients with mixed metabolic disorders' above.)
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