As shown in Table 27.4, the normal reference range for AG is 12 ± 4. This value was derived from older methods of electrolyte determinations using colorimetry and flame photometry. With the introduction of ion-selective electrode methodology, the normal AG levels are much lower, ranging from 3 to11. These low values are related to high Cl⁻ determination. Variations in normal values of AG are frequently seen from laboratory to laboratory, and the clinician should follow his or her laboratory values for proper interpretation of AG in clinical medicine.

It is always debated whether or not AG should be calculated using measured serum Na⁺ or corrected Na⁺ in a patient with severe hyperglycemia. It is suggested that only measured Na⁺ should be used for AG, and not the corrected Na⁺. This suggestion is based on the assumption that Cl⁻ and HCO₃ ⁻ are equally diluted as Na⁺ by movement of water from inside to outside of the cell caused by hyperglycemia. When AG is calculated using only corrected Na⁺ and not corrected Cl⁻ and HCO₃ ⁻ for hyperglycemia, the AG is overestimated with the implication of underlying high AG metabolic acidosis. Na⁺ decreases by 1.6 mEq/dL for each increase in 100 mg/dL glucose above normal glucose levels, but no such number is given for either Cl⁻ or HCO₃ ⁻. It is, thus, emphasized that only measured Na⁺ should be used to calculate the serum AG.

Traditionally, the AG is classified into high, normal, or low AG metabolic acidosis. High AG is due to accumulation of unmeasured anions, whereas normal AG is usually related to high Cl⁻ level. Low AG implies a substantial decrease in unmeasured anions or an increase in unmeasured cations.

The mnemonic to remember AG is GOLD MARK (Glycols (ethylene and propylene), Oxoproline (pyroglutamic acid), L-lactate, D-lactate, Methanol, Aspirin, Renal failure, Ketoacidosis). Table 27.5 shows various causes of high AG metabolic acidoses.

Table 27.6 shows causes for normal (hyperchloremic) AG metabolic acidoses

Other than laboratory error, the most common cause of low AG acidosis in hospitalized patients is hypoalbuminemia. As shown in Table 27.4, albumin is the major contributor for unmeasured anions and thus AG. A decrease in albumin from 4.0 to 2.0 g/dL reduces AG by 5.0 mEq/dL (for each gram decrease in albumin from normal value, the AG decreases by 2.5). Thus, a patient with chronic kidney disease (CKD) stages 4–5 and low albumin may seem to have a normal AG metabolic acidosis, but when corrected for normal albumin the acid–base disorder is a high AG metabolic acidosis . It should be remembered that hypoalbuminemia reduces AG, and therefore, it is necessary to establish a new baseline AG for each patient. For example, the above patient with CKD stages 4–5 has a calculated AG of 12, albumin of 2.0 g/dL and the laboratory reference AG of 10. This shows that the patient has only 2 excess anions (12–10 = 2). However, when AG is adjusted downwards and corrected for hypoalbuminemia, the baseline AG is 5 (10–5 = 5), and the excess anions are 7 (12–5 = 7) instead of 2. Thus, albumin levels should be obtained whenever an ABG is ordered, particularly in critically ill patients.

In addition to a decrease in unmeasured anions, an increase in unmeasured cations causes low AG. For example, a patient with IgG myeloma will have low AG because IgG molecules carry a positive charge at a pH of 7.4. Also, ingestion of bromide or iodine-containing medications or intoxication of these halides can raise the concentration of unmeasured anions, and lower AG due to measurements of these halides as Cl⁻. Occasionally, patients with severe hypertriglyceridemia may present with low AG due to a different laboratory measurement.

Not only is AG useful in the classification of metabolic acidosis but it is also indirectly helpful in analyzing mixed acid–base disorders . In a simple or uncomplicated high AG metabolic acidosis such as ketoacidosis, the increase in AG above normal (called ∆AG) is equal to the decrease in HCO₃ ⁻ from normal value (called ∆HCO₃). In other words, for every 1 mEq/L rise in the AG, there is a concomitant fall of 1 mEq/L in HCO₃ ⁻. This is defined as ∆AG/∆HCO₃ ⁻. In a simple high AG metabolic acidosis, the ∆AG/∆HCO₃ ⁻ ratio is 1. Any significant deviation from 1 is indicative of a mixed acid–base disorder. For example, a patient with diarrhea typically develops a hyperchloremic or normal AG metabolic acidosis. In this condition, the decrease in HCO₃ ⁻ results in a reciprocal increase in Cl⁻ so that the AG does not change. As a result, the ∆AG/∆HCO₃ ⁻ ratio is 0. If this patient develops hypotension and subsequent lactic acidosis, the HCO₃ ⁻ decreases even further. In other words, the ∆HCO₃ ⁻ is greater than ∆AG, and the ∆AG/∆HCO₃ ⁻ ratio is < 1 (above 0 but below 1), indicating a mixed high and normal AG metabolic acidosis.