The Anion Gap (AG) measures the difference between the major measured positive ions (cations) and negative ions (anions) in the blood serum. This calculation reflects the unmeasured charged particles necessary to maintain electrical neutrality in the body. A low Anion Gap (LAG) is a rare laboratory finding, often prompting investigation to rule out technical or physiological causes. In specific, uncommon instances, a truly low Anion Gap can signal an underlying malignancy.
Understanding the Anion Gap and Low Anion Gap
The Anion Gap is calculated using the formula: Sodium (\(\text{Na}^+\)) minus the sum of Chloride (\(\text{Cl}^-\)) and Bicarbonate (\(\text{HCO}_3^-\)) concentrations. The normal range is typically between 4 and 12 milliequivalents per liter (\(\text{mEq/L}\)), though this can vary by laboratory. The gap exists because the calculation only includes the most abundant ions, while total positive and negative charges in the blood remain equal.
The resulting gap represents the concentration of “unmeasured anions,” which are negatively charged particles not included in the standard formula. Albumin, a protein, is the largest contributor to this unmeasured negative charge, accounting for most of the normal anion gap. Therefore, the most common physiological cause of a low Anion Gap is hypoalbuminemia (low albumin levels).
When albumin levels drop, the concentration of unmeasured negative charges decreases, directly lowering the calculated Anion Gap. For every 1 gram per deciliter (\(\text{g/dL}\)) decrease in albumin below normal, the Anion Gap decreases by approximately 2.3 to 2.5 \(\text{mEq/L}\). A truly low Anion Gap can also result from laboratory error or the presence of unmeasured positive ions, which is the mechanism linked to certain cancers.
Cancer-Related Mechanisms Leading to Low Anion Gap
The primary mechanism linking cancer to a low Anion Gap involves the overproduction of abnormal proteins, known as paraproteins or monoclonal immunoglobulins. These paraproteins are produced in large amounts by certain blood cancers and act as “unmeasured cations”—positively charged particles not accounted for in the standard AG formula.
When the concentration of these positively charged paraproteins increases, they effectively reduce the calculated gap by neutralizing unmeasured anions. To maintain electrical neutrality, the body balances the massive introduction of unmeasured positive charge by retaining measured negative ions, specifically chloride and bicarbonate. This results in a measured increase in \(\text{Cl}^-\) and \(\text{HCO}_3^-\), the two negative ions subtracted in the AG formula.
This process often leads to hyperchloremia, where high levels of measured chloride result in an artificially low, or even negative, calculated Anion Gap. This effect is pronounced with Immunoglobulin G (\(\text{IgG}\)) paraproteins, which carry a net positive charge at normal pH. The presence of these highly concentrated, abnormal positive proteins offsets the normal contribution of unmeasured negative charges, creating the appearance of a low Anion Gap.
Specific Malignancies Associated with Low Anion Gap
The malignancies most closely associated with a low Anion Gap are hematological cancers characterized by the excessive production of paraproteins. The cancer most frequently utilizing this mechanism is Multiple Myeloma, a plasma cell malignancy of the bone marrow. In Multiple Myeloma, plasma cells proliferate and secrete a large quantity of a single immunoglobulin type, often \(\text{IgG}\), which causes the unmeasured cation effect.
Another associated condition is Waldenström’s Macroglobulinemia, a rare, slow-growing lymphoma involving the overproduction of monoclonal Immunoglobulin M (\(\text{IgM}\)). Although \(\text{IgM}\) paraproteins are less commonly linked to a low Anion Gap than \(\text{IgG}\), Waldenström’s remains a plasma cell dyscrasia that can cause this finding. A low Anion Gap should prompt investigation for these underlying plasma cell disorders, especially after ruling out common causes like hypoalbuminemia.
Other conditions related to abnormal protein production may also be involved, such as Monoclonal Gammopathy of Undetermined Significance (\(\text{MGUS}\)), a precursor to Multiple Myeloma. Cryoglobulinemia, where abnormal proteins precipitate in cold temperatures, can also be associated with a low Anion Gap due to the proteins’ physical properties and charges. In these cases, the low Anion Gap serves as a specific, though rare, biochemical clue pointing toward a blood cancer actively producing abnormal, positively charged proteins.