Metabolic Biomarkers: Anion Gap

Optimal Takeaways

Measuring the anion gap (AG) is useful in the evaluation of metabolic acidosis and its underlying causes. The AG reflects the difference between positively charged cations and negatively charged anions in the blood. The difference represents the anions not included in the equation such as proteins, lactate, keto acids, and sulfates. 

A high anion gap is associated with metabolic acidosis, inflammation, glucose dysregulation, and thiamine deficiency. A low anion gap may be associated with decreased anionic proteins such as albumin, increased cationic immunoglobulins such as IgG, or unmeasured cations including calcium and magnesium.

Standard Range: 6.00 - 16.00 mEq/L (6.00 - 16.00 mmol/L)

The ODX Range: 7.00 - 12.00 mEq/L (7.00 - 12.00 mmol/L)

Low anion gap may be seen with excess alkali intake, chronic vomiting or GI losses, multiple myeloma, hyperaldosteronism, loss of anionic proteins (e.g., nephrotic syndrome), an increase in cationic proteins, or an increase in unmeasured cations such as calcium or magnesium. Hyperlipidemia may falsely decrease AG. Many drugs can decrease AG as well, including lithium, acetazolamide, spironolactone, and sulindac (Pagana 2021). A low anion gap may be seen with hypoalbuminemia, increased cationic immunoglobulins such as IgG, or intoxication with iodide, lithium, or bromide (Kraut 2007).

High anion gap is associated with metabolic acidosis, inflammation (Farwell 2010), hypertension, insulin resistance (Abramowitz 2012), impaired fasting glucose, diabetes risk, low serum bicarbonate, progression to end-stage renal disease (Zhang 2021), lactic acidosis, diabetic or alcoholic ketoacidosis, starvation, renal failure, renal tubular acidosis, increased GI loss of bicarbonate (e.g., fistulae or diarrhea), and hypoaldosteronism. Many drugs can increase AG including ethanol, methanol, salicylate, and carbonic anhydrase inhibitors (Pagana 2021). Acetaminophen and D-lactate from gut bacteria can also increase anion gap as can massive rhabdomyolysis (Brubaker 2021). Increased anion gap may also be seen with thiamine deficiency due to its manifestation of lactic acidosis (Sriram 2012), hyperphosphatemia, and metabolic alkalosis (Kraut 2007).

Overview

The serum anion gap (AG) is used to assess acid-base disorders. It measures the difference between the sum of positive cations and negative anions in the blood, i.e., [sodium + potassium] – [chloride + bicarbonate] = AG. The difference represents the anions not featured in the equation, e.g., proteins, lactate, keto acids, phosphates, sulfates, and other organic anions (Pagana 2021). If potassium is not used in the equation, then the acceptable range is shifted downward. Normally, as acids build up, serum bicarbonate (HCO3) is able to neutralize them, correct the metabolic acidosis, and maintain a normal blood pH of 7.35-7.45 (Brinkman 2022).

However, if bicarbonate is depleted, blood pH will decrease, and the AG will increase. This indicates anion gap metabolic acidosis in which acid anions other than chloride increase. Anion gap metabolic acidosis, characterized by a normal serum chloride, may be associated with thiamine deficiency, lactic acidosis, diabetic ketoacidosis, uremia, loss of bicarbonate via GI or kidney routes, or ingestion of toxins such as alcohol, methanol, ethylene glycol, or paraldehyde. If a decreased bicarbonate is balanced by an increase in serum chloride, then the condition is considered nongap metabolic acidosis and the AG will be normal (Raymond 2021).

Proteins can have a significant effect on anion gap and should be considered in a clinical assessment. An increase in an anionic (negatively charged) protein such as albumin will increase AG while a decrease or loss in anionic proteins will reduce it. For example, a 1 g/dL decrease in serum protein translates into a 2.5 mEq/L decrease in AG (Pagana 2021). If albumin is low, it may make a high AG appear normal. Therefore, add 2.5 mEq for each 1 g/dL of albumin below 4 to correct the AG accordingly. Interventions for correcting severe anion gap metabolic acidosis (below 7.1 in general or below 6.9 in diabetic ketoacidosis) include sodium bicarbonate, sodium citrate, or potassium citrate (Brubaker 2021).

Evaluation of the population based NHANES study found that an increasing anion gap was associated with increases in WBCs and CRP, highlighting a possible connection between metabolic acidosis, inflammation, and chronic disease. Researchers note that for every 1 mEq/L increase in anion gap, WBC count was increased by 1.5 k/cumm and CRP was increased by 0.11 mg/L (1.8 nmol/L). Elevated anion gap was also associated with higher ferritin, platelet count, and mean platelet volume, as well as increased blood pressure and insulin resistance (Farwell 2010). Another population-based study of 1,192 subjects observed that those with a higher anion gap were more likely to develop impaired fasting glucose and progress to diabetes. Researchers recommend a cut-off of 13.76 and above as predictive of impaired fasting glucose (Zhang 2021).

A higher anion gap and lower bicarbonate were associated with decreased cardiorespiratory fitness in 2,714 young adults participating in the NHANES surveys. Those with an AG of 11.2 or greater had significantly lower serum bicarbonate at 23.3 mEq/L and significantly higher CRP. An interesting evaluation found that consumption of sugar-sweetened beverages was associated with a decrease in serum bicarbonate of 0.36 mEq/L and an increase in AG of 0.69 mEq/L; while diet soft drinks were associated with a decrease in bicarbonate of 0.19 mEq/L and an increase in AG of 0.24 mEq/L. A CRP of 1 mg/dL or above was associated with a significant increase in AG as well (Abramowitz 2012).

References

Abramowitz, Matthew K et al. “Lower serum bicarbonate and a higher anion gap are associated with lower cardiorespiratory fitness in young adults.” Kidney international vol. 81,10 (2012): 1033-1042. doi:10.1038/ki.2011.479

Brinkman, Joshua E. and Sandeep Sharma. “Physiology, Metabolic Alkalosis.” StatPearls, StatPearls Publishing, 18 July 2022.

Brubaker, Ross H., et al. “High Anion Gap Metabolic Acidosis.” StatPearls, StatPearls Publishing, 11 August 2021.

Farwell, Wildon R, and Eric N Taylor. “Serum anion gap, bicarbonate and biomarkers of inflammation in healthy individuals in a national survey.” CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne vol. 182,2 (2010): 137-41. doi:10.1503/cmaj.090329

Kraut, Jeffrey A, and Nicolaos E Madias. “Serum anion gap: its uses and limitations in clinical medicine.” Clinical journal of the American Society of Nephrology : CJASN vol. 2,1 (2007): 162-74. doi:10.2215/CJN.03020906

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 15th ed., Mosby, 2021.

Raymond, Janice L., et al. Krause and Mahan's Food & the Nutrition Care Process. Elsevier, 2021.

Sriram, Krishnan et al. “Thiamine in nutrition therapy.” Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition vol. 27,1 (2012): 41-50. doi:10.1177/0884533611426149

Zhang, Yingchao et al. “A Higher Serum Anion Gap Is Associated with the Risk of Progressing to Impaired Fasting Glucose and Diabetes.” International journal of endocrinology vol. 2021 4350418. 13 Dec. 2021, doi:10.1155/2021/4350418