Serum anion gap revisited: a verified reference interval for contemporary use

Abstract

Background: The anion gap (AG) is often used to evaluate acid-base disorders. The reference interval for normal AG is used to differentiate between raised (gap) or normal AG (non-gap) acidosis. Historically accepted AG values may not be valid with the evolution of modern analytical techniques and the reference interval requires revalidation.

Aims: To determine the reference interval for AG based on current laboratory techniques.

Methods: During a health-screening exercise, 284 participants with no major illnesses volunteered surplus blood for analysis. The samples were tested in an internationally accredited clinical laboratory. AG was calculated by [Na⁺ ] - [Cl^- ] - [HCO₃ ^- ] and AG_K by [Na⁺ ] + [K⁺ ] - [Cl^- ] - [HCO₃ ^- ]. The reference interval was determined at 2.5th-97.5th percentiles. Analysis was further undertaken for a subcohort of 156 individuals with no suboptimal health indicators.

Results: Median age was 35 years, body mass index 23.4 kg/m² and the glomerular filtration rate was 106 mL/min/1.73 m² . Median AG was 13 mmol/L and the reference interval for normal AG is 10-18 mmol/L with a 99% level of confidence. Statistically significant differences in AG were detected for sex, race, obesity and serum albumin, but the difference was 1 mmol/L between subgroups. The reference interval was the same for the sub-cohort of 156 individuals. Median AG_K was 17.7 mmol/L and reference interval was 14.6-22.5 mmol/L.

Conclusions: The AG reference interval of 10-18 mmol/L is valid for laboratories with similar reference intervals for electrolytes. Lower values expected with current laboratory techniques were not observed. The median AG of 13 mmol/L may be used to differentiate gap acidosis, non-gap acidosis or mixed acid-base disorders.

Keywords: acid-base; acidosis; anion gap; critical care; physiology.