Serum anion gap,bicarbonate and biomarkers of inflammation in healthy individuals in a national survey

Background

In vitro data suggest that lower extracellular pH activates the immune system. We conducted a population-based study of the relation between serum acid–base status and inflammation.

Methods

We examined the serum anion gap and serum levels of bicarbonate and inflammatory biomarkers in 4525 healthy adults who participated in the National Health and Nutrition Examination Survey during 1999–2006. We excluded participants who had chronic disease, recent infection and an estimated glomerular filtration rate of less than 60 mL/min per 1.73 m².

Results

The mean values of serum anion gap, bicarbonate level, leukocyte count and C-reactive protein level were all within normal limits. After adjustment for age, sex, ethnic background, body mass index, serum albumin level and other factors, we found that a higher anion gap and lower bicarbonate level were associated with a higher leukocyte count and higher C-reactive protein level. Compared with participants in the lowest quartile of anion gap, those in the highest quartile had a leukocyte count that was 1.0 × 0⁹/L higher and a C-reactive protein level that was 10.9 nmol/L higher (p < 0.01). Compared with participants in the highest quartile of bicarbonate level, those in the lowest quartile had a leukocyte count that was 0.7 × 10⁹/L higher and a C-reactive protein level that was 4.0 nmol/L higher (p ≤ 0.02). A higher anion gap and lower bicarbonate level were also associated with a higher platelet count, a larger mean platelet volume and a higher ferritin level.

Interpretation

A higher serum anion gap and lower bicarbonate level were associated with higher levels of inflammatory biomarkers in a healthy sample of the general population. Further studies are needed to elucidate the relation between acid–base status and inflammation.Higher levels of inflammatory biomarkers are associated with increased mortality and the development of chronic disease. A recent study reported that all-cause mortality increased 11% for every increase of 1.0 × 0⁹/L in leukocyte count above 3.5 × 10⁹/L.¹ Other studies also reported a significant relation between mortality and markers of inflammation.² A higher leukocyte count, C-reactive protein level and mean platelet volume predict the development of cardiovascular disease and cancer.^3–5Despite the importance of low-grade inflammation in the pathogenesis of chronic disease, factors influencing inflammation in apparently healthy individuals are not well delineated. In vitro data suggest that extracellular pH may modulate inflammation. Trevani and colleagues reported that neutrophils were less active at a pH of 7.4 than at a lower pH.⁶ Lower extracellular pH also appeared to increase neutrophil production and delay neutrophil apoptosis. Additional studies have shown that lower extracellular pH activates other components of the immune system, including other immune cells⁷ and the complement system.⁸Existing studies linking acidosis to inflammation have generally examined the impact of acute large reductions in extracellular pH. However, chronic small reductions in pH affect a variety of physiologic processes and may have a substantial impact on inflammation and the development of chronic disease.⁹ For example, we previously reported that small increases in serum anion gap and small decreases in bicarbonate levels in healthy individuals whose acid–base parameters were within normal limits were associated with elevated blood pressure and increased insulin resistance,^10,11 independent of body size and kidney function.We conducted a population-based study of the relation between serum acid–base status and inflammation. We examined the association between serum anion gap and serum levels of bicarbonate and inflammatory biomarkers in healthy individuals who participated in the National Health and Nutrition Examination Survey during 1999–2006.