Buenos Aires 01 de Agosto del 2020
Anion gap in conditions other than metabolic acidosis
Burton D. Rose,Richard M. Stems
_ Up Date to MAYO -2009
Determination of the plasma anion gap (AG) is primarily used in the differential diagnosis of metabolic acidosis [1,2]. However, the AG also changes in other conditions, a finding that may be of diagnostic importance [1,2]
The plasma AG is calculated from the following formula:
AG = Measured cations - measured anions
Since Na is the primary measured cation and Cl and HCO3 are the primary measured anions:
AG = Na - (Cl + HCO3)
In normal subjects, the AG is between 3 and 11 meq/L (average of approximately 6 meq/L) and is primarily determined by the negative charges on the plasma proteins .
The factors that affect the AG can be most easily appreciated by rewriting the first equation . In addition to being equal to the difference between measured cations and anions, the AG is also equal to:
AG = Unmeasured anions - unmeasured cations
HIGH ANION GAP - An elevated AG can be produced by an increase in unmeasured anions (as in several causes of metabolic acidosis) or by a reduction in unmeasured cations. The latter is usually of minor importance, since hypokalemia, hypocalcemia, or hypomagnesemia will only raise the AG by a few meq/L.
A mild elevation in AG can also occur in metabolic alkalosis . Three factors may contribute to this finding: (1) a rise in the plasma albumin concentration due to extracellular volume depletion; (2) an increase in the number of negative charges per albumin molecule, since the pH is further away from the isoelectric point for albumin of approximately 5.4; and (3) an appropriate alkalemia-induced increase in lactate production in an attempt to lower the pH toward normal.
Additional causes of an increased AG reportedly include the overproduction of an anionic paraprotein and hyperphosphatemia [3,5-7].
LOW ANION GAP - The most common cause of a low anion gap (less than 7 meq/L) is laboratory error . As an example, in one single center study of 67,740 consecutive measurements, a low anion gap was noted in 304 patients (0.8 percent) . Of these, 285 (94 percent) could not be confirmed upon repeat measurement and were therefore attributed to laboratory error.
A verifiably low AG can be induced by a fall in the unmeasured anions (primarily due to hypoalbuminemia) or by a rise in unmeasured cations [3,9]. The latter can occur with hyperkalemia, hypercalcemia, hypermagnesemia, or severe lithium intoxication [1,3,10].
If none of these disorders is present, a serum protein electrophoresis should be obtained to look for a cationic paraprotein that is present in some patients with multiple myeloma [3,11]. Since IgG is commonly cationic, a lower anion gap is more likely to be observed in patients with IgG myeloma . A reduced anion gap has also been reported in patients with polyclonal IgG gammopathy [12,13].
With hypoalbuminemia, the expected normal values for the AG can be adjusted downward in patients. The AG falls by about 2.5 meq/L for every 1 g/dL (10 g/L) reduction in the plasma albumin concentration .
In rare cases, the anion gap has a negative value. This is most often due to a laboratory artifact in severe hypernatremia (at levels above 170 meq/L, the true concentration of sodium is underestimated), marked hyperlipidemia (where light scattering in the colorimetric assay can result in marked overestimation of the plasma chloride concentration, occasionally to above 200 meq/L), or bromide intoxication [3,14-16].
The last problem may be seen in patients taking pyridostigmine bromide for myasthenia gravis and some herbal medications [3,15,16]; it does not occur with Bromo-SeltzerTM which no longer contains bromide . In several of the commonly used laboratory assays for chloride, there is a greater affinity for bromide; as a result, each meq of bromide may be measured as 2 to 3 meq of chloride, leading to overestimation of the plasma chloride concentration and a low or even negative anion gap. As an example, the average anion in patients taking physiologic doses of pyridostigmine bromide is 4 meq/L, 8 meq/L lower than in normal subjects .
- 1. Gabow, PA. Disorders associated with an altered anion gap. Kidney Int 1985; 27:472.
- 2. Rose, BD, Post, TW, Clinical Physiology of Acid-Base and Electrolyte Disorders, 5thed, McGraw-Hill, New York, 2001, pp. 583-588.
- 3. Kraut, JA, Madias, NE. Serum anion gap: its uses and limitations in clinical medicine. Clin J Am Soc Nephrol 2007; 2:162.
- 4. Madias, NE, Ayus, JC, Adrogue, HJ. Increased anion gap in metabolic alkalosis: The role of plasma-protein equivalency. N Engl J Med 1979; 300:1421.
- 5. Murray, T, Long, W, Narins, R. Multiple myeloma and anion gap. N Engl J Med 1975: 292:574.
- 6. Thatte, L, Oster, JR, Singer, I, et al. Review of the literature: severe hyperphosphatemia. Am J Med Sci 1995; 310:167.
- 7. Kirschbaum, B. The acidosis of exogenous phosphate intoxication. Arch Intern Med 1998; 158:405.
- 8. Goldstein, RJ, Lichtenstein, NS, Souder, D. The myth of the low anion gap. JAMA 1980; 243:1737.
- 9. Figge, J, Jabor, A, Kazda, A, Fenci, V. Anion gap and hypoalbuminemia. Crit Care Med 1998; 26:1807.
- 10. Kelleher, SP, Raciti, A, Arbeit, LA. Reduced or absent serum anion gap as a marker for severe lithium carbonate intoxication. Arch Intern Med 1986; 146:1839.
- 11. De Troyer, A, Stolarczyk, A, de Beyl, DZ, Stryckmans, P. Value of anion-gap determination in multiple myeloma. N Engl J Med 1977; 296:858.
- 12. Qujeq, D, Mohiti, J. Decreased anion gap in polyclonal hypergammaglobulinemia. Clin Biochem 2002; 35:73.
- 13. Keshgegian, AA. Decreased anion gap in diffuse polyclonal hypergammaglobulinemia. N Engl J Med 1978; 299:99.
- 14. Graber, ML, Quigg, RJ, Stempsey, WE, Weis, S. Spurious hyperchloremia and decreased anion gap in hyperlipidemia. Ann Intern Med 1983; 98:607.
- 15. Faradji-Hazan, V, Oster, JR, Fedeman, DG, et al. Effect of pyridostigmine bromide on serum bicarbonate concentration and the anion gap. J Am Soc Nephrol 1991; 1:1123.
- 16. Wacks, I, Oster, JR, Perez, GO, Kett, DH. Spurious hyperchloremia and hyperbicarbonatemia in a patient receiving pyridostigmine bromide therapy for myasthenia gravis. Am J Kidney Dis 1990; 16:76.