What are the common causes of an elevated anion gap and a low anion gap?

Causes of Anion Gap Abnormalities

Elevated Anion Gap

An elevated anion gap (>12 mmol/L) indicates high anion gap metabolic acidosis and requires immediate evaluation for life-threatening conditions including diabetic ketoacidosis, lactic acidosis, toxic ingestions, and uremic acidosis. 1, 2, 1

Common Causes of Elevated Anion Gap

The primary causes of elevated anion gap metabolic acidosis can be systematically approached using clinical context and specific laboratory findings:

Diabetic Ketoacidosis (DKA)

• Anion gap >10 mmol/L in mild DKA, >12 mmol/L in moderate-to-severe DKA 1
• Accompanied by hyperglycemia (>250 mg/dL), positive ketones, and arterial pH <7.3 1, 2
• Serum bicarbonate <15 mEq/L with variable effective serum osmolality 1

Toxic Ingestions

• Salicylate, methanol, ethylene glycol, and paraldehyde poisoning produce high anion gap acidosis 1, 2
• Ethylene glycol suggested by calcium oxalate and hippurate crystals in urine 1
• For ethylene glycol poisoning with anion gap >27 mmol/L, extracorporeal treatment is recommended; for anion gap 23-27 mmol/L, it is suggested 3
• Paraldehyde identified by characteristic strong odor on breath 1
• These low-molecular weight compounds produce both osmolar gap and anion gap acidosis 1

Lactic Acidosis

• Results from decreased oxygen delivery or defective oxygen utilization 4
• Associated with high mortality and requires measurement of blood lactate 1
• Metformin use should be sought in clinical history 1

Chronic Renal Failure

• Produces mild acidosis from decreased ammonia secretion and retention of unmeasured anions 4
• More typically presents as hyperchloremic acidosis rather than high anion gap acidosis 1, 2
• Common cause of increased anion gap in hospitalized patients 5, 6

Other Common Causes in Hospitalized Patients

• Hypertensive disease, malignant neoplasms, heart disease, and diabetes mellitus 5
• Congestive heart failure 6

Clinical Significance of Anion Gap Values

Mean and range of increased anion gap: 16 mmol/L (central 90% range: 13-20 mmol/L) with modern ion-selective electrode methods 5

• Anion gap >24 mmol/L is rare and strongly suggests metabolic acidosis or laboratory error 5
• Values exceeding 30 mmol/L are uncommon and warrant verification 6
• Albumin-corrected anion gap (ACAG) >24.54 predicts secondary acute myocardial injury in acute poisoning cases 7

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Low Anion Gap

A low anion gap (<3 mmol/L with modern methods) should prompt evaluation for hypoalbuminemia, paraproteinemia (multiple myeloma), laboratory error, or bromide intoxication. 5, 8, 9

Common Causes of Low Anion Gap

Hypoalbuminemia

• Most common cause of decreased anion gap 6, 8
• Associated with nephrotic syndrome, liver cirrhosis, intestinal obstruction, and severe hemorrhage 5, 6
• Results from loss of negatively charged albumin, reducing unmeasured anions 6, 8
• However, not all hypoalbuminemic patients have decreased anion gap 6

Paraproteinemia

• IgG multiple myeloma and monoclonal gammopathy produce low anion gap from unmeasured cation contribution by paraprotein 5, 10, 8
• Diffuse polyclonal hypergammaglobulinemia (>3 g/dL) also significantly lowers anion gap 10
• Mean anion gap of 8.7 mEq/L in patients with immunoglobulin >4 g/dL versus 11.9 mEq/L in controls 10
• Independent of specific immunoglobulin class contribution 10

Laboratory Error and Specimen Issues

• High incidence of anion gap <2 mmol/L should trigger quality control review 5, 11
• Specimen contamination or interference 11
• Negative anion gap values (-1 or less) are rare and warrant investigation 11

Other Causes

• Bromide intoxication (bromism) 8, 9
• Extreme hyperkalemia 11

Clinical Significance

Mean and range of decreased anion gap: 3 mmol/L (central 90% range: 2-4 mmol/L) 5

• Values <2 mmol/L are rare (incidence 2.9% among hospitalized patients) 5, 6
• Baseline low anion gap may mask identification of concurrent high anion gap metabolic acidosis 8, 9
• Can provide valuable diagnostic clues for life-threatening intoxications or occult neoplasms 8, 9

Important Pitfall

The reference range for anion gap has decreased from 8-16 mmol/L to 3-11 mmol/L (or 5-12 mmol/L) due to ion-selective electrode methodology, but many clinicians still use outdated reference values, leading to misinterpretation 5, 8