High Anion Gap Metabolic Acidosis in Diabetes Mellitus
The primary acid-base disturbance in diabetes mellitus is high anion gap metabolic acidosis, most commonly from diabetic ketoacidosis (DKA), though mixed acid-base disorders occur frequently and can present with paradoxical alkalemia in up to 23% of cases. 1, 2
Primary Acid-Base Disturbance
High anion gap metabolic acidosis is the hallmark acid-base disorder in diabetes mellitus, characterized by: 3, 1, 2
- pH <7.3 (mild DKA: 7.25-7.30; moderate: 7.00-7.24; severe: <7.00) 2
- Bicarbonate <18 mEq/L (mild DKA) to <10 mEq/L (moderate to severe DKA) 3, 2
- Anion gap >10-12 mEq/L (moderate to severe: >12 mEq/L) 1, 2
- Ketone bodies (beta-hydroxybutyrate and acetoacetate) are the primary organic anions causing the elevated anion gap 1, 4
The pathophysiology involves insulin deficiency and elevated counterregulatory hormones leading to unrestrained lipolysis, hepatic fatty acid oxidation, and ketone body production. 1
Mixed Acid-Base Disorders Are Common
A critical pitfall is assuming all DKA presents with acidemia—mixed disorders are extremely common and alter the clinical presentation: 5, 6
Diabetic Ketoalkalosis (pH >7.4)
- Occurs in 23.3% of DKA cases despite severe ketoacidosis 5
- Results from concurrent metabolic alkalosis (47.2% of cases) and/or respiratory alkalosis (81.1% of cases) superimposed on the underlying high anion gap metabolic acidosis 5
- 34% of these patients have severe ketoacidosis (beta-hydroxybutyrate ≥3 mmol/L) requiring full DKA treatment despite alkalemic pH 5
- Commonly caused by recurrent vomiting (metabolic alkalosis) or hyperventilation (respiratory alkalosis) 6
DKA with Mild Acidemia (pH 7.3-7.4)
- Accounts for 27.8% of DKA presentations 5
- Represents partial compensation or concurrent alkalotic processes 5
Hyperchloremic Metabolic Acidosis
- Develops in 7 of 40 patients (17.5%) with DKA, particularly in better-hydrated patients 6
- Can occur during DKA treatment as ketones are cleared but chloride accumulates from saline resuscitation 3, 4
- Rarely, DKA can present with normal anion gap hyperchloremic acidosis from the outset 7
- May present with high anion gap in atypical cases 8
Concurrent Lactic Acidosis
- Can occur simultaneously with DKA, further contributing to the high anion gap metabolic acidosis 1
- Requires aggressive fluid resuscitation to restore tissue perfusion 1
Diagnostic Approach
When evaluating suspected DKA, always calculate both the anion gap AND the delta-delta ratio (ΔAG/ΔHCO3) to detect mixed disorders: 3, 6
- Anion gap calculation: (Na+) - (Cl- + HCO3-) 3
- Delta-delta ratio: Changes in this ratio indicate concurrent metabolic alkalosis or hyperchloremic acidosis 6
- Hydration status (urea/creatinine ratio) influences which mixed disorder develops 6
Essential laboratory assessment includes: 1
- Arterial blood gases (pH, PaCO2, bicarbonate)
- Serum electrolytes with calculated anion gap
- Serum ketones (beta-hydroxybutyrate preferred)
- Blood glucose
Differential Diagnosis of High Anion Gap Metabolic Acidosis
DKA must be distinguished from other causes of high anion gap metabolic acidosis: 3
- Lactic acidosis (measure blood lactate) 3, 1
- Toxic ingestions: salicylate, methanol, ethylene glycol (calcium oxalate crystals in urine), paraldehyde (characteristic breath odor) 3
- Chronic renal failure (though typically presents as hyperchloremic acidosis early, progressing to high anion gap uremic acidosis in advanced stages) 3, 2
- Alcoholic ketoacidosis: glucose typically normal to mildly elevated (rarely >250 mg/dL) or hypoglycemic, versus DKA with glucose >250 mg/dL 9
- Starvation ketosis: bicarbonate usually not lower than 18 mEq/L 3, 9
Special Considerations
Euglycemic DKA occurs in approximately 10% of cases with glucose <250 mg/dL but still demonstrates high anion gap metabolic acidosis with positive ketones. 1 Risk factors include SGLT2 inhibitor use, pregnancy, reduced food intake, alcohol use, or liver failure. 1