What is the clinical significance of hyperglycemia with an elevated anion gap?

Clinical Significance of Glucose 135 mg/dL with Anion Gap 15 mEq/L

A glucose of 135 mg/dL with an anion gap of 15 mEq/L indicates mild metabolic acidosis that requires immediate investigation for diabetic ketoacidosis (including euglycemic DKA), lactic acidosis, or other causes of high anion gap acidosis, even though the glucose appears relatively controlled. 1

Immediate Diagnostic Workup Required

The anion gap of 15 mEq/L is elevated (normal 8-12 mEq/L) and demands urgent evaluation regardless of the seemingly controlled glucose level 1, 2. This combination is particularly concerning because:

• Obtain arterial or venous blood gas immediately to assess pH and bicarbonate levels—venous pH is acceptable and typically 0.03 units lower than arterial 1
• Measure serum beta-hydroxybutyrate and urine ketones to evaluate for diabetic ketoacidosis, as this is the most common cause of elevated anion gap in diabetic patients 1, 3
• Check serum lactate to rule out lactic acidosis from tissue hypoperfusion or medication effects 1
• Obtain complete metabolic panel including BUN and creatinine to assess for uremic acidosis 1
• Measure serum osmolality with calculated osmolar gap if toxic ingestion is suspected 1

Critical Differential Diagnosis

Euglycemic Diabetic Ketoacidosis (Most Important)

If the patient is taking an SGLT2 inhibitor, euglycemic ketoacidosis must be strongly suspected, as these medications cause ketoacidosis even with glucose levels <200 mg/dL 1, 4. This represents a dangerous diagnostic pitfall where clinicians may dismiss DKA due to "controlled" glucose 4.

• Euglycemic DKA presents with the same metabolic acidosis and ketosis as classic DKA but with relatively normal glucose (typically <250 mg/dL, and sometimes <200 mg/dL) 4
• Discontinue SGLT2 inhibitors immediately if present, as cessation reduces risk of high anion gap acidosis 1
• Precipitating factors include infection, trauma, surgery, strenuous exercise, fasting, alcohol intake, and acute vascular events 4

Other High Anion Gap Causes

• Lactic acidosis from tissue hypoperfusion, sepsis, or medications (metformin in renal dysfunction) 1, 3
• Uremic acidosis from acute or chronic kidney injury 1, 3
• Starvation ketosis can occur even with relatively normal glucose 1
• Toxic ingestions (methanol, ethylene glycol, salicylates) require osmolar gap calculation 1, 2

Management Algorithm Based on pH and Bicarbonate

If pH >7.3 and Bicarbonate ≥18 mEq/L (Mild Acidosis)

• Monitor closely with repeat electrolytes, glucose, and venous pH every 2-4 hours 1
• Identify and treat underlying cause: discontinue SGLT2 inhibitors, address dehydration, treat infection 1
• No bicarbonate therapy needed at pH >7.3 1
• Track anion gap normalization to ≤12 mEq/L as the most reliable marker of treatment response 1, 2

If pH 7.0-7.3 or Bicarbonate <18 mEq/L (Moderate Acidosis)

• Initiate aggressive treatment immediately: fluid resuscitation with isotonic crystalloid, continuous IV regular insulin infusion, and potassium replacement 1
• Monitor potassium closely as insulin drives potassium intracellularly and hypokalemia occurs in approximately 50% of cases during treatment 5
• Severe hypokalemia (<2.5 mEq/L) is associated with increased inpatient mortality 5
• Continuous insulin infusion is the preferred regimen for hyperglycemic crises 5

If pH <7.0 (Severe Acidosis)

• Consider sodium bicarbonate administration in addition to all aggressive measures above 1
• Transfer to ICU for continuous monitoring and management 5

Common Diagnostic Pitfalls to Avoid

• Never dismiss elevated anion gap based on "controlled" glucose alone—euglycemic DKA is a real and dangerous entity, particularly with SGLT2 inhibitors 1, 4
• Rare cases of DKA can present with normal anion gap due to hyperchloremic acidosis, so normal anion gap does not exclude DKA if clinical suspicion is high 6
• Always ask about SGLT2 inhibitor use (empagliflozin, dapagliflozin, canagliflozin) in any diabetic patient with elevated anion gap 1, 4
• Concomitant acute kidney injury can complicate the picture by contributing to both uremic acidosis and impaired ketone clearance 2
• Check for co-ingestions (lithium, barium) that can artificially lower anion gap and mask severity 2

Monitoring Parameters During Treatment

• Anion gap provides the most reliable marker of treatment response regardless of specific ketone species 1
• Track normalization to anion gap ≤12 mEq/L, glucose <200 mg/dL, bicarbonate ≥18 mEq/L, and venous pH >7.3 1
• Recheck every 2-4 hours until stabilized 1, 2
• Monitor potassium levels closely to prevent life-threatening hypokalemia, respiratory paralysis, and ventricular arrhythmias 5, 7