What are the key biochemistry parameters to differentiate between diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) in patients with suspected hyperglycemia?

Biochemical Parameters to Differentiate DKA from HHS

The key biochemical parameters that distinguish DKA from HHS are: plasma glucose (DKA typically >250 mg/dL vs HHS ≥600 mg/dL), arterial pH (DKA <7.30 vs HHS >7.30), serum bicarbonate (DKA <18 mEq/L vs HHS >15 mEq/L), ketone presence (DKA strongly positive vs HHS small/trace), and effective serum osmolality (DKA variable vs HHS ≥320 mOsm/kg). 1

Primary Distinguishing Parameters

Plasma Glucose

• DKA: Typically >250 mg/dL, though can present with euglycemia (especially with SGLT2 inhibitor use) 1, 2
• HHS: ≥600 mg/dL, representing much more severe hyperglycemia 1

Arterial pH

• DKA severity stratification 1, 2:
  • Mild: pH 7.25–7.30
  • Moderate: pH 7.00–7.24
  • Severe: pH <7.00
• HHS: pH >7.30 (minimal to no acidosis) 1

Serum Bicarbonate

• DKA severity stratification 1, 2:
  • Mild: 15–18 mEq/L
  • Moderate: 10 to <15 mEq/L
  • Severe: <10 mEq/L
• HHS: >15 mEq/L 1

Ketone Bodies

• DKA: Strongly positive serum and urine ketones 1
  • Critical point: β-hydroxybutyrate (β-OHB) measurement in blood is the preferred diagnostic method, as it is the predominant ketone in DKA 2
  • Nitroprusside-based tests (urine dipsticks, serum tablets) only detect acetoacetate and acetone, NOT β-OHB, and can be misleading during treatment 2
• HHS: Small or trace ketones 1

Effective Serum Osmolality

• DKA: Variable, not a defining feature 1
• HHS: ≥320 mOsm/kg (calculated as: 2[measured Na (mEq/L)] + glucose (mg/dL)/18) 1

Anion Gap

• DKA severity stratification 1, 3:
  • Mild: >10 mEq/L
  • Moderate/Severe: >12 mEq/L
  • Calculated as: (Na) - (Cl + HCO₃) (mEq/L) 1
• HHS: Variable, may be elevated but less prominent than in DKA 1

Mental Status Correlation

Mental status changes correlate with severity 1:

• DKA:
  • Mild: Alert
  • Moderate: Alert/drowsy
  • Severe: Stupor/coma
• HHS: Typically stupor/coma due to severe hyperosmolality 1

Essential Initial Laboratory Workup

When differentiating these conditions, obtain 1, 2:

• Plasma glucose
• Arterial blood gas (pH, bicarbonate) or venous pH
• Serum electrolytes with calculated anion gap
• Blood urea nitrogen/creatinine
• Serum β-hydroxybutyrate (preferred) or serum/urine ketones
• Serum osmolality
• Complete blood count with differential
• Urinalysis
• Electrocardiogram

Critical Differential Diagnosis Pitfall

Do not confuse DKA with alcoholic ketoacidosis (AKA), which presents with 1, 4:

• Normal to mildly elevated glucose (rarely >250 mg/dL) or even hypoglycemia
• Profound acidosis possible
• Clinical history of alcohol use distinguishes it from DKA

Overlapping Presentations

Important caveat: Features of both disorders can coexist in the same patient, with varying degrees of ketoacidosis and hyperosmolality 5, 6. Both conditions share the common pathophysiology of insulinopenia and severe hyperglycemia, differing primarily in the magnitude of dehydration and degree of ketoacidosis 7.