What are the key differences between Hyperosmolar Hyperglycemic State (HHS) and Diabetic Ketoacidosis (DKA)?

Differentiating HHS from DKA

The key to distinguishing HHS from DKA lies in five critical biochemical parameters: glucose level (HHS >600 mg/dL vs DKA >250 mg/dL), ketone presence (minimal/absent in HHS vs strongly positive in DKA), pH (HHS >7.30 vs DKA <7.30), serum osmolality (HHS >320 mOsm/kg vs variable in DKA), and time course of onset (HHS develops over days-to-weeks vs DKA within 24 hours). 1

Biochemical Distinctions

Glucose Levels

• HHS presents with markedly elevated plasma glucose >600 mg/dL, reflecting profound hyperglycemia 1, 2
• DKA typically shows plasma glucose >250 mg/dL, which is significantly lower than HHS 1, 3
• Note the critical caveat: euglycemic DKA can occur with SGLT2 inhibitors, presenting with glucose <250 mg/dL while still meeting acidosis criteria 1, 3

Ketone Bodies and Acidosis

• DKA is characterized by strongly positive urine and serum ketones due to unregulated lipolysis and ketogenesis from severe insulin deficiency 1
• HHS shows small or negative ketones because residual insulin is adequate to prevent lipolysis but insufficient to control hyperglycemia 1, 2
• Arterial pH in DKA ranges from <7.0 to 7.30 with serum bicarbonate ≤18 mEq/L 1, 3
• HHS maintains arterial pH >7.30 with serum bicarbonate >15 mEq/L 1, 2

Osmolality and Anion Gap

• Effective serum osmolality is markedly elevated in HHS at >320 mOsm/kg, calculated as 2[measured Na (mEq/L)] + glucose (mg/dL)/18 1, 2
• DKA shows variable osmolality, not necessarily reaching the extreme elevations seen in HHS 1
• The anion gap is elevated (>10-12 mEq/L) in DKA due to accumulation of ketoacids 1
• HHS typically shows variable and not significantly elevated anion gap 1

Clinical Presentation Differences

Time Course of Development

• DKA evolves rapidly, typically within 24 hours, allowing for acute presentation with minimal warning 1
• HHS develops insidiously over several days to weeks, reflecting the slower progression of severe dehydration 1, 4

Mental Status

• Patients with DKA range from alert to drowsy, with stupor/coma only in severe cases 1, 3
• Stupor and coma are much more frequent in HHS, correlating with the degree of hyperosmolality 1, 2
• The degree of mental obtundation in HHS typically correlates with the severity of hyperosmolarity 2

Respiratory Pattern

• Kussmaul respirations (deep, rapid breathing) are characteristic of DKA, representing respiratory compensation for metabolic acidosis 1
• Kussmaul respirations are absent in HHS due to lack of significant acidosis 1

Gastrointestinal Symptoms

• Abdominal pain and vomiting occur in up to 25% of patients with DKA, sometimes with coffee-ground emesis from hemorrhagic gastritis 1
• Abdominal pain is not a typical feature of HHS 1

Pathophysiologic Mechanisms

Insulin Deficiency Patterns

• DKA is triggered by absolute or near-absolute insulin deficiency combined with elevated counterregulatory hormones, leading to uncontrolled lipolysis and ketone body production 1, 5
• HHS is characterized by residual beta-cell function providing enough insulin to suppress lipolysis and prevent ketogenesis, but remaining inadequate to facilitate peripheral glucose utilization 1, 5

Dehydration Severity

• Moderate dehydration occurs in DKA from osmotic diuresis 1
• Profound dehydration is the hallmark of HHS, often more severe than in DKA (total body water deficit approximately 9 liters or 100-220 mL/kg), contributing to the higher mortality 1, 2, 4

Mortality and Prognosis

• The mortality rate for DKA is approximately 5% in experienced centers, with lower rates in younger patients 1, 6
• The mortality rate for HHS remains significantly higher at approximately 15%, reflecting the older age of patients, greater comorbidity burden, and severity of hyperosmolality 1, 6, 5
• Both conditions have worse outcomes at extremes of age (>65 years), in the presence of coma, hypotension, and hypothermia 1, 5

Critical Diagnostic Pitfalls

Euglycemic DKA

• Euglycemic DKA can occur with SGLT2 inhibitors, causing DKA with glucose levels <250 mg/dL, potentially delaying diagnosis if clinicians rely solely on glucose thresholds 1, 3
• Diagnosis requires metabolic acidosis (pH <7.3, bicarbonate <18 mEq/L) and elevated β-hydroxybutyrate despite normal glucose 3

Ketone Measurement

• β-hydroxybutyrate (βOHB) measurement in blood is the preferred method for diagnosing DKA, not nitroprusside-based tests 3
• Nitroprusside methods (urine dipsticks, serum tablets) only detect acetoacetate and acetone, NOT βOHB, which is the predominant ketone in DKA 3
• During treatment, βOHB converts to acetoacetate, making nitroprusside tests falsely suggest worsening ketosis when the patient is actually improving 3

Mixed Presentations

• Features of both disorders with ketoacidosis and hyperosmolality may coexist, particularly in patients with overlapping risk factors 4, 7

Hypothermia as Poor Prognostic Sign

• Hypothermia is a poor prognostic sign, indicating peripheral vasodilation and potentially masking infection 1