DKA vs HHS: Pathophysiology
Both DKA and HHS share a common pathophysiological foundation of insulin deficiency combined with elevated counterregulatory hormones, but they diverge dramatically in their metabolic consequences—DKA produces severe ketoacidosis from unrestrained lipolysis, while HHS maintains just enough residual insulin to prevent ketosis but not hyperglycemia, resulting in profound hyperosmolarity. 1, 2
Core Pathophysiological Mechanism
Both conditions arise from the same fundamental metabolic derangement: reduction in effective insulin action combined with increased counterregulatory hormones (glucagon, catecholamines, cortisol, and growth hormone) 2. This hormonal imbalance triggers altered metabolism of carbohydrate, protein, and fat, leading to varying degrees of osmotic diuresis, dehydration, ketosis, and acidosis 3.
The Critical Divergence Point
The key pathophysiological distinction lies in the degree of insulin deficiency 2:
In DKA: Absolute insulin deficiency combined with elevated catecholamines results in accelerated lipolysis and excess fatty acid production, leading to beta-oxidation and ketogenesis 2. This produces the hallmark ketoacidosis with pH <7.3, bicarbonate <15 mEq/L, and moderate to severe ketonemia 1, 4.
In HHS: Residual beta-cell function provides just enough insulin to prevent lipolysis but remains inadequate to prevent severe hyperglycemia 2. This explains why HHS patients develop marked hyperglycemia (often >600 mg/dL) and profound hyperosmolarity without significant ketosis 1.
Metabolic Consequences
Carbohydrate Metabolism
Both conditions feature hyperglycemia from three mechanisms 2:
- Increased hepatic glucose production (gluconeogenesis and glycogenolysis)
- Decreased peripheral glucose utilization
- Osmotic diuresis leading to volume depletion
DKA typically presents with glucose >250 mg/dL, while HHS demonstrates much higher levels, often >600 mg/dL 1, 2.
Fat Metabolism (The Defining Difference)
In DKA, absolute insulin deficiency unleashes unrestrained lipolysis 2:
- Adipose tissue releases massive amounts of free fatty acids
- Hepatic beta-oxidation converts these to ketone bodies (β-hydroxybutyrate and acetoacetate)
- Ketone accumulation produces high anion gap metabolic acidosis
- Arterial pH drops below 7.3 with bicarbonate <15 mEq/L 1, 4
In HHS, residual insulin is sufficient to suppress lipolysis 2:
- Minimal ketone body formation
- Little to no acidosis (pH typically >7.3)
- Bicarbonate usually >15 mEq/L 1
Fluid and Electrolyte Derangements
Both conditions produce severe total body deficits, but HHS is more extreme 1:
Water deficits 1:
- DKA: approximately 6 liters (100 mL/kg)
- HHS: approximately 9 liters (100-200 mL/kg)
Electrolyte losses per kg body weight 1:
- Sodium: 7-10 mEq/kg in DKA vs 5-15 mEq/kg in HHS
- Potassium: 3-5 mEq/kg in DKA vs 5-15 mEq/kg in HHS
- Chloride: similar losses in both
- Phosphate, magnesium, calcium: comparable deficits
The osmotic diuresis from severe hyperglycemia drives these losses, with HHS patients experiencing more prolonged hyperglycemia before presentation, explaining their greater fluid deficits 3, 2.
Clinical Presentation Spectrum
Approximately one-third of patients present with mixed features of both DKA and HHS 3. These mixed presentations share pathophysiological elements of both conditions and require treatment tailored to the dominant clinical features 3.
Mental Status
HHS produces more profound alterations in consciousness due to severe hyperosmolarity (effective osmolality often >320 mOsm/kg), ranging from lethargy to coma 1, 2. DKA patients are typically more alert unless severely acidotic 1.
Time Course
HHS develops over days to weeks, allowing more time for severe dehydration and hyperosmolarity to accumulate 2. DKA evolves more rapidly (hours to days) due to the acute metabolic crisis of ketoacidosis 2.
Critical Pathophysiological Pitfalls
The presence of residual insulin in HHS is protective against ketosis but allows more severe hyperglycemia to develop unchecked 2. This explains why HHS patients often present later and sicker, with mortality rates of approximately 15% compared to 3.4-4.6% in DKA 2.
Both conditions represent a spectrum rather than discrete entities 3, 2. The underlying pathophysiology differs only in magnitude of dehydration and degree of ketoacidosis, not in fundamental mechanism 2. This is why treatment principles overlap substantially, with fluid resuscitation critical for both, though insulin is the cornerstone for DKA while fluid replacement is the cornerstone for HHS 3.