What is the pathophysiology of hyperosmolar hyperglycemic state (HHS) in type 2 diabetes?

Pathophysiology of Hyperosmolar Hyperglycemic State (HHS)

Core Metabolic Mechanism

HHS results from relative insulin deficiency combined with elevated counterregulatory hormones, but unlike DKA, residual insulin action remains sufficient to prevent significant ketogenesis while being inadequate to control hyperglycemia. 1, 2

The fundamental pathophysiologic cascade involves:

• Insulin deficiency (relative, not absolute) triggers excessive hepatic glucose production and impaired peripheral glucose uptake, leading to progressive hyperglycemia that typically exceeds 600 mg/dL 1, 2
• Residual insulin activity suppresses lipolysis and ketogenesis, explaining why ketones remain minimal or absent (≤3.0 mmol/L) and pH stays ≥7.30—the key distinction from DKA 1, 2
• Counterregulatory hormone elevation (cortisol, catecholamines, glucagon, growth hormone) further amplifies hepatic glucose output and peripheral insulin resistance 3, 4

Progressive Dehydration and Hyperosmolarity

The hallmark of HHS is severe osmotic diuresis leading to profound volume depletion (100-220 mL/kg or approximately 9 liters total body water deficit) and marked hyperosmolarity (≥320 mOsm/kg). 1, 5

The dehydration cascade unfolds as follows:

• Marked hyperglycemia (≥600 mg/dL) exceeds the renal threshold for glucose reabsorption, causing massive osmotic diuresis 1, 2
• Osmotic water loss far exceeds electrolyte losses, resulting in hypernatremia and rising effective osmolality calculated as: 2[Na+ (mEq/L)] + glucose (mg/dL)/18 1
• Hypovolemia reduces glomerular filtration rate, creating a vicious cycle where impaired renal glucose clearance worsens hyperglycemia 3, 6
• Prerenal azotemia develops from decreased renal perfusion 3

Age-Related Vulnerability

Elderly patients are particularly susceptible to HHS due to physiologic changes that impair compensatory mechanisms. 3, 7

Key age-related factors include:

• Reduced glomerular filtration rate and elevated renal threshold for glucose prevent adequate osmotic diuresis correction of hyperglycemia 7
• Impaired thirst mechanisms fail to trigger appropriate fluid intake despite severe dehydration 7
• Increased insulin resistance in muscle and adipose tissue, compounded by abdominal obesity and elevated free fatty acids 3
• Blunted glucose-induced insulin release from pancreatic beta cells 3
• Elevated inflammatory markers (TNF-α, IL-6) that worsen insulin resistance 3

Timeline of Development

HHS evolves gradually over days to weeks, fundamentally different from DKA which develops over hours to days. 1, 2, 8

The prolonged timeline reflects:

• A precipitating illness (infection most common) triggers the cascade in a patient with type 2 diabetes 1, 5
• Progressive hyperglycemia and osmotic diuresis develop over several days 1
• Polyuria, polydipsia, and weight loss precede mental status changes by days 1
• The gradual evolution allows more severe dehydration and higher osmolality than typically seen in DKA 8

Neurological Consequences

Altered mental status correlates directly with the degree of hyperosmolarity and occurs more frequently in HHS than DKA, ranging from lethargy to stupor/coma. 1, 2

The neurological impact results from:

• Hyperosmolarity-induced cellular dehydration in the central nervous system 1, 6
• Osmotic shifts that impair neuronal function proportional to effective osmolality 6
• Mental obtundation severity directly correlates with osmolality levels ≥320 mOsm/kg 1

Systemic Effects of Hyperglycemia

Acute hyperglycemia causes multiple detrimental effects beyond osmotic diuresis. 3

These include:

• Impaired leukocyte function with decreased phagocytosis, bacterial killing, and chemotaxis, predisposing to infections and poor wound healing 3
• Activation of NF-κB and production of proinflammatory cytokines, leading to oxidative stress 3
• Increased vascular permeability and mitochondrial dysfunction 3
• Endothelial dysfunction through suppressed nitric oxide formation and impaired flow-mediated dilation 3

Common Precipitating Factors

Infection is the most common trigger, but multiple factors can precipitate HHS by increasing insulin requirements or impairing glucose control. 1, 5

Major precipitants include:

• Infections (pneumonia, urinary tract infections, sepsis) are the leading cause 1, 5
• Cardiovascular events (myocardial infarction, stroke) particularly in elderly patients 1, 5
• Medications affecting carbohydrate metabolism: thiazide diuretics, corticosteroids, SGLT2 inhibitors, sympathomimetic agents, beta-blockers 3, 1, 5
• Non-adherence to diabetes therapy or newly diagnosed diabetes 1, 5

Critical Pitfall to Avoid

Do not assume HHS requires altered mental status—patients meeting metabolic criteria (glucose ≥600 mg/dL, osmolality ≥320 mOsm/kg) warrant HHS management even if fully alert. 1 The absence of mental status changes does not exclude HHS diagnosis when other criteria are met, and delayed recognition increases the 15% mortality rate 1, 2.