Hyperosmolar Hyperglycemic State: Pathophysiology, Clinical Manifestations, and Management Considerations

Metabolic Mechanisms

Relative insulin deficiency in type 2 diabetes drives excessive hepatic glucose production and impaired peripheral uptake, producing severe hyperglycemia typically > 600 mg/dL, while enough residual insulin suppresses ketogenesis (ketones ≤ 3 mmol/L, pH ≥ 7.30), distinguishing HHS from DKA. 1
Elevated counter‑regulatory hormones (cortisol, catecholamines, glucagon, growth hormone) further increase hepatic glucose output and peripheral insulin resistance. 2

Massive osmotic diuresis leads to profound volume depletion (≈ 100–220 mL/kg, ~9 L total body water deficit) and serum osmolality ≥ 320 mOsm/kg. 1
Hyperglycemia above the renal glucose‑reabsorption threshold causes osmotic water loss that exceeds electrolyte loss, producing hypernatremia; effective osmolality is calculated as 2 [Na⁺] + glucose/18. 1
Resulting hypovolemia lowers glomerular filtration rate, creating a feedback loop that worsens hyperglycemia. 2
Decreased renal perfusion precipitates prerenal azotemia. 2

Older adults have reduced renal clearance, heightened insulin resistance, and elevated inflammatory cytokines (TNF‑α, IL‑6), increasing susceptibility to HHS. 2

HHS develops gradually over days to weeks, often triggered by an acute illness such as infection in a patient with type 2 diabetes. 1

Altered mental status correlates with the degree of hyperosmolarity; effective osmolality ≥ 320 mOsm/kg is associated with lethargy to coma. 1

Impaired leukocyte function (reduced phagocytosis, bacterial killing, chemotaxis) heightens infection risk. 2
Activation of NF‑κB and pro‑inflammatory cytokine release cause oxidative stress. 2
Increased vascular permeability and mitochondrial dysfunction contribute to organ injury. 2
Endothelial dysfunction via reduced nitric‑oxide production impairs flow‑mediated dilation. 2

Infections (e.g., pneumonia, urinary‑tract infection, sepsis) are the leading trigger. 1
Cardiovascular events (myocardial infarction, stroke), especially in the elderly. 1
Medications that raise glucose levels or impair insulin action: thiazide diuretics, systemic corticosteroids, SGLT2 inhibitors, sympathomimetic agents, beta‑blockers. 2
Non‑adherence to diabetes therapy or newly diagnosed diabetes. 1

Absence of altered mental status does not exclude HHS; patients meeting metabolic criteria (glucose ≥ 600 mg/dL, osmolality ≥ 320 mOsm/kg) require HHS management, and delayed recognition raises mortality to ≈ 15 %. 1

Acute myocardial infarction frequently precipitates HHNK, especially in older adults with pre‑existing coronary artery disease. 3
Cerebrovascular accidents (stroke) commonly trigger HHNK and complicate management because anti‑edema therapy can conflict with aggressive fluid resuscitation. 3

Thiazide diuretics increase insulin resistance and promote volume depletion through osmotic diuresis, heightening HHNK risk. 4
Systemic corticosteroids raise counter‑regulatory hormone levels and directly impair glucose metabolism, contributing to HHNK development. 4
Beta‑blockers blunt counter‑regulatory responses and can mask hypoglycaemic symptoms, increasing the likelihood of HHNK. 4

Elderly individuals are especially susceptible to HHNK due to a combination of reduced renal clearance, impaired thirst mechanisms, heightened insulin resistance, diminished β‑cell insulin release, elevated inflammatory cytokines, and increased abdominal adiposity. 3, 5
Reduced glomerular filtration rate in older adults impairs glucose excretion, worsening hyperglycaemia. 3
Impaired thirst perception in the elderly limits fluid intake despite severe dehydration, facilitating HHNK onset. 3
Aging‑related increase in peripheral insulin resistance (muscle and adipose tissue) predisposes older patients to HHNK. 3, 5
Diminished glucose‑stimulated insulin secretion from pancreatic β‑cells in the elderly reduces endogenous glucose control. 3, 5
Higher circulating inflammatory markers (e.g., TNF‑α, IL‑6) in older adults exacerbate insulin resistance, raising HHNK risk. 3, 5
Greater prevalence of abdominal obesity and elevated free fatty acids in the elderly further impairs insulin sensitivity. 3, 5

The typical hyperglycaemic symptoms (polyuria, polydipsia) are often absent in older patients because the renal threshold for glycosuria rises with age and thirst mechanisms are blunted, leading to delayed HHNK diagnosis. 3, 5
Elderly patients frequently present with non‑specific signs such as weight loss, fatigue, or confusion, which are mistakenly attributed to aging or cognitive decline, further postponing appropriate treatment. 3, 5