What are the causes of high serum osmolality?

Causes of High Serum Osmolality

High serum osmolality (>300 mOsm/kg) results from accumulation of osmotically active solutes—primarily hyperglycemia, hypernatremia, exogenous osmotic agents (mannitol), or toxic alcohol ingestions.

Primary Causes by Category

Hyperglycemic States

• Hyperosmolar Hyperglycemic State (HHS) is characterized by serum osmolality >320 mOsm/kg with plasma glucose >600 mg/dL, representing the most severe hyperglycemic cause 1
• Diabetic Ketoacidosis (DKA) causes variable serum osmolality elevation (typically <320 mOsm/kg) with plasma glucose >250 mg/dL 1
• The pathophysiology involves insulin deficiency coupled with elevated counterregulatory hormones (glucagon, catecholamines, cortisol, growth hormone), leading to increased hepatic glucose production and impaired peripheral glucose utilization 1

Hypernatremia and Dehydration

• Low-intake dehydration (inadequate fluid consumption) raises serum osmolality >300 mOsm/kg through concentration of all serum components, particularly sodium, chloride, bicarbonate, and potassium 1
• This threshold (>300 mOsm/kg) doubles the risk of 4-year disability and significantly increases mortality in older adults 2
• Diabetes insipidus (central or nephrogenic) produces inappropriately dilute urine (<200 mOsm/kg) combined with high-normal or elevated serum sodium, which is pathognomonic for this condition 3

Exogenous Osmotic Agents

• Mannitol administration directly increases serum osmolality and can cause hyperosmolarity, particularly with accumulation due to insufficient renal excretion 4
• Mannitol-induced hyperosmolarity may result in CNS toxicity (confusion, lethargy, coma) from intracellular dehydration within the CNS, especially with impaired renal function 4
• At high concentrations, mannitol crosses the blood-brain barrier and interferes with cerebrospinal fluid pH maintenance 4

Toxic Alcohol Ingestions

• Methanol, ethylene glycol, diethylene glycol, propylene glycol, or isopropanol ingestion causes increased serum osmolality and osmolal gap 5
• These low-molecular weight organic compounds produce an osmolar gap (difference between measured osmolality and calculated osmolarity) in addition to potential high-anion-gap metabolic acidosis 1, 5
• The osmolal gap increase can occur with or without metabolic acidosis depending on baseline osmolal gap, molecular weight of the alcohol, and stage of alcohol metabolism 5

Diagnostic Approach

Calculate the Osmolal Gap

• Measured serum osmolality minus calculated osmolarity identifies unmeasured osmotically active substances 6, 5
• Use the equation: osmolarity = 1.86 × (Na⁺ + K⁺) + 1.15 × glucose + urea + 14 (all in mmol/L) when direct measurement is unavailable 1, 3
• An elevated osmolal gap suggests toxic alcohol ingestion or exogenous osmotic agents not included in standard calculations 6, 5

Interpret Serum Osmolality in Context

• Check serum glucose and urea levels to determine if they account for the elevated osmolality; if elevated, these should be normalized by treatment before attributing hyperosmolality to dehydration 1
• In low-intake dehydration, serum osmolality >300 mOsm/kg often occurs despite all major components (sodium, potassium, urea, glucose) remaining within normal range—small rises within normal range in all components cause the elevation 1
• Serum sodium is the major determinant of serum osmolality under normal conditions 6

Distinguish Effective vs. Ineffective Osmoles

• Effective osmolality (tonicity) is created by solutes capable of creating an osmotic gradient across cell membranes (sodium, glucose, mannitol) 6
• Urea is an ineffective osmole that freely crosses cell membranes and does not cause water shifts, though it contributes to measured osmolality 6

Critical Pitfalls to Avoid

• Do NOT rely on clinical signs like skin turgor, mouth dryness, weight change, or urine color to assess dehydration in older adults—these are highly unreliable 1, 3
• Do NOT assume normal individual components exclude hyperosmolality—in dehydration, small increases in multiple components within their normal ranges collectively raise osmolality 1
• Do NOT overlook renal function when interpreting osmolality, as impaired renal excretion increases risk of mannitol accumulation and hyperosmolarity 4
• Mannitol interferes with laboratory tests: high concentrations cause falsely low inorganic phosphorus results and false positive ethylene glycol results 4

Additional Differential Considerations

• Diabetic ketoacidosis, alcoholic ketoacidosis, acute kidney injury, chronic kidney disease, and lactic acidosis can all cause high-anion-gap metabolic acidosis with increased osmolal gap 5
• Pseudohyponatremia from hyperlipidemia or hyperproteinemia causes hyponatremia with normal plasma osmolality 7
• Hyperglycemia alone causes hyponatremia with increased plasma osmolality through osmotic water shifts from intracellular to extracellular compartments 7