When Does the "Onset Time" of HHS Begin?
The "days to weeks" onset time for HHS refers to the evolution of the entire clinical syndrome from the initial precipitating event (such as infection) through the progressive development of hyperglycemia, dehydration, and metabolic derangements—not from when mental status changes first appear. Mental status changes are a late manifestation that occurs after the metabolic process is already well-established 1.
Understanding the Timeline of HHS Development
The Complete Evolution Process
HHS develops over days to a week as a progressive metabolic deterioration that begins with the precipitating factor (most commonly infection, stroke, or myocardial infarction) 1, 2.
The process starts when the precipitating illness triggers inadequate insulin action combined with elevated counter-regulatory hormones, leading to progressive hyperglycemia and osmotic diuresis 1.
This is fundamentally different from DKA, which evolves over hours to days 1. The prolonged timeline of HHS is what distinguishes it clinically 3, 4.
The Sequential Pathophysiology
The onset timeline follows this progression:
Initial precipitating event (infection, stroke, MI, medication changes) occurs first 1, 2
Progressive hyperglycemia develops over subsequent days as glucose production increases and utilization decreases 1
Osmotic diuresis begins, causing water and electrolyte losses (total body water deficit reaches 100-220 mL/kg or approximately 9 liters) 2, 4
Dehydration worsens progressively as patients—particularly elderly or institutionalized individuals—cannot compensate with adequate fluid intake 1, 5
Mental status changes appear late as a consequence of severe hyperosmolarity (≥320 mOsm/kg), not as the beginning of the syndrome 1, 6, 2
Why Mental Status Changes Are NOT the Starting Point
Mental Status Is a Late Consequence
Mental status changes correlate directly with the degree of hyperosmolarity, meaning they worsen as osmolality increases—they don't mark the beginning of HHS 1, 6.
Patients can meet full metabolic criteria for HHS (glucose ≥600 mg/dL, osmolality ≥320 mOsm/kg) while still alert, particularly in earlier presentations 2.
The severity of altered consciousness ranges from full alertness to profound coma, with stupor/coma being more common in HHS than DKA, but not universally present at onset 1, 6, 2.
Clinical Implications
Polyuria, polydipsia, and weight loss typically precede mental status changes by days, representing the earlier symptomatic phase 1, 6.
The "days to weeks" evolution refers to the entire pathophysiologic cascade from precipitating illness through progressive metabolic derangement 1, 3.
By the time mental status changes appear, patients already have severe dehydration (9L deficit), marked hyperglycemia (≥600 mg/dL), and profound hyperosmolarity (≥320 mOsm/kg) 2, 4.
Common Clinical Pitfall
A critical error is waiting for altered mental status to diagnose or treat HHS. Patients presenting with marked hyperglycemia (≥600 mg/dL) and hyperosmolarity (≥320 mOsm/kg) warrant immediate HHS management even if fully alert 2. The absence of mental status changes does not exclude HHS diagnosis when metabolic criteria are met 2.
Practical Application
When counting the onset time:
Start from the precipitating event (when infection began, when stroke occurred, when medications were changed) 1, 2
Not from when the patient became confused or lethargic, as this represents advanced disease 1, 6
The slowly decreasing mental status is part of the progressive syndrome, not its beginning 1, 3, 4
This understanding is crucial because HHS has mortality rates up to 15% (higher than DKA's 5%), and early recognition before profound mental status changes develop can improve outcomes 1, 6, 3.