What are the common etiologies of hyperosmolar hyperglycemic non‑ketotic (HHNK) syndrome in older adults with type 2 diabetes?

Common Etiologies of HHNK

Infection is the single most common precipitating cause of hyperosmolar hyperglycemic non-ketotic (HHNK) syndrome, followed by cardiovascular events and medications that impair glucose metabolism or insulin action. 1, 2

Primary Precipitating Factors

Infections (Most Common Trigger)

• Pneumonia and urinary tract infections are the leading infectious causes that precipitate HHNK in older adults with type 2 diabetes 1, 3, 2
• Sepsis represents a particularly dangerous precipitant, as it combines infection with hemodynamic instability 1
• Infection should be actively sought in every HHNK presentation through bacterial cultures (blood, urine, throat) and chest X-ray when clinically indicated 4

Cardiovascular Events

• Acute myocardial infarction is a frequent precipitant, particularly in elderly patients with underlying coronary disease 5, 1, 3
• Cerebrovascular accidents (stroke) commonly trigger HHNK and complicate management because anti-edema therapy conflicts with aggressive fluid resuscitation 5, 1, 3
• Congestive heart failure both precipitates HHNK and makes fluid replacement challenging, contributing to higher mortality 3

Medications That Raise Glucose or Impair Insulin Action

• Thiazide diuretics increase insulin resistance and promote volume depletion through osmotic diuresis 5, 1, 3, 6
• Systemic corticosteroids elevate counterregulatory hormones and directly impair glucose metabolism 5, 1, 3, 6
• SGLT2 inhibitors can precipitate hyperglycemic crises, though more commonly associated with euglycemic DKA 1
• Beta-blockers interfere with counterregulatory responses and mask hypoglycemic symptoms 5, 3, 6
• Phenytoin impairs insulin secretion and increases risk in elderly patients 3, 6
• Sympathomimetic agents (e.g., dobutamine, terbutaline) elevate counterregulatory hormones 1

Secondary Contributing Factors

Non-Adherence and Undiagnosed Diabetes

• Insulin omission or non-adherence to diabetes therapy is a common precipitant, particularly in patients with economic barriers or psychiatric illness 1, 2
• Newly diagnosed type 2 diabetes may present initially as HHNK, especially in children and adolescents where this syndrome is increasingly recognized 2

Other Acute Illnesses

• Gastrointestinal hemorrhage causes hemodynamic instability and stress hormone elevation 3
• Pancreatitis impairs insulin secretion and increases counterregulatory hormones 3, 2
• Severe burns create massive fluid losses and metabolic stress 6

Iatrogenic Causes

• Parenteral hyperalimentation delivers excessive glucose loads that overwhelm insulin capacity 6
• Peritoneal dialysis or hemodialysis with high-glucose dialysate can precipitate hyperglycemia 6

Age-Related Vulnerability Factors

Elderly patients are particularly susceptible to HHNK due to multiple physiologic changes: 5, 1, 3

• Reduced glomerular filtration rate impairs glucose excretion and worsens hyperglycemia 5, 3
• Elevated renal threshold for glucose prevents osmotic diuresis from correcting hyperglycemia 3
• Impaired thirst mechanisms prevent adequate fluid intake despite severe dehydration 5, 3
• Increased insulin resistance in peripheral tissues (muscle and adipose) with aging 5
• Reduced glucose-induced insulin release from pancreatic beta cells 5
• Elevated inflammatory markers (TNF-α, IL-6) that worsen insulin resistance 5, 1
• Abdominal obesity and increased free fatty acids common in elderly populations 5

High-Risk Clinical Scenarios

Institutionalized Elderly

• Patients in nursing homes or chronic care facilities who become hyperglycemic and cannot access fluids independently are at markedly increased risk 3
• Inadequate supervision of fluid intake in these settings is a preventable cause of HHNK 3

Substance Abuse

• Cocaine use can precipitate HHNK through sympathomimetic effects and volume depletion 1, 2
• Alcohol abuse may contribute through poor nutrition and medication non-adherence 2

Critical Clinical Pitfall

The absence of typical hyperglycemic symptoms (polyuria, polydipsia) in elderly patients delays diagnosis because the renal threshold for glycosuria increases with age and thirst mechanisms are impaired. 5 Elderly patients often present instead with non-specific symptoms such as weight loss, fatigue, or confusion that are mistakenly attributed to aging or dementia rather than HHNK 5. This diagnostic delay contributes to the 15% mortality rate associated with HHNK 1.