What are the possible causes of persistent hypoglycemia in an adult without a history of diabetes?

Causes of Persistent Hypoglycemia in Adults Without Diabetes

In adults without diabetes presenting with persistent hypoglycemia, the most critical distinction is between spontaneous hypoglycemia (which carries worse prognosis and higher mortality) versus iatrogenic causes, with the primary etiologies being insulinoma, non-islet cell tumor hypoglycemia (NICTH), autoimmune hypoglycemia, genetic disorders of metabolism, and critical illness-related causes. 1, 2

Immediate Diagnostic Framework

The timing of hypoglycemic episodes relative to meals provides the most critical diagnostic clue:

Fasting Hypoglycemia (>6 hours after eating)

• Insulinoma: Characterized by inappropriately elevated insulin and C-peptide levels during documented hypoglycemia 2
• Non-Islet Cell Tumor Hypoglycemia (NICTH): Large tumors secreting Big-IGF2, with suppressed insulin, C-peptide, and IGF-1 levels 2
• Glycogen storage disorders (types 0, I, or III): Present with hepatomegaly and systemic involvement 2
• Fatty acid oxidation disorders: Triggered by prolonged fasting, often with rhabdomyolysis 2
• Gluconeogenesis defects: Present with fasting intolerance and metabolic acidosis 2

Postprandial Hypoglycemia (1-3 hours after eating)

• Post-bariatric hypoglycemia: Occurs after Roux-en-Y gastric bypass or sleeve gastrectomy due to rapid glucose absorption, excessive GLP-1 secretion, and insulin oversecretion 3
• Genetic hyperinsulinism: Glucokinase-activating mutations or insulin receptor mutations causing major postprandial hyperinsulinism 2
• Inherited fructose intolerance: Triggered specifically by fructose-containing foods 2
• Autoimmune hypoglycemia (Hirata syndrome): Anti-insulin antibodies, especially associated with Graves' disease 2
• Anti-insulin receptor antibodies: Cause erratic insulin signaling 2

Exercise-Induced Hypoglycemia

• SLC16A1 gene mutations: Activating mutations causing exercise-induced hyperinsulinism 2

Critical Illness and Organ Failure

Renal failure is one of the most important risk factors for persistent hypoglycemia in non-diabetic adults, with mortality odds ratio of 3.67 even after adjustment for other factors. 1

Mechanisms in renal insufficiency include:

• Decreased renal gluconeogenesis (kidneys normally account for 20-40% of total gluconeogenesis, increasing 2-3 fold during fasting) 1
• Impaired insulin clearance and degradation 1
• Lack of gluconeogenic substrates with decreased food intake 1
• Impaired counterregulatory hormone responses 1

Sepsis and low albumin levels are additional predictive markers of hypoglycemia with poor outcomes. 1

Endocrine Causes

Cortisol Insufficiency

• Hypopituitarism: Loss of ACTH and cortisol impairs gluconeogenesis 2
• Primary adrenal insufficiency: Direct loss of cortisol production 2

Glucagon Deficiency

• Rare but can occur after pancreas transplantation 2

Malnutrition and Malignancy

Malnutrition, malignancies, and frailty increase vulnerability to persistent hypoglycemia through multiple mechanisms including decreased gluconeogenic substrate availability and altered metabolic demands. 1

Surreptitious Insulin or Sulfonylurea Use

This must always be considered in unexplained hypoglycemia, particularly with:

• Elevated insulin levels with suppressed C-peptide (exogenous insulin) 2
• Elevated insulin and C-peptide (sulfonylurea use) 2

Alcohol-Related Hypoglycemia

Alcohol inhibits gluconeogenesis and can cause severe hypoglycemia, especially in malnourished individuals or those with depleted glycogen stores 2

Essential Diagnostic Workup

During a documented hypoglycemic episode (glucose <55 mg/dL), obtain:

• Insulin level
• C-peptide level
• Proinsulin level
• Beta-hydroxybutyrate (should be suppressed if insulin-mediated)
• Cortisol and ACTH
• IGF-1 and IGF-2 levels
• Sulfonylurea screen
• Anti-insulin antibodies
• Anti-insulin receptor antibodies 2

Between episodes, obtain:

• Comprehensive metabolic panel (renal function, albumin, liver function) 4
• Complete blood count (infection, sepsis) 4
• Nutritional assessment and recent weight changes 4
• Imaging if NICTH suspected (CT chest/abdomen/pelvis for large tumors) 2

Critical Pitfalls to Avoid

The most dangerous error is assuming that spontaneous hypoglycemia in a non-diabetic adult is benign—it carries significantly worse prognosis than medication-induced hypoglycemia and demands urgent investigation for underlying malignancy, insulinoma, or critical illness. 1

Hospitalization should be strongly considered if:

• The cause remains unclear after initial evaluation 4
• Recurrent episodes occur despite intervention 4
• Serious underlying illness is suspected (sepsis, malignancy, organ failure) 4

Family history of hypoglycemia, rhabdomyolysis after fasting/exercise, heart disease, or hepatomegaly should prompt evaluation for inherited metabolic disorders, even in adults. 2