What are the etiologies of hypoglycemic episodes?

Etiologies of Hypoglycemic Episodes

Hypoglycemia in hospitalized patients stems primarily from iatrogenic insulin-related errors, nutrition-insulin mismatch, and acute kidney injury, while in non-diabetic adults, endogenous hyperinsulinism, critical illness, and hormonal deficiencies are the main culprits.

Medication-Related Causes (Most Common in Hospital Settings)

Insulin-Related Hypoglycemia

• Insulin is the most common drug causing adverse events in hospitalized patients, with errors occurring in dosing, administration timing, and insulin type selection 1
• Errors span the entire medication chain: prescriber ordering mistakes, pharmacy dispensing errors, and nursing administration errors including missed doses 1
• Inappropriate timing of short- or rapid-acting insulin relative to meals is a frequent preventable cause 1
• In type 1 diabetes, dosing insulin based solely on premeal glucose without accounting for basal requirements increases hypoglycemia risk 1

Other Glucose-Lowering Medications

• Sulfonylureas cause prolonged hypoglycemia, especially first-generation agents, and may require glucose infusion for treatment 2
• Improper prescribing of oral glucose-lowering medications beyond insulin contributes significantly 1
• Drug interactions potentiate hypoglycemia: quinolones, heparin, beta-blockers, and trimethoprim-sulfamethoxazole increase blood-glucose-lowering effects 3
• Beta-blockers, clonidine, guanethidine, and reserpine mask hypoglycemia symptoms, delaying recognition 3

Nutrition-Insulin Mismatch

Interruption of Nutritional Intake

• Unexpected interruption of enteral or parenteral feedings creates critical nutrition-insulin mismatch 1, 3
• Reduced oral intake, emesis, or malnutrition decrease glucose availability 1, 3
• Reduced infusion rate of intravenous dextrose without corresponding insulin adjustment 1
• Irregular food intake is particularly problematic in the perioperative period 3

Inappropriate Management After First Episode

• Inappropriate management of the first hypoglycemic episode is a common preventable source 1
• 75% of patients did not have their basal insulin dose changed before the next administration despite documented hypoglycemia 1

Renal and Hepatic Dysfunction

Acute Kidney Injury and Chronic Kidney Disease

• Acute kidney injury is an important risk factor for hypoglycemia in hospitalized patients, likely due to decreased insulin clearance 1, 3
• Kidneys normally contribute 20-40% of overall glucose production, which can increase two- to threefold during fasting 4
• Decreased gluconeogenesis by the kidneys is a fundamental pathophysiologic mechanism 4
• Impaired insulin clearance occurs because kidneys metabolize a larger proportion of exogenous insulin, leading to prolonged insulin action 4
• Reduced insulin degradation by kidney, liver, and muscle due to uremia extends insulin half-life 4
• Insulin requirements typically decrease by 40-50% when patients transition to dialysis 4

Dialysis-Specific Mechanisms

• Increased erythrocyte glucose uptake during hemodialysis creates an additional glucose sink 4
• Dialysate glucose concentration is the main determinant of plasma glucose levels after hemodialysis, with glucose-free or low-glucose dialysate significantly increasing risk 4
• Impaired counterregulatory hormone responses result in blunted hormonal responses to falling glucose 4

Hepatic Insufficiency

• Liver disease impairs gluconeogenesis and glycogenolysis 5, 6
• Hepatic dysfunction is associated with hypoglycemia in critically ill patients 6

Endocrine and Hormonal Causes

Cortisol and Growth Hormone Deficiency

• Cortisol insufficiency including hypopituitarism causes hypoglycemia 7
• Sudden reduction of corticosteroid dose induces iatrogenic hypoglycemia 1
• Hormonal deficiencies impair counterregulatory responses 5, 8

Endogenous Hyperinsulinism (Non-Diabetic Adults)

• Insulinoma causes hyperinsulinism with raised plasma insulin, C-peptide, and proinsulin levels during hypoglycemia 5
• Postbariatric hypoglycemia and noninsulinoma pancreatogenous hypoglycemia are increasingly recognized causes 8
• Monogenic congenital hyperinsulinism, especially mutations of glucokinase-activating gene or insulin receptors, causes postprandial hypoglycemia 7
• Exercise-induced hyperinsulinism is mainly related to activating mutation of the SLC16A1 gene 7

Non-Islet Cell Tumor Hypoglycemia (NICTH)

• Large tumors secrete Big-IGF2, causing hypoglycemia with low insulin, C-peptide, and IGF-1 levels 7, 5
• NICTH tends to occur in older patients with appropriately suppressed insulin levels 5

Autoimmune Hypoglycemia

• Autoantibodies against insulin (Hirata syndrome), especially with Graves' disease 7, 5
• Autoantibodies against insulin receptor 7, 5

Critical Illness and Systemic Conditions

Sepsis and Infection

• Sepsis including malaria causes hypoglycemia through multiple mechanisms 5, 6
• Infections are a recognized cause in hospitalized patients 6

Other Critical Illness Factors

• Congestive cardiac failure 5
• Extensive burns 6
• Total parenteral nutrition complications 6
• Pregnancy 6

Alcohol and Toxins

Ethanol-Induced Hypoglycemia

• Ethanol is the most common cause of hypoglycemia after insulin and sulfonylureas 2
• Hypoglycemia typically develops 6-24 hours after moderate or heavy alcohol intake in persons with insufficient food intake for 1-2 days 2
• Alcohol inhibits hepatic glucose release and exacerbates hypoglycemia 9

Other Exogenous Toxins

• Various exogenous toxins beyond alcohol can cause hypoglycemia 5

Genetic and Metabolic Causes (Rare in Adults)

Inborn Errors of Metabolism

• Type 0, I, or III glycogen synthesis disorders cause fasting hypoglycemia 7
• Fatty acid oxidation or gluconeogenesis disorders present with fasting hypoglycemia 7
• Inherited fructose intolerance causes postprandial hypoglycemia 7
• IEM may present with systemic involvement: rhabdomyolysis after fasting or exercise, heart disease, hepatomegaly 7

Recurrent Hypoglycemia and Hypoglycemia-Associated Autonomic Failure (HAAF)

Impaired Counterregulation

• 84% of patients with severe hypoglycemia (<40 mg/dL) had a preceding episode of hypoglycemia (<70 mg/dL) during the same admission 1, 3
• Prior hypoglycemia impairs counterregulatory responses, increasing risk for subsequent events 1
• Approximately 40% of type 1 diabetes and 10% of insulin-treated type 2 diabetes patients develop HAAF 9
• Hypoglycemia unawareness occurs in 20-40% of type 1 diabetic patients and increases severe hypoglycemia risk 6-20 fold 3

Nocturnal Hypoglycemia

• 78% of patients with hypoglycemic episodes were using basal insulin, with incidence peaking between midnight and 6:00 A.M. 1
• Nocturnal hypoglycemia occurs in 14-47% of patients and may be asymptomatic 9

Special Populations at Risk

Elderly Patients

• Elderly patients particularly fail to perceive neuroglycopenic and autonomic hypoglycemic symptoms despite comparable reaction time prolongation 4
• Altered ability to report symptoms increases risk 1

Patients with Altered Mental Status

• A significant proportion of hospitalized patients with hypoglycemia are either asymptomatic or present with altered mental status 6
• Altered ability of the patient to report symptoms is a risk factor 1

Clinical Pitfalls to Avoid

• Never ignore a blood glucose <70 mg/dL: treatment regimens must be reviewed and changed immediately to prevent recurrence 1, 3
• Do not assume normal glucose at symptom check excludes hypoglycemia; treat unexplained malaise in diabetic patients as possible hypoglycemia until proven otherwise 9
• Recognize that symptom failure can occur even in insulin-treated diabetic patients 2
• Near-normalization of blood glucose levels increases the incidence of severe hypoglycemia by lowering the threshold for counterregulatory responses 2