What is the pathophysiology of diabetic ketoacidosis (DKA) in a patient with a history of diabetes, particularly type 1 diabetes?

Pathophysiology of Diabetic Ketoacidosis

DKA results from absolute or relative insulin deficiency combined with elevated counterregulatory hormones (glucagon, cortisol, catecholamines, growth hormone), which together trigger three core metabolic derangements: hyperglycemia from impaired glucose utilization and increased hepatic glucose production, uncontrolled lipolysis releasing free fatty acids from adipose tissue, and unregulated hepatic ketogenesis producing acetoacetate and β-hydroxybutyrate. 1

Core Metabolic Cascade

Insulin Deficiency and Counterregulatory Hormone Excess

• The fundamental defect is severe insulin deficiency (absolute in type 1 diabetes, relative in type 2 diabetes) coupled with excessive secretion of counterregulatory hormones 1, 2
• This hormonal imbalance drives three parallel pathologic processes that define DKA 3

Hyperglycemia Mechanism

• Reduced effective insulin action impairs glucose uptake and utilization in peripheral tissues (muscle, adipose) 1
• Simultaneously, elevated counterregulatory hormones stimulate hepatic and renal glucose production through glycogenolysis and gluconeogenesis 1
• The resulting hyperglycemia (typically >250 mg/dL) causes osmotic diuresis, leading to profound dehydration, electrolyte losses (sodium, potassium, chloride, phosphate, magnesium), and hyperosmolality 2, 4

Ketogenesis and Acidosis

• Insulin deficiency combined with elevated counterregulatory hormones triggers massive lipolysis, releasing free fatty acids from adipose tissue 1, 2
• These free fatty acids undergo unregulated hepatic oxidation to ketone bodies (acetoacetate, β-hydroxybutyrate, acetone) 1
• Ketone accumulation overwhelms the body's buffering capacity, producing high anion gap metabolic acidosis (anion gap >10-12 mEq/L) 2, 5
• The acidosis drives compensatory hyperventilation (Kussmaul respirations) to eliminate CO₂ and partially correct pH 2

Electrolyte Derangements

• Osmotic diuresis causes total body deficits of sodium (average 7-10 mEq/kg), potassium (3-5 mEq/kg), chloride, phosphate, and magnesium 3
• Serum potassium may appear normal or even elevated initially due to transcellular shifts from acidosis and insulin deficiency, but total body potassium is always depleted 6
• Insulin therapy drives potassium intracellularly, potentially causing life-threatening hypokalemia, respiratory paralysis, ventricular arrhythmias, and death if not monitored and replaced 6

Biochemical Diagnostic Criteria

• Traditional DKA triad: plasma glucose >250 mg/dL, arterial pH <7.30, serum bicarbonate ≤18 mEq/L, elevated anion gap (>10-12 mEq/L), and positive serum/urine ketones 2, 5, 4
• Severity classification by pH: severe (<7.0), moderate (7.0-7.24), mild (7.25-7.30) 2
• Critical caveat: Euglycemic DKA (glucose <250 mg/dL or even 177-180 mg/dL) increasingly occurs with SGLT2 inhibitors, potentially delaying diagnosis if clinicians rely solely on glucose thresholds 1, 2

Distinction from Hyperosmolar Hyperglycemic State (HHS)

• HHS differs fundamentally: residual beta-cell function provides enough insulin to suppress lipolysis and prevent significant ketogenesis, but remains inadequate to control hyperglycemia 2, 5
• HHS presents with markedly higher glucose (>600 mg/dL), severe hyperosmolality (>320 mOsm/kg), minimal ketones, pH >7.30, bicarbonate >15 mEq/L, and more profound dehydration 2, 5
• DKA evolves rapidly (within 24 hours) while HHS develops insidiously over days to weeks 2, 5
• Approximately one-third of patients present with mixed features of both DKA and HHS 3

Common Precipitating Factors

• Infection is the single most common precipitant in established diabetes, requiring empiric antibiotics if clinically suspected rather than waiting for confirmatory tests 1
• SGLT2 inhibitors are now a leading cause through multiple mechanisms: reduced insulin doses from improved glycemic control, increased glucagon levels enhancing lipolysis and ketone production, decreased renal ketone clearance, and risk present even in non-diabetic patients using these drugs for heart failure or chronic kidney disease 1
• Insulin omission accounts for nearly all recurrent DKA cases, particularly in patients with psychiatric illness, eating disorders, single-parent homes, or inadequate insurance/financial resources 1
• Acute illness/infection increases insulin requirements through stress hormone elevation 1
• First presentation of type 1 diabetes, especially in children and adolescents 1
• Reduced caloric intake is particularly dangerous in patients on SGLT2 inhibitors 1
• Pregnancy in type 1 diabetes (up to 2% of pregnancies complicated by DKA) 1
• Medications: corticosteroids, sympathomimetics (dobutamine, terbutaline), thiazides 1

Clinical Presentation Timeline

• DKA symptoms develop rapidly, typically within 24 hours 2
• Early symptoms: polyuria, polydipsia, weight loss, fatigue 4
• Progressive symptoms: nausea, vomiting (up to 25% of patients), abdominal pain (sometimes with coffee-ground emesis from hemorrhagic gastritis), Kussmaul respirations, fruity breath odor (acetone), drowsiness 2, 6
• Severe cases: stupor, coma (correlating with degree of acidosis and hyperosmolality), hypothermia (poor prognostic sign), hypotension, tachycardia 2, 7

Critical Complications

• Cerebral edema is the most feared complication, particularly in children, though incidence is low 8
• Hypokalemia from insulin therapy can cause respiratory paralysis, ventricular arrhythmias, and death 6
• Mortality rate approximately 5% in experienced centers for DKA, higher at extremes of age (>65 years), with coma, hypotension, or hypothermia 2
• Vascular occlusion from severe dehydration and hyperosmolality 3