Pathophysiology of Ketoacidosis: Core Curriculum 2026

Ketoacidosis is a metabolic state characterized by overproduction and accumulation of ketone bodies (ketoacids), leading to potentially life-threatening drops in blood pH. Common to these disorders is a reduction in the insulin-glucagon ratio signaling a lack of available cellular fuel. This change promotes lipolysis and subsequent hepatic β-oxidation of fatty acids, yielding acetyl-CoA that is converted into ketone bodies (acetoacetate, β-hydroxybutyrate, and acetone). Additionally, increased levels of other counterregulatory hormones (eg, catecholamines, cortisol, and growth hormone) often play a key role in exacerbating ketogenesis and the catabolic state. This core curriculum explores the physiological and pathological spectrum of ketoacidosis, beginning with the benign state of starvation ketosis. Diabetic ketoacidosis is a severe complication of diabetes mellitus resulting from profound absolute or relative insulin deficiency and counterregulatory hormone excess. Other forms discussed include pregnancy-associated ketoacidosis (often triggered by starvation or illness), alcoholic ketoacidosis (resulting from the metabolism of alcohol in association with reduced food intake), ketoacidosis associated with chronic salicylate poisoning, sodium/glucose cotransporter 2 inhibitor-induced ketoacidosis, and development of euglycemic ketoacidosis in patients undergoing continuous kidney replacement therapy. Understanding the distinct pathophysiology of each condition is crucial for accurate diagnosis and timely, targeted therapeutic intervention.