Pathophysiology of Diabetic Ketoacidosis

Diabetic ketoacidosis (DKA) is a life-threatening metabolic disorder resulting from decreased effective circulating insulin, insulin resistance and increased production of counter-regulatory hormones. The frequency of DKA ranges from 16%-80% of children newly diagnosed with diabetes, depending on geographic location. It is the leading cause of morbidity and is the most common cause of diabetes-related deaths in children and adolescents with type 1 diabetes. Mortality is predominantly due to cerebral oedema which occurs in 0.3% to 1% of all episodes of diabetic ketoacidosis in children.

Pathophysiology:

DKA results from insulin deficiency from new-onset diabetes, insulin noncompliance, prescription or illicit drug use, and increased insulin need because of infection. This insulin deficiency stimulates the elevation of the counter regulatory hormones (glucagon, catecholamines, cortisol, and growth hormone). Without the ability to use glucose, the body needs alternative energy sources.

Lipase activity increases, causing a breakdown of adipose tissue that yields free fatty acids. These components are converted to acetyl coenzyme A, some of which enter the Krebs cycle for energy production; the remainder are broken down into ketones (acetone, acetoacetate, and β-hydroxybutyrate). Ketones can be used for energy, but accumulate rapidly. Glycogen and proteins are catabolized to form glucose. Together, these factors promote hyperglycemia, which leads to an osmotic diuresis resulting in dehydration, metabolic acidosis, and a hyperosmolar state.

• Increased hepatic and renal glucose production and impaired peripheral glucose utilisation, leading to hyperglycaemia and hyperosmolality,
• Increased lipolysis and unrestrained production of ketoacids (betahydroxybutyrate and acetoacetate), resulting in ketonaemia and metabolic acidosis.
• Osmotic diuresis (due to hyperglycaemia), loss of electrolytes and dehydration, which can exacerbate the metabolic acidosis.

Causes of Diabetic Ketoacidosis

Drugs
• Antipsychotic agents: clozapine (Clozaril),10 olanzapine (Zyprexa),11 risperidone (Risperdal)12 Illicit drugs (cocaine13) and alcohol4
• Others: corticosteroids, glucagon, interferon,14 pentamidine,14 sympathomimetic agents,14 thiazide diuretics 4

Infection

• Pneumonia, sepsis, urinary tract infection
• Lack of insulin
• Insulin pump failure
• Nonadherence to insulin treatment plans: body image issues,15 financial problems, psychological factors
• Unrecognized symptoms of new-onset diabetes mellitus

Other physiologic stressors

• Acromegaly,14 arterial thrombosis,14 cerebrovascular accident,
• Cushing disease,16 hemochromatosis,14 myocardial infarction,
• pancreatitis,14 pregnancy,14 psychological stress,16
• shock/hypovolemia, trauma16