What are the possible causes of ketoacidosis?

Causes of Ketoacidosis

Ketoacidosis results from absolute or relative insulin deficiency combined with elevated counterregulatory hormones (glucagon, catecholamines, cortisol, growth hormone), which together trigger uncontrolled lipolysis and ketogenesis. 1

Core Pathophysiologic Mechanism

The fundamental defect involves reduced effective insulin action paired with excess counterregulatory hormones, leading to:

• Unregulated lipolysis: Elevated counterregulatory hormones combined with insulin deficiency trigger release of free fatty acids from adipose tissue 1
• Hepatic ketogenesis: These free fatty acids undergo β-oxidation in the liver, producing excessive ketone bodies (acetoacetate, β-hydroxybutyrate, acetone) 2, 1
• Metabolic acidosis: Ketone bodies accumulate and lower blood pH, creating the acidotic state 2

Most Common Precipitating Factors

Infection (Leading Cause)

• Infection is the single most common precipitating cause of ketoacidosis, occurring in 30-50% of cases 2, 1, 3
• Urinary tract infections and pneumonia account for the majority of infectious triggers 3
• Patients can be normothermic or even hypothermic despite serious infection; hypothermia is a poor prognostic sign 2

Insulin-Related Issues

• Discontinuation or inadequate insulin therapy in established type 1 diabetes commonly leads to ketoacidosis 2
• Insulin omission is the most common cause of recurrent ketoacidosis, particularly in patients with psychiatric illness, those from single-parent homes, and underinsured patients 1
• Psychological problems and lack of financial resources are the most common causes in patients with established diabetes 1
• Urban African-Americans are at particular risk of discontinuing insulin due to economic barriers 1

New-Onset Diabetes

• First presentation of type 1 diabetes, particularly in children and adolescents, may present with ketoacidosis as the initial manifestation 1
• Newly onset diabetes in elderly individuals, particularly residents of chronic care facilities, can precipitate hyperglycemic crises 2

Medication-Induced Ketoacidosis

SGLT2 Inhibitors (Emerging Major Cause)

• SGLT2 inhibitors are now a leading cause of ketoacidosis, including euglycemic ketoacidosis (glucose <250 mg/dL), particularly as their use expands to heart failure and chronic kidney disease in non-diabetic patients 1, 4
• The mechanism involves reduction in insulin doses due to improved glycemic control, increased glucagon levels leading to enhanced lipolysis and ketone production, and decreased renal clearance of ketones 1
• Risk is present in both diabetic and non-diabetic patients taking SGLT2 inhibitors 1
• Reduced caloric intake is particularly dangerous in patients on SGLT2 inhibitors 1

Other Medications

• Corticosteroids affect carbohydrate metabolism and may precipitate ketoacidosis 2
• Thiazide diuretics can trigger hyperglycemic crises 2
• Sympathomimetic agents (dobutamine, terbutaline) may precipitate ketoacidosis 2, 1

Acute Medical Conditions

Cardiovascular Events

• Myocardial infarction can precipitate ketoacidosis through stress hormone elevation 2
• Cerebrovascular accident is a recognized precipitating factor 2

Other Acute Illnesses

• Pancreatitis can trigger ketoacidosis 2
• Trauma increases insulin requirements through stress response 2
• Surgery creates a stressful condition that can precipitate ketoacidosis in susceptible patients 3
• Alcohol abuse is a precipitating factor 2

High-Risk Clinical Scenarios

Acute Illness

• Any febrile illness increases insulin requirements through stress hormone elevation 1
• Intercurrent illnesses (myocardial ischemia, trauma) can trigger ketoacidosis 3

Pregnancy

• Pregnancy, especially in type 1 diabetes, with up to 2% of pregnancies complicated by ketoacidosis 1

Insulin Pump Issues

• Insulin pump failure or disconnection creates immediate lack of continuous rapid-acting insulin, leading to absolute insulin deficiency and ketoacidosis within a few hours 1
• Interruption of any insulin delivery can precipitate ketoacidosis rapidly, often within 4-10 hours depending on the insulin formulation 1

Special Populations at Elevated Risk

Age-Related Vulnerability

• Children and adolescents experience the fastest progression to ketoacidosis because β-cell destruction is most rapid in this age group 1
• Ketoacidosis can evolve from modest hyperglycemia to severe acidosis within hours in children, especially when infection or other stressors are present 1
• Elderly individuals in chronic care facilities who become hyperglycemic and cannot access fluids are at high risk 2, 1

Behavioral Factors

• Children and adolescents with eating disorders have a higher frequency of recurrent ketoacidosis 1
• Patients with psychiatric illness have higher rates of recurrent episodes 1

Autoimmune Diabetes

• Patients with autoimmunity initially thought to have type 2 diabetes are at risk for ketoacidosis 1
• Some patients with new-onset diabetes retain residual β-cell function initially but eventually become insulin-dependent and at risk 1

Critical Pitfalls to Avoid

• Never discontinue basal insulin, even when blood glucose appears normal, because stopping basal insulin markedly increases the risk of rapid ketosis and ketoacidosis within 4-10 hours 1
• Do not rely solely on glucose thresholds for diagnosis—euglycemic ketoacidosis with SGLT2 inhibitors can present with glucose levels as low as 177-180 mg/dL or even lower 1, 4
• Temperature is unreliable in ketoacidosis patients; they can be normothermic or hypothermic despite serious infection 2, 1
• Abdominal pain in ketoacidosis can be either a result or a cause of the condition and requires further evaluation if it does not resolve with treatment 2