Euglycemic Ketoacidosis and Lactic Acidosis Associated with Metformin Toxicity

Metformin-associated lactic acidosis (MALA) in the setting of acute renal failure is well documented, however, metformin-associated lactic acidosis and euglycemic ketoacidosis (MALKA) is less studied. With mortality rate reaching 50%, a high index of suspicion is required in patients who are taking metformin and presenting with acute renal failure and euglycemia.

Case Description:

A 67-year-old female with past medical history of diabetes mellitus type 2, stage 3A chronic kidney disease, hypertension, atrial fibrillation, and hypothyroidism, was brought to the emergency department due to falling, confusion, headaches, polyuria, poor oral intake, nausea, diarrhea for approximately 5 days, and blood glucose of 50 mg/dL at home. Home regimen was metformin 500mg twice daily, glimepiride 4mg daily, glipizide 10mg twice daily, levothyroxine 75mcg daily, and recently started regular insulin 6 units with meals. On examination, vitals were unremarkable, she was confused, disorientated but otherwise non-focal. Initial workup showed blood glucose of 53 mg/dL, HgbA1c of 9.8%, bicarbonate of 11 mmol/L, creatinine of 9.43 mg/dL, blood urea nitrogen of 89 mg/dL, corrected anion gap of 27.3, delta gap of 14, and delta ratio of 1.1 suggestive of a pure high anion gap metabolic acidosis.

During admission, the patient sustained a cardiac arrest with pulseless electrical activity (PEA) but achieved return of spontaneous circulation. Suspected cause of the PEA was severe metabolic acidosis. She was intubated and started on mechanical ventilation. An arterial blood gas showed pH 6.62, pCO2 28 mmHg, pO2 547 mmHg, HCO3 2.9 mmol/L, CO2 11. Lactic acid was 32 mmol/L (reference 0.4 - 2.0). Beta-hydroxybutyrate/acetoacetate was 40.8 mg/dL (reference 0.2 - 2.8). Metformin level was 15 mcg/mL (reference 0-2mcg/ml). She was started on hemodialysis and DKA protocol with glucose and bicarbonate infusion. The gap improved within 48 hours. Patient recovered and was discharged on only glimepiride 4mg daily with recommendations to monitor blood glucose and follow with her primary care provider.

Discussion:

Metformin-induced lactic acidosis has been an area of interest for decades. It is unclear if metformin can be a cause of euglycemic or hypoglycemic ketoacidosis, or if the presentation was confounded by other factors. Our patient likely represents a case of lactic acidosis due to hypoxia and circulatory collapse with diabetic ketoacidosis due to extreme stress and failure of gluconeogenesis due to metformin in the presence of acute renal failure. MALKA presents a diagnostic challenge especially in the presence of confounding factors such as medication-induced hypoglycemia.