Severe anion gap metabolic acidosis in a patient with type 2 diabetes
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A man aged 51 years with a history of alcohol use disorder and type 2 diabetes treated with metformin and glimepiride and alcohol presented to the hospital for a witnessed cardiac arrest at home.
Family members said he had been complaining of dyspnea and chest pain for an hour beforehand. Emergency medical technicians who resuscitated him in the field noted severe hypoglycemia and administered IV dextrose. Family reported the patient has been experiencing depression recently and was noted to be taking “a lot of pills.”
In the ED, the patient was sedated, intubated and mechanically ventilated. His initial blood pressure was 136 mm Hg/74 mm Hg; however, it dropped to 81 mm Hg/40 mm Hg over 2 hours and he was started on medications to support his BP.
Initial plasma chemistries showed: glucose of 127 mg/dL and was as low as 24 mg/dL approximately 5 hours later; blood urea nitrogen (BUN) 12 mg/dL; creatinine 1.54 mg/dL from a baseline level of approximately 0.7 mg/dL 2 months prior; sodium (Na) 144 mmol/L; potassium (K) 3.5 mmol/L; and total carbon dioxide (CO2) 4 mmol/L. The anion gap was 41. The plasma osmolarity was 314 mOsm/L. The plasma lactate was 25.9 mmol/L. The plasma pH was less than 6.8. His urine drug screen was negative for illicit drugs or ethanol.
What’s your diagnosis?
- Metformin overdose
- Methanol ingestion
- Ethylene glycol ingestion
- Inborn error of metabolism
Answer and discussion
The correct answer is A: Metformin overdose.
Metformin has been known to be associated with lactic acidosis. Risk factors include impaired kidney function, age older than 80 years, liver disease, congestive heart failure, lung disease with risk for hypoxemia and heavy ethanol use. Based on the family discussion and presenting lab results, the patient likely ingested an overdose of metformin, developed severe acidemia that resulted in a cardiac arrest followed by acute kidney injury, which worsened his clinical status due to his impaired renal elimination of the ingested metformin. He subsequently developed anuric kidney failure from his shock state and was swiftly placed on continuous renal replacement therapy. His subsequent metformin level, which came back after several days, was elevated at 180 µg/mL (therapeutic range, 1-2 µg/mL).
Patients who present for toxic alcohol ingestion such as methanol or ethylene glycol would generally have an elevated osmolar gap. The plasma osmolar gap is the measured osmolarity minus the estimated osmolarity. The plasma osmolarity can be estimated as 2 [Na + K] + [BUN]/2.8 + [glucose]/18. A normal osmolar gap is considered less than 10 mOsm/L and an osmolar gap of more than 20 mOsm/L can suggest the presence of a low-molecular-weight solute like an alcohol in the plasma. In this patient, the osmolar gap was 8 mOsm/L, which argues against a role for toxic alcohols. Although metabolism of alcohols by alcohol dehydrogenase lowers the redox potential and may lead to lactic acidosis, it generally does not cause lactic acidosis of this severity. Finally, it is also important to note that in toxic alcohol ingestion, the osmolar gap will decline and the anion gap will rise as the toxic alcohol is being metabolized by alcohol dehydrogenase. As such, a patient late in their course may present with severe acidemia and a very high anion gap without an osmolar gap. However, the plasma lactate will help distinguish between toxic alcohol ingestion and another underlying toxin such as metformin.
The patient had been hospitalized twice in the past for symptoms of alcohol withdrawal. Although he had a metabolic acidosis during several of those hospitalizations as well, it was always a non-anion gap metabolic acidosis in the setting of diarrhea, and his bicarbonate levels returned to normal at discharge. Therefore, a congenital inborn error of metabolism is likely not causing his elevated lactate.
For more information:
Michael Chau, DO, is an internal medicine resident at Cooper University Hospital in Camden, New Jersey.
Lawrence S. Weisberg, MD, MACP, FASN, is a nephrologist at Cooper University Hospital and professor of medicine at Rowan University in Glassboro, New Jersey. He also serves as associate dean for professional development and associate director of the Cooper Medical School of Rowan University (CMSRU) Center for Humanism. He represents the Renal Physicians Association of the American College of Physicians Council of Subspecialty Societies.
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