Case Presentation: A 71 year old male presents to the ED with diffuse abdominal pain and nausea for the day. He has an extensive medical history including Type II DM, CAD, HFpEF, and COPD. He was recently prescribed Bactrim for a UTI, but notes persistent dysuria and suprapubic discomfort which prompted him to take an extra dose of Bactrim this morning. He endorses abdominal pain, nausea, vomiting, constipation, dysuria, and poor oral intake. He denies hematemesis, melena, chest pain, shortness of breath, fever, chills, and fatigue. Initial work up shows hypoglycemia (44), acute kidney injury (AKI) (Creatinine 2.95), hyperkalemia (K 6.7), metabolic acidosis (pH 7.21/PCO2 35/Bicarbonate 12) with elevated anion gap (29), and leukocytosis (WBC 15.5). CT abdomen and pelvis shows significant stool burden. Given his medical history and abdominal pain with nausea, EKG is obtained and shows no evidence of ischemia. His lactate is elevated on presentation and continues to trend up, peaking at 16.5. Notably, he was taking metformin in the setting of his AKI. ICU is consulted for the lactic acidosis, and the patient is started on a D5W drip with bicarbonate. Home diabetes medications are held and laxatives are given. The patient’s lactate trends down and his abdominal pain resolves throughout his hospitalization. Metformin use in the setting of a prerenal AKI secondary to poor oral intake and excess Bactrim use is believed to have caused his lactic acidosis. The patient is discharged home with a normal lactate level and resolution of AKI.

Discussion: Metformin-associated lactic acidosis (MALA) is a potentially life threatening complication of metformin use, occurring through a mechanism that increases anaerobic metabolism and lactate levels (1,2). While its reported incidence is low (< 10 cases per 100,000 patient-years), the mortality rate for untreated MALA can be as high as 50% (1). MALA presents nonspecifically and commonly occurs after metformin use in situations reducing renal blood flow, as seen in our patient (1,2). While metabolic acidosis is common among hospitalized patients, diagnosing MALA requires excluding other causes with arterial pH < 7.35 and plasma lactate concentrations > 5.0 mmol/l. Once lactic acidosis is identified, distinguishing between Type A (caused by hypoxia, often during sepsis or inadequate tissue perfusion) and Type B (caused in the absence of hypoxemia by factors such as liver disease, thiamine deficiency, toxins, or malignancy) is crucial (2). Treatment approaches vary, with some advocating for hemodialysis and others favoring sodium bicarbonate drips or supportive measures (1). While MALA can result in severe complications, it generally has a good prognosis if treated (1).

Conclusions: While hospitalists frequently encounter metabolic acidosis, they should be especially aware of metformin’s association with lactic acidosis since prompt initiation of treatment minimizes morbidity and mortality. Moreover, when confronted with a high anion gap metabolic acidosis of unknown origin, hospitalists should conduct a thorough review of all medications to identify potential contributing drugs. Additionally, discontinuation of metformin is crucial in patients with conditions that diminish renal perfusion. Since guidelines for metformin use in patients with renal dysfunction are not well defined, a significant proportion of diabetic patients are left vulnerable to metformin toxicity. This case underscores the need for increased knowledge and awareness of MALA.

IMAGE 1: Figure 1: Mechanism of Metformin Associated Lactic Acidosis (MALA) in the Setting of a Kidney Injury. Impaired metformin clearance results in accumulation of metformin, which inhibits gluconeogenesis enzyme, pyruvate carboxylase, from converting pyruvate to glucose. Pyruvate is then increasingly converted to lactate. Metformin accumulation also inhibits the mitochondrial electron transport chain, resulting in increased NADH. NADH is subsequently used to reduce pyruvate to lactate. Impaired tissue oxygenation and impaired lactate metabolism are additional mechanisms by which lactate can increase.