Knowing a patient’s pharmacologic history is key to an accurate diagnosis and appropriate treatment.
Case Presentation
A 68-year-old male with a history of type II diabetes mellitus, hypertension, hypercholesterolemia, and hypothyroidism presented to the emergency department with lightheadedness that began two days prior. He reported associated nausea, vomiting, shortness of breath, and non-bloody diarrhea. Patient denied fevers, chills, cough, congestion, chest pain, dysuria, or back pain. He had been working outdoors for the past few days. Patient reported compliance with his medications as prescribed including glipizide, levothyroxine, metformin. He denied any recent sick contacts, travel, new foods, or antibiotic use. Initial vitals were heart rate – 82 beats per minute, blood pressure - 171/67 mmHg, temperature - 37.2° Celsius (oral), SpO2 - 100% on room air. Physical exam was remarkable for dry mucous membranes, mild tachypnea, and mild abdominal discomfort. Mental status was within normal limits.
Initial laboratory results showed a complete blood count remarkable for a leukocytosis of 16 x 1,000/mm3 with neutrophilic predominance. Complete metabolic panel revealed sodium of 142 mmol/L, potassium of 5.7 mmol/L, chloride of 90 mmol/L, CO2 of 3 mmol/L, anion gap of 49, blood urea nitrogen of 82 mg/dL, creatinine of 11 mg/dL. Liver enzymes were within normal limits. Initial lactate was 15.5 mmol/L. The VBG was remarkable for pH of 6.88, pCO2 of 21 mmHg, and HCO3 of 4 mEQ/L.
IV fluids, ondansetron IV, and multiple pushes of sodium bicarbonate were given. Nephrology and MICU were consulted, and the patient was started on a continuous bicarbonate infusion. The differential included sepsis, other causes of anion gap metabolic acidosis including toxic ingestion, mesenteric ischemia, bowel obstruction, which are all ruled out. Therefore, given the history along with exam findings, the suspected diagnosis is metformin associated lactic acidosis (MALA). This is suspected to be precipitated by dehydration leading to acute kidney injury (AKI), causing metformin accumulation, and finally worsening the AKI.
Discussion
Metformin is a commonly prescribed anti-diabetic agent and regularly places in the top 10 most prescribed medications in the United States each year.1 Metformin is a biguanide that is recommended for prevention of progression in patients at high risk for developing Type 2 diabetes, for glycemic control in diabetes, and as first line therapy for elderly adults with diabetes. It is relatively well-tolerated, relatively low-cost, rarely causes hypoglycemia compared to insulin or sulfonylureas, and is recommended by the American Diabetes Association.2,3,4 Though exceedingly rare, affecting approximately 1 in 30,000 patients,5 metformin has an FDA black box warning due to lactic acidosis, which could cause multi-organ failure and death.6 An estimation of MALA incidence is about 6.3 per 100,000 patient-years with 50% mortality.7
Lactate elevation and subsequent acidosis is a relatively non-specific finding seen in many pathologies and can be divided into two sub-categories. Type A is an elevation due to anaerobic metabolism from hypoxia or hypoperfusion. Type B is unrelated to hypoxia or hypoperfusion.8 MALA pathology begins at the cellular level. Lactate elevation occurs due to inhibition of complex I of the electron transport chain, shifting ATP generation to anaerobic metabolism and lactate formation. Additionally, through metformin’s inhibitory effects on gluconeogenesis, hepatic clearance of lactate is decreased, further potentiating the acidosis.9,10 MALA typically occurs secondary to an underlying condition, in most cases renal injury or disease. Risk factors for MALA include sepsis, liver disease, heart or lung disease, alcohol use, and history of MALA.2
To date, there is no diagnostic test to confirm the specific diagnosis of MALA. Metformin levels can be obtained; however, they are of limited use in the ED as they require sending the sample to a reference laboratory and may take days to result. Additionally, metformin levels do not correlate with the severity of MALA.2 While the diagnostic criteria are not well defined, literature suggests consideration of MALA with a pH <7.35 and a lactate of >5mmol/L in the context of known metformin exposure.6 Additionally, several other causes of lactic acidosis, many reversible, must also be evaluated prior to making this diagnosis.
Management
Regarding predictions of outcomes for MALA, there is controversy regarding pH and lactate association with patient mortality. There have been case reports showing possible associations ;2 however, there are larger studies that suggest outcome is relative to the complexity and reason for MALA.11
Recognizing MALA is key for quick initiation of treatment, made challenging by the fact that MALA is associated with nonspecific symptoms including altered mental status, vision changes, breathing problems, gastrointestinal symptoms, and dizziness.2,12
Supportive care is recommended, including airway management and blood pressure stabilization. Sodium bicarbonate is recommended for bicarbonate level <5mEQ/L. Hemodialysis is recommended in severe cases to correct the acidosis. It is encouraged if lactate is greater than 20 mmol/L, pH is less than or equal to 7, or if other therapies including sodium bicarbonate have been utilized without improvement in the patient’s clinical condition.2,4
Case Resolution
The patient was admitted to the MICU for acute renal failure requiring emergent dialysis. An internal jugular dialysis catheter was placed for emergent dialysis in the ED, and intermittent hemodialysis was initiated in the ICU followed by continuous renal replacement therapy (CRRT). The bicarbonate drip was also continued to treat acidosis.
Additionally, given concern for prerenal contribution to renal injury given time spent outdoors in the heat, vomiting, and diarrhea, maintenance fluids were started. These treatments resulted in significant improvement in the patient's clinical status, with resolution of acidosis, improvement of Cr from 11 mg/dL to 1.8 mg/dL, lactate peaking at 29 mmol/L prior to dialysis, and down to within normal limits after hemodialysis and CRRT.
Soon after, the patient began tolerating oral intake with resolution of nausea, vomiting, diarrhea, and was deemed medically stable for transfer to the floor. The next day, he was discharged from the hospital with nephrology recommending stopping metformin. The patient followed up in the clinic 1 month later and reported feeling well, with full resolution of symptoms.
References
- Fuentes AV, Pineda MD, Venkata KCN. Comprehension of Top 200 Prescribed Drugs in the US as a Resource for Pharmacy Teaching, Training and Practice. Pharmacy (Basel). 2018;6(2):43. Published 2018 May 14. doi:10.3390/pharmacy6020043
- Nelson LS, Howland M, Lewin NA, Smith SW, Goldfrank LR, Hoffman RS. eds. Goldfrank's Toxicologic Emergencies, 11e. McGraw-Hill Education; 2019. Accessed April 21, 2024.
- American Diabetes Association Professional Practice Committee. Introduction and Methodology: Standards of Care in Diabetes—2024. Diabetes Care. 2024;47 (Supplement_1): S1–S4.
- Moleno R, Haynes A, Koyfman A, Alerhand S. Metformin-Associated Lactic Acidosis (MALA): ED Focused Management. emDocs. Published May 21, 2018. Accessed May 29, 2024.
- Mahmood R, Maccourtney D, Vashi M, Mohamed A. A Case of Metformin-Associated Lactic Acidosis. Cureus. 2023;15(4):e38222.
- Federal Drug Administration. Glucophage. Updated 2017. Accessed April 2024.
- Asif S, Bennett J, Marakkath B. Metformin-associated Lactic Acidosis: An Unexpected Scenario. Cureus. 2019;11(4):e4397.
- Redant S, Hussein H, Mugisha A, et al. Differentiating Hyperlactatemia Type A From Type B: How Does the Lactate/pyruvate Ratio Help?. J Transl Int Med. 2019;7(2):43-45.
- DeFronzo R, Fleming GA, Chen K, Bicsak TA. Metformin-associated lactic acidosis: Current perspectives on causes and risk. Metabolism. 2016;65(2):20-29.
- Blough B, Moreland A, Mora A Jr. Metformin-induced lactic acidosis with emphasis on the anion gap. Proc (Bayl Univ Med Cent). 2015;28(1):31-33.
- Kajbaf F, Lalau JD. The prognostic value of blood pH and lactate and metformin concentrations in severe metformin-associated lactic acidosis. BMC Pharmacol Toxicol. 2013;14:22.
- Biradar V, Moran JL, Peake SL, Peter JV. Metformin-associated lactic acidosis (MALA): clinical profile and outcomes in patients admitted to the intensive care unit. Crit Care Resusc. 2010;12(3):191-195.