Ruiz‑Ramos et al. J Med Case Reports (2021) 15:17 https://doi.org/10.1186/s13256-020-02655-8 CASE REPORT Open Access The usefulness of measuring the anion gap in diagnosing metformin‑associated lactic acidosis: a case series Jesus Ruiz‑Ramos1* , Laura Lozano‑Polo2, Ana Juanes‑Borrego1, Iván Agra‑Montava2, Mireia Puig‑Campmany2 and María Antonia Mangues‑Bafalluy1 Abstract Background: Metformin-associated lactic acidosis (MALA) is a widely documented adverse event of metformin. Despite being considered one of the main causes of metabolic acidosis, the association between an anion gap and MALA diagnosis is still uncertain. Case presentation: Cases involving six Caucasian patients with suspected MALA who were admitted to the emer‑ gency department were analysed. All these patients presented with pH values < 7.35, lactate levels > 2 mmol/L, and estimated glomerular filtration < 30 mL/min. Metformin plasma concentrations were > 2.5 mg/L in all the patients. The highest metformin concentrations were not found in the patients with the highest lactate levels. The anion gap values ranged from 12.3 to 39.3, with only two patients exhibiting values > 14. Conclusions: In patients with MALA, there is a significant variability in the anion gap values, which is not related to the level of metformin accumulation, and therefore, it is doubtful whether measuring anion gaps is useful as an approach for MALA diagnosis. Keywords: Metformin, Acidosis, Acute renal failure, Emergency care, Diabetes, Anion gap Background It has been established that a pH bellow 7.35, a high Since the 1950s, metformin has been successfully used as lactate level, and compatible symptomatology are key a first-line pharmacotherapy for treating individuals with elements in detecting the presence of MALA [5]. The type II diabetes [1]. Although it is considered as a drug anion gap, which measure the difference between cati- with a broad safety profile, metformin-associated lactic ons and anions in serum, is an useful tool when attempt- acidosis (MALA) is a widely documented adverse event ing to identify the cause of metabolic acidosis. Despite a [2, 3]. MALA is a rare condition associated with poor high anion gap being considered one of the main causes prognoses and has an estimated mortality of between of metabolic acidosis, it is still uncertain whether there 25 and 50% [4]. It develops more frequently in elderly is an association between an anion gap and MALA diag- patients with impaired kidney function and liver failure nosis. In this report, we present a case series of suspected [5] MALA patients with the aim of highlighting the impor- tance of the anion gap value in MALA diagnoses. Case presentation *Correspondence: Jruizr@santpau.cat; jrzrms@gmail.com Cases involving six Caucasian patients with sus- 1 Pharmacy Department, Hospital Santa Creu i Sant Pau, C/San Quintín 89, pected MALA who visited the emergency department 08041 Barcelona, Spain Full list of author information is available at the end of the article between September 2019 and December 2019 were © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat​iveco​mmons​.org/licen​ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat​iveco​ mmons​.org/publi​cdoma​in/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Ruiz‑Ramos et al. J Med Case Reports (2021) 15:17 Page 2 of 4 analysed. The main characteristics of these patients are Discussion and conclusions presented in Table 1. The mean age was 75.5 (stand- The results of our series demonstrate that in the case of ard deviation = 6.3) years. All the patients exhibited severe metformin intoxication, the anion gap value may respiratory symptoms at admission; further, based on be normal or slightly elevated, with no relation to the a blood gas analysis performed at emergency depart- metformin plasma concentrations. Anion gap altera- ment admission, almost all of them presented with a tions can occur in different situations involving acid-base pH value < 7.35 and lactate level > 2 mmol/L while imbalance, and monitoring these alterations is a useful only one patient had a lactate level of > 5 mmol/L, approach in determining the aetiology of metabolic aci- which is one of the established criteria for an MALA dosis. One of the most common causes is lactic acidosis. diagnosis [7]. Lactate level was analysed by the “GEM Metformin inhibits cellular mitochondrial respiration, premier 3500 in Instrumentation Laboratory” auto- causing an increase in anaerobic metabolism and lactate mated blood gas analysis system blood gas analyser production [9]. This situation leads to type B lactic aci- (ABL90, Radiometer, Bronshoj, Denmark). Alternative dosis [10] that overlaps with type A lactic acidosis due to causes of metabolic acidosis such concomitant drugs hypoperfusion in patients with haemodynamic failure in or toxics substances were excluded, based on medi- case of systemic collapse. cal history review and patients or relatives interview. The association between severity and mortality on Four patients presented with chronic kidney disease admission and the lactate value is well known. How- as a comorbidity. However, the estimated glomerular ever, the association between the anion gap value and filtration rate (calculated by the modification of diet mortality remains unclear. The sensitivity of using the in renal disease (MDRD) formula [6]) was less than anion gap has been reported to be poor in detecting the 30 mL/min at admission in all cases. All the patients levels of acidosis when it is mediated by lactate [11]. In had metformin plasma concentrations above the upper our patients, we observed that very high concentrations limit of the therapeutic range (> 2.5 mg/L) [7]. The of metformin with an increase in lactate levels did not highest metformin concentrations were not found in lead to a relevant increase in the anion gap. Therefore, patients with the highest lactate values. this series reinforces the view that measuring the anion Only two of the included patients met the haemodi- gap has limited utility in predicting the accumulation of alysis criteria established by the extracorporeal treat- this drug because of the different factors that can coexist ments in poisoning (EXTRIP) recommendations [8] in these patients. The toxicity found in our patients was (lactate > 20 mmol/L, pH ≤ 7.0, or failure of standard possibly due to mixed acidosis caused by a combination treatment, including bicarbonate); further, only one of of accumulated metformin, diabetic ketoacidosis, tis- them received haemodialysis, and therefore, the thera- sue hypoxia, and kidney failure, which resulted in a wide peutic effort upon admission was limited to the other range of anion gap values. The absence of plasma albumin patient. Two patients died during hospitalisation, and levels has prevented from obtaining corrected anion gap these patients had the highest metformin plasma con- values, which is a limitation of our study since it could centrations (> 30 mg/L). The anion gap values (cal- partly affect the results obtained. Among the limitations culated as ­[Na+] + ­[K+] − ­[Cl−] − ­[HCO3−]) ranged associated with our series, the one worth noting is that at from 12.3 to 39.3, with only two patients exhibiting admission, there was a lack of data on albumin levels that values greater than 14. can significantly modify the value of the anion gap. On the other hand, it is known that the severity of lactic acidosis is not proportional to metformin plasma Table 1 Characteristics of patients included No Age CKD Creatinine (mg/ Metformin pH Lactate 0 hour Anion 24 hours Anion Exitus dL) (mg/L) (mmol/L) gap gap 24 hours 1 73 No 7.87 34.7 7.07 12.5 37.7 36.6 Si 2 77 Yes 2.02 10.32 7.03 2.7 16.7 17.1 No 3 82 Yes 4.14 44.66 7.13 2.8 12.3 14.2 Si 4 64 No 7.85 15.8 6.74 7.9 39.3 44.8 No 5 78 No 1.86 18.1 7.30 2 14.2 12.2 No 6 79 Yes 4.68 8.27 7.21 5.7 16.3 24.9 No CKD chronic kidney disease Ruiz‑Ramos et al. J Med Case Reports (2021) 15:17 Page 3 of 4 concentrations, as patients described as having severe Authors’ contributions LL, and IA were on the inpatient team that provided treatment for the clinical symptoms exhibited slightly elevated concen- patient. JR, AJ, and MM wrote the primary manuscript. MP provided trations, and those without MALA had high concen- guidance and assistance in writing the manuscript. All authors read and trations of metformin; despite these findings, high approved the final manuscript. concentrations have been associated with higher mor- Funding tality rates in patients with MALA [12]. The small The authors declare not funding has been used for the preparation of this sample size in our series prevented us from drawing manuscript. conclusions regarding the association between met- Availability of data and materials formin concentrations and mortality. Despite this, we Not applicable. observed that the patients with the highest metformin Ethics approval and consent to participate concentrations were those who died, which contributes This study was conducted in accordance with the fundamental principles to fuelling this debate. of the Declaration of Helsinki. The study was approved by the Local Hospital Likewise, changes in pH, lactate levels, and bicarbonate ethical committee (no Ref.: IISB-MET-2019-9i). values are critical for making a selection among thera- Consent for publication peutic options. It should be noted that only one of the six Written informed consent was obtained from the patients for publication patients had a lactate value of > 5 mmol/L, an established of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. criterion for the diagnosis of MALA [5]. However, all the patients in our series had serious clinical conditions. For Competing interests this reason, it must be considered that lower levels of lac- The authors declare they have no competing interests. tate may indicate significant accumulations of metformin Author details and severe clinical presentations, given that the anion 1 Pharmacy Department, Hospital Santa Creu i Sant Pau, C/San Quintín 89, gap value could not aid in diagnosing these cases. 08041 Barcelona, Spain. 2 Emergency Department, Hospital Santa Creu i Sant Pau, Barcelona, Spain. Two of the six patients (33.3%) died during hospitali- sation. Previous studies have reported mortality rates Received: 5 November 2020 Accepted: 28 December 2020 between 25 and 50% [4], highlighting the severity of this complication. Despite the fact that owing to its benefits in terms of the incidence of cardiovascular events and mortality, metformin is recommended by different guide- References lines for patients with mild or moderate impairment of 1. American Diabetes Association. 9. 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