Metformin-Induced Lactic Acidosis (MILA): Review of current diagnostic paradigm

doi:10.1016/j.ajem.2018.01.097

The American Journal of Emergency Medicine

Volume 36, Issue 5, May 2018, Pages 908.e3-908.e5

https://doi.org/10.1016/j.ajem.2018.01.097 Get rights and content

Abstract

A new diagnostic paradigm has been proposed to better categorize causes of Metformin-Associated Lactic Acidosis (MALA). The diagnostic criteria defines a link between Metformin and lactic acidosis if lactate is >5 mmol/L, Ph < 7.35 and Metformin assay > 5mg/L. Metformin assays are not readily available in emergency departments including nationwide Veteran’s Affairs Hospitals; thereby making this proposed classification tool difficult to use in today’s clinical practice. We describe a case report of a 45-year-old male, who took twice the amount of Metformin prescribed and presented with Metformin-induced lactic acidosis. According to the new criterion, our case would be classified as “Lactic Acidosis in Metformin-Treated Patients (LAMT).” However, the term LAMT does not distinguish between a septic patient taking Metformin with lactic acidosis, and a patient who ingested toxic amounts of Metformin and has lactic acidosis (in absence of Metformin assay). Our case highlights the importance of medication reconciliation done on arrival to emergency department. Timing and dosing of Metformin in patients who present to the emergency department with lactic acidosis may cinch the diagnosis of Metformin-Induced Lactic Acidosis (MILA) in the absence of a Metformin assay but in the right clinical context.

Section snippets

Case

A 45-year-old male with type 2 diabetes, hypertension, chronic kidney disease stage 2, bipolar disorder and substance abuse presents to the emergency department with 1-day history of nausea, vomiting, abdominal pain and appetite loss. Review of systems was otherwise negative except he had difficulty sleeping, therefore, was prescribed Trazodone 300 mg nightly by his psychiatrist (started three nights prior). On presentation, rectal temperature was 92.7 °F, pulse 86 beats per minute, respiratory

Discussion

Metformin is absorbed by enterocytes in the small intestine and delivered to liver via portal vein. Before leaving the intestine, Metformin increases production of lactate by promoting glycolysis and changing glucose metabolism from aerobic to anaerobic pathways [2,3]. A well-controlled type 2 diabetic, without renal impairment, taking Metformin appropriately will have inhibition of gluconeogenesis to prevent hyperglycemia, but will not have enough effect to produce significant lactate [4]. In

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Cited by (8)

High risk and low prevalence diseases: Toxic alcohol ingestion
2023, American Journal of Emergency Medicine
Toxic alcohol ingestion is a rare but serious condition that carries with it a high rate of morbidity and mortality.
This review highlights the pearls and pitfalls of toxic alcohol ingestion, including presentation, diagnosis, and management in the emergency department (ED) based on current evidence.
Toxic alcohols include ethylene glycol, methanol, isopropyl alcohol, propylene glycol, and diethylene glycol. These substances can be found in several settings including hospitals, hardware stores, and the household, and ingestion can be accidental or intentional. Toxic alcohol ingestion presents with various degrees of inebriation, acidemia, and end-organ damage depending on the substance. Timely diagnosis is critical to prevent irreversible organ damage or death and is based primarily on clinical history and consideration of this entity. Laboratory evidence of toxic alcohol ingestion includes worsening osmolar gap or anion-gap acidemia and end organ injury. Treatment depends on the ingestion and severity of illness but includes alcohol dehydrogenase blockade with fomepizole or ethanol and special considerations for the initiation of hemodialysis.
An understanding of toxic alcohol ingestion can assist emergency clinicians in diagnosing and managing this potentially deadly disease.
Metformin lactic acidosis: Should we still be afraid?
2019, Diabetes Research and Clinical Practice
Citation Excerpt :
Without these, particularly if circulating metformin level is missing, it is impossible to distinguish between LA by metformin accumulation in the setting of overdosing or kidney failure and LA by systemic conditions (sepsis, cardiac failure, haemorrhage, etc.) in a patient taking metformin in which biguanide use may be merely concomitant, without any causal role [22]. To better categorize LA causes, a diagnostic paradigm has been proposed by Krowl et al., according to which a causal link with metformin may be defined if lactate is >5 mmol/L, pH < 7.35 and metformin circulating level >5 mg/L [23]. Unfortunately, metformin assay is not readily available in emergency wards, thereby making this classification tool difficult to use in today's clinical practice.
Metformin, the first choice drug for type 2 diabetes treatment in all stages of therapy, and one of the most widely prescribed anti-hyperglycemic agents worldwide, represents a rare example of an old drug which continues to display new beneficial effects in various fields. However, lactic acidosis (LA) persists as a serious adverse effect. LA incidence is low and is not necessarily determined by the administration of metformin. Unfortunately, the concern for this complication has negatively affected the drug use, particularly in chronic kidney disease, which may impair drug excretion, and in congestive heart failure and chronic liver disease, which may promote lactate accumulation. This review describes how not only these historical contraindications have been considerably scaled back, though rather a recent large body of evidence supports a protective effect of biguanide on kidney, heart and liver and, maybe, against lactic acidosis itself.
It is worthy to slow down both contraindications and precautions to metformin use, not to deprive a significant number of diabetic patients, as those with kidney, heart and liver comorbidities, from its potential benefits, and not to hamper in the near future the putative advantages in a wide spectrum of conditions outside of diabetes.
Reversible Acute Blindness in Suspected Metformin-Associated Lactic Acidosis
2019, Journal of Emergency Medicine
Citation Excerpt :
It is, therefore, impossible to measure blood concentrations of metformin in routine clinical practice. Consequently, MALA should be suspected in patients with a history of metformin intake, irrespective of whether plasma levels of metformin are known (17–20). In our case, although the plasma concentration of metformin was not estimated, treatment for MALA was instituted immediately, based on the history of metformin intake, the presence of metabolic acidosis, and renal insufficiency, with successful results.
Metformin is commonly used for the treatment of type 2 diabetes mellitus. Renal insufficiency is one of the contraindications for its use. Inadvertent prescription in patients with renal insufficiency may lead to metformin-associated lactic acidosis (MALA), which is associated with a high risk of mortality. Consequently, the early recognition and management of MALA is essential.
We present the case of a 68-year-old man who had reversible blindness resulting from severe lactic acidosis. On presentation, he was alert, oriented, and had no complaints except mild abdominal discomfort and blindness. He denied any history of trauma or drug abuse. The results of the laboratory studies showed severe metabolic acidosis with a high anion gap and increased levels of serum creatinine. There were no predisposing ocular or neurologic lesions that could have induced the blindness. Although the blood levels of methanol, ethanol, and metformin were not estimated, correction of acidosis and hemodialysis led to a complete recovery.
Rarely, transient blindness may occur in patients with fatal severe metabolic acidosis. Evaluation for the presence of metabolic acidosis and a detailed medical history are essential in the management of acute blindness in such patients.
Reversible acute blindness in suspected metformin-associated lactic acidosis: a case report
2023, Journal of Medical Case Reports
Reversible Acute Blindness in Suspected Metformin- Associated Lactic Acidosis
2023, Research Square
Metformin in therapeutic applications in human diseases: its mechanism of action and clinical study
2022, Molecular Biomedicine

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The authors declare no conflict of interest.

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Case ReportMetformin-Induced Lactic Acidosis (MILA): Review of current diagnostic paradigm☆

Abstract

Section snippets

Case

Discussion

Case 23-2013: a 54-year-old woman with abdominal pain, vomiting, and confusion

N Engl J Med

Pathophysiology of experimental lactic acidosis in dogs

Am J Physiol

Effects of metformin on lactate uptake and gluconeogenesis in the perfused rat liver

Diabetes

Metformin-associated lactic acidosis (MALA): moving towards a new paradigm

Diabetes Obes Metab

Metformin-associated lactic acidosis and acute renal failure in a type 2 diabetic patient

J Chin Med Assoc

Case Report
Metformin-Induced Lactic Acidosis (MILA): Review of current diagnostic paradigm☆