OBJECTIVE. The relationship between metformin accumulation and lactate increase is still debated. This observational case series aims to evaluate the correlation of metformin plasma levels with the pH, lactate and creatinine levels, and with the mortality rate in selected patients with metformin accumulation confirmed through metformin plasma concentration detection at hospital admission. MATERIAL AND METHODS. All cases of lactic acidosis (pH, ≤ 7.35; arterial lactate, ≥ 5 mmol/L) related to metformin accumulation (plasma level ≥ 4 mcg/mL) from 2007 to 2011 were retrospectively reviewed. Erroneous ingestion and voluntary overdoses were excluded. Epidemiological, medical history, clinical and laboratory data were evaluated in all cases. RESULTS. Sixty-six patients were included. Thirty-one patients (47%) had contraindication to therapy with metformin. All patients showed severe lactic acidosis (pH, 6.91 ± 0.18; lactate, 14.36 ± 4.90 mmol/L) and acute renal failure (creatinine, 7.24 ± 3.29 mg/dL). The mean metformin plasma concentration was 40.68 ± 27.70 mcg/mL. Metformin plasma concentrations showed a correlation, statistically significant even if not strong, with creatinine (p = 0.002, R = 0.37), pH (p < 0.0001, R = - 0.43) and plasma lactate levels (p = 0.001, R = 0.41). Sixty-two (94%) underwent dialysis. Early mortality (before discharge from ICU) was 26% (17 cases). Lactate and metformin concentrations had mean levels not statistically different in surviving and deceased patients. CONCLUSIONS. Patients on chronic therapy with metformin may develop a mitochondrial-related toxicity that should be considered when patients present with lactic acidosis, renal failure, and frequently, a medical history of gastrointestinal manifestations during the days preceding the hospital admission. The correlation between metformin plasma concentrations and creatinine, pH, and lactate levels seems to be related to the mechanism of action (inhibition of complex I of the mitochondrial respiratory chain) and to the kinetic properties (high distribution volume and low protein binding) of the drug. The relevant early mortality seems not correlated with the levels of metformin or lactates: this could be due to the possible role of concurrent illness even if, such as for the relationships with lactate and creatinine, a more proper toxicological evaluation could be obtained by assessing metformin erythrocyte concentrations instead of the plasmatic ones.

IntroductionLactic acidosis can develop during biguanide (metformin and phenformin) intoxication, possibly as a consequence of mitochondrial dysfunction. To verify this hypothesis, we investigated whether body oxygen consumption (VO2), that primarily depends on mitochondrial respiration, is depressed in patients with biguanide intoxication.MethodsMulticentre retrospective analysis of data collected from 24 patients with lactic acidosis (pH 6.93 ± 0.20; lactate 18 ± 6 mM at hospital admission) due to metformin (n = 23) or phenformin (n = 1) intoxication. In 11 patients, VO2 was computed as the product of simultaneously recorded arterio-venous difference in O2 content [C(a-v)O2] and cardiac index (CI). In 13 additional cases, C(a-v)O2, but not CI, was available.ResultsOn day 1, VO2 was markedly depressed (67 ± 28 ml/min/m2) despite a normal CI (3.4 ± 1.2 L/min/m2). C(a-v)O2 was abnormally low in both patients either with (2.0 ± 1.0 ml O2/100 ml) or without (2.5 ± 1.1 ml O2/100 ml) CI (and VO2) monitoring. Clearance of the accumulated drug was associated with the resolution of lactic acidosis and a parallel increase in VO2 (P < 0.001) and C(a-v)O2 (P < 0.05). Plasma lactate and VO2 were inversely correlated (R2 0.43; P < 0.001, n = 32).ConclusionsVO2 is abnormally low in patients with lactic acidosis due to biguanide intoxication. This finding is in line with the hypothesis of inhibited mitochondrial respiration and consequent hyperlactatemia.

IntroductionWe have recently demonstrated that metformin intoxication causes mitochondrial dysfunction in several porcine tissues, including platelets. The aim of the present work was to clarify whether it also causes mitochondrial dysfunction (and secondary lactate overproduction) in human platelets, in vitro and ex vivo.MethodsHuman platelets were incubated for 72 hours with saline or increasing doses of metformin (in vitro experiments). Lactate production, respiratory chain complex activities (spectrophotometry), mitochondrial membrane potential (flow-cytometry after staining with JC-1) and oxygen consumption (Clark-type electrode) were then measured. Platelets were also obtained from ten patients with lactic acidosis (arterial pH 6.97 ± 0.18 and lactate 16 ± 7 mmol/L) due to accidental metformin intoxication (serum drug level 32 ± 14 mg/L) and ten healthy volunteers of similar sex and age. Respiratory chain complex activities were measured as above (ex vivo experiments).ResultsIn vitro, metformin dose-dependently increased lactate production (P < 0.001), decreased respiratory chain complex I activity (P = 0.009), mitochondrial membrane potential (P = 0.003) and oxygen consumption (P < 0.001) of human platelets. Ex vivo, platelets taken from intoxicated patients had significantly lower complex I (P = 0.045) and complex IV (P < 0.001) activity compared to controls.ConclusionsDepending on dose, metformin can cause mitochondrial dysfunction and lactate overproduction in human platelets in vitro and, possibly, in vivo.Trial registrationNCT 00942123.

Despite its rarity, infliximab-related hepatitis constitutes a cutting edge and challenging problem. In December 2004, a drug warning was issued by the Food and Drug Administration to alert healthcare professionals to the risk of hepatotoxicity in course of infliximab therapy. Subsequently, several reports of probable infliximab hepatitis have been published and interest is growing in trying to elucidate the impact of these events on clinical practice. After discussing our case report, the main characteristics of infliximab-mediated liver injury are analyzed, coupled with a review of the medical literature. Infliximab seems to provoke both immunomediated and a direct liver injury, but how this latter happens remains unclear. Moreover, infliximab immunomediated liver dysfunction resembles that of autoimmune hepatitis type I, with elevation of antinuclear, anti-smooth muscle, anti-double-strand DNA antibodies, and a clear preference for female sex. Finally, a flow chart is proposed with the purpose to help clinicians in the management of patients who develop signs of liver dysfunction during treatment with infliximab.