Bariatric surgery and changes in metformin distribution: About a fatal case

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Metformin is an hypoglycemic drug, represented as the « gold standard » for the treatment of maturity-onset diabetes. Lactic acidosis is a well known and feared adverse effect of this substance.The authors present the case of a 65 year-old woman, suffering from mellitus type 2 diabetes and obesity, who died at home, only three days after bariatric surgery (Roux-en-Y gastric by-pass, RYGB). Her treatment, including metformin and dapagliflozin, was stopped before surgery and not postoperatively resumed. The woman was visited by a friend 15 hours before the body discovery, and no information was available about the symptoms presented by the patient before the death, excepted asthenia. A forensic autopsy was performed. Cardiac and femoral blood, urine, gastric content and hair were collected for toxicological investigations. Metformin was specifically tested on a GC-MS/MS system. Liquid matrices (0.2 mL) were subject to protein precipitation with 3 mL of acetonitrile in the presence of merformin-d6 used as internal standard. After agitation and centrifugation, the surpernatant was evaporate to dryness and the dry extract was derivatized with MBTFA. Metformine was extracted from 20 mg of hair with methanol. Detection of metformin was achieved using two transitions: m/z 303 > 288 and m/z 303 > 125. No evidence of digestive perforation or peritonitis was identified during autopsy, excluding an early surgery complication as the cause of death. These findings were confirmed by the histological analysis which showed a physiological intestinal inflammatory reaction related to the recent surgery. Toxicological analysis revealed the presence of acetone in the blood (0.25 g/L) and in the urine (0.58 g/L), confirming diabetes. Metformin tested positive in blood (148 mg/L), urine (49 mg/L), intestinal content (> 100 mg/L) and hair (1.9 ng/mg). Blood concentration was considered potentially fatal. The low concentration in urine indicated rapid death after exposure. Hair concentration was in the therapeutic range. The pathologist concluded that the death was due to lactic acidosis caused by an overdose of metformin. With no evidence for suicide by ingestion of metformin, the hypothesis raised by the authors was that the bariatric surgery might have caused changes in the absorption of metformin, leading to a rapid overdose and death. In the literature, it has been demonstrated in gastric bypass patients that there is a significant increase in the bioavailability of metformin following oral administration. RYGB would increases intestinal transit time and thus the duration of exposure to small intestinal mucosa. Changes induced by the surgical procedure are probably not sufficient to explain the massive concentrations of metformin found in the postmortem samples but the context of the corpse discovery was not suggestive of suicide. As this represents the first case of metformin overdose following bariatric surgery, further cases will be needed to confirm our initial observations. It can be anticipated that a therapeutic dose can become toxic when administrated to a subject who recently modified her digestive equipment. This case highlights the doubts that can be encountered by pathologists and toxicologists in forensic medicine and that evidences must constantly be reconsidered.