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Published in: International Journal of Legal Medicine 3/2014

01-05-2014 | Case Report

Fatal metformin overdose: case report and postmortem biochemistry contribution

Authors: Alessandro Bonsignore, Fulvia Pozzi, Giulio Fraternali Orcioni, Francesco Ventura, Cristian Palmiere

Published in: International Journal of Legal Medicine | Issue 3/2014

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Abstract

Metformin is an oral antihyperglycemic agent used in the management of type 2 diabetes mellitus. Lactic acidosis from metformin overdose is a rare complication of metformin therapy and occurs infrequently with therapeutic use. Fatal cases, both accidental and intentional, are extremely rare in clinical practice. Metformin is eliminated by the kidneys, and impaired renal function can result in an increased plasma concentration of the drug. In this report, we describe an autopsy case involving a 70-year-old woman suffering from diabetes mellitus and impaired renal function who received metformin treatment. Metformin concentrations in the peripheral blood collected during hospitalization and femoral blood collected during autopsy were 42 and 47.3 µg/ml, respectively. Lactic acidosis (29.10 mmol/l) was objectified during hospitalization. Furthermore, postmortem biochemistry allowed ketoacidosis to be diagnosed (blood β-hydroxybutyrate, 10,500 µmol/l). Death was attributed to lactic acidosis due to metformin intoxication. Increased plasma concentrations of the drug were attributed to severely impaired renal function. The case emphasizes the usefulness of performing exhaustive toxicology and postmortem biochemistry towards the more complete understanding of the pathophysiological mechanisms that may be involved in the death process.
Literature
1.
go back to reference Al-Abri SA, Hayashi S, Thoren KL, Olson KR (2013) Metformin overdose-induced hypoglycemia in the absence of other antidiabetic drugs. Clin Toxicol (Phila) 51(5):444–447CrossRef Al-Abri SA, Hayashi S, Thoren KL, Olson KR (2013) Metformin overdose-induced hypoglycemia in the absence of other antidiabetic drugs. Clin Toxicol (Phila) 51(5):444–447CrossRef
2.
go back to reference Moore KA, Levine B, Titus JM, Fowler DR (2003) Analysis of metformin in antemortem serum and postmortem specimens by a novel HPLC method and application to an intoxication case. J Anal Toxicol 27(8):592–594PubMedCrossRef Moore KA, Levine B, Titus JM, Fowler DR (2003) Analysis of metformin in antemortem serum and postmortem specimens by a novel HPLC method and application to an intoxication case. J Anal Toxicol 27(8):592–594PubMedCrossRef
3.
go back to reference Dell’Aglio DM, Perino LJ, Kazzi Z, Abramson J, Schwartz MD, Morgan BW (2009) Acute metformin overdose: examining serum pH, lactate level, and metformin concentrations in survivors versus nonsurvivors: a systematic review of the literature. Ann Emerg Med 54(6):818–823PubMedCrossRef Dell’Aglio DM, Perino LJ, Kazzi Z, Abramson J, Schwartz MD, Morgan BW (2009) Acute metformin overdose: examining serum pH, lactate level, and metformin concentrations in survivors versus nonsurvivors: a systematic review of the literature. Ann Emerg Med 54(6):818–823PubMedCrossRef
4.
go back to reference Suchard JR, Grotsky TA (2008) Fatal metformin overdose presenting with progressive hyperglycemia. West J Emerg Med 9(3):160–164PubMedCentralPubMed Suchard JR, Grotsky TA (2008) Fatal metformin overdose presenting with progressive hyperglycemia. West J Emerg Med 9(3):160–164PubMedCentralPubMed
5.
go back to reference Mizzi A, Landoni G, Corno L, Fichera M, Nuzzi M, Zangrillo A (2009) How to explain a PaO2 of 140 mmHg in a venous line? Acta Biomed 80(3):262–264PubMed Mizzi A, Landoni G, Corno L, Fichera M, Nuzzi M, Zangrillo A (2009) How to explain a PaO2 of 140 mmHg in a venous line? Acta Biomed 80(3):262–264PubMed
6.
go back to reference Lalau JD (2010) Lactic acidosis induced by metformin: incidence, management and prevention. Drug Saf 33(9):727–740PubMedCrossRef Lalau JD (2010) Lactic acidosis induced by metformin: incidence, management and prevention. Drug Saf 33(9):727–740PubMedCrossRef
7.
go back to reference Eurich DT, Majumdar SR, McAlister FA, Tsuyuki RT, Johnson JA (2008) Levels of evidence needed for changing indications, contraindications, and Food and Drug Administration labeling: the case of metformin. Arch Intern Med 171(11):1042–1043CrossRef Eurich DT, Majumdar SR, McAlister FA, Tsuyuki RT, Johnson JA (2008) Levels of evidence needed for changing indications, contraindications, and Food and Drug Administration labeling: the case of metformin. Arch Intern Med 171(11):1042–1043CrossRef
8.
go back to reference Nye HJ, Herrington WG (2011) Metformin: the safest hypoglycaemic agent in chronic kidney disease? Nephron Clin Pract 118(4):c380–c383PubMedCrossRef Nye HJ, Herrington WG (2011) Metformin: the safest hypoglycaemic agent in chronic kidney disease? Nephron Clin Pract 118(4):c380–c383PubMedCrossRef
9.
go back to reference Krzymień J, Karnafel W (2013) Lactic acidosis in patients with diabetes. Pol Arch Med Wewn 123(3):91–97PubMed Krzymień J, Karnafel W (2013) Lactic acidosis in patients with diabetes. Pol Arch Med Wewn 123(3):91–97PubMed
10.
go back to reference Spiller HA, Sawyer TS (2006) Toxicology of oral antidiabetic medications. Am J Health Syst Pharm 63(10):929–938PubMedCrossRef Spiller HA, Sawyer TS (2006) Toxicology of oral antidiabetic medications. Am J Health Syst Pharm 63(10):929–938PubMedCrossRef
11.
go back to reference Mujtaba M, Geara AS, Madhrira M, Agarwala R, Anderson H, Cheng JT, Mohan S (2012) Toxicokinetics of metformin-associated lactic acidosis with continuous renal replacement therapy. Eur J Grud Metab Pharmacokinet 37(4):249–253CrossRef Mujtaba M, Geara AS, Madhrira M, Agarwala R, Anderson H, Cheng JT, Mohan S (2012) Toxicokinetics of metformin-associated lactic acidosis with continuous renal replacement therapy. Eur J Grud Metab Pharmacokinet 37(4):249–253CrossRef
12.
go back to reference Wills BK, Bryant SM, Buckley P, Seo B (2010) Can acute overdose of metformin lead to lactic acidosis? Am J Emerg Med 28(8):857–861PubMedCrossRef Wills BK, Bryant SM, Buckley P, Seo B (2010) Can acute overdose of metformin lead to lactic acidosis? Am J Emerg Med 28(8):857–861PubMedCrossRef
13.
go back to reference Spiller HA, Quadrani DA (2004) Toxic effects from metformin exposure. Ann Pharmacother 38(5):776–780PubMedCrossRef Spiller HA, Quadrani DA (2004) Toxic effects from metformin exposure. Ann Pharmacother 38(5):776–780PubMedCrossRef
14.
go back to reference Lalau JD, Mourlhon C, Bergeret A, Lacroix C (1998) Consequences of metformin intoxication. Diabetes Care 21(11):2036–2037PubMedCrossRef Lalau JD, Mourlhon C, Bergeret A, Lacroix C (1998) Consequences of metformin intoxication. Diabetes Care 21(11):2036–2037PubMedCrossRef
15.
go back to reference Duong JK, Furlong TJ, Roberts DM, Graham GG, Greenfield JR, Williams KM, Day RO (2013) The role of metformin in metformin-associated lactic acidosis (MALA): case series and formulation of a model of pathogenesis. Drug Saf. doi:10.1007/s40264-013-0038-6 PubMed Duong JK, Furlong TJ, Roberts DM, Graham GG, Greenfield JR, Williams KM, Day RO (2013) The role of metformin in metformin-associated lactic acidosis (MALA): case series and formulation of a model of pathogenesis. Drug Saf. doi:10.​1007/​s40264-013-0038-6 PubMed
16.
go back to reference Lacher M, Hermanns-Clausen M, Haeffner K, Brandis M, Pohl M (2005) Severe metformin intoxication with lactic acidosis in an adolescent. Eur J Pediatr 164(6):362–365PubMedCrossRef Lacher M, Hermanns-Clausen M, Haeffner K, Brandis M, Pohl M (2005) Severe metformin intoxication with lactic acidosis in an adolescent. Eur J Pediatr 164(6):362–365PubMedCrossRef
17.
go back to reference Cantrell LF, Nelson CL, Gary RD, McIntyre IM (2012) Fatal metformin intoxication with markedly elevated blood and liver concentrations. J Anal Toxicol 36(9):657–659PubMedCrossRef Cantrell LF, Nelson CL, Gary RD, McIntyre IM (2012) Fatal metformin intoxication with markedly elevated blood and liver concentrations. J Anal Toxicol 36(9):657–659PubMedCrossRef
18.
go back to reference Gambaro V, Dell’acqua L, Farè F, Fidani M, Froldi R, Saligari E (2007) A case of fatal intoxication from metformin. J Forensic Sci 52(4):988–991PubMedCrossRef Gambaro V, Dell’acqua L, Farè F, Fidani M, Froldi R, Saligari E (2007) A case of fatal intoxication from metformin. J Forensic Sci 52(4):988–991PubMedCrossRef
19.
go back to reference Nisse P, Mathieu-Nolf M, Deveaux M, Forceville X, Combes A (2003) A fatal case of metformin poisoning. J Toxicol Clin Toxicol 41(7):1035–1036PubMedCrossRef Nisse P, Mathieu-Nolf M, Deveaux M, Forceville X, Combes A (2003) A fatal case of metformin poisoning. J Toxicol Clin Toxicol 41(7):1035–1036PubMedCrossRef
20.
go back to reference Hermann LS, Magnusson S, Möller B, Casey C, Tucker GT, Woods HF (1981) Lactic acidosis during metformin treatment in an elderly diabetic patient with impaired renal function. Acta Med Scand 209(6):519–520PubMed Hermann LS, Magnusson S, Möller B, Casey C, Tucker GT, Woods HF (1981) Lactic acidosis during metformin treatment in an elderly diabetic patient with impaired renal function. Acta Med Scand 209(6):519–520PubMed
21.
go back to reference Sánchez-Rubio Ferrández L, Martínez Iturriaga S, Hurtado Gómez MF, Apiñaniz Apiñaniz R (2013) Suicide to massive ingestion of metformin (85 g): lactic acidosis followed by rhabdomyolysis with fatal heart damage. Farm Hosp 37(2):166–167PubMed Sánchez-Rubio Ferrández L, Martínez Iturriaga S, Hurtado Gómez MF, Apiñaniz Apiñaniz R (2013) Suicide to massive ingestion of metformin (85 g): lactic acidosis followed by rhabdomyolysis with fatal heart damage. Farm Hosp 37(2):166–167PubMed
22.
go back to reference Orban JC, Giunti C, Levraut J, Grimaud D, Ichai C (2003) Metformin-associated lactic acidosis remains a serious complication of metformin therapy. Ann Fr Anesth Reanim 22(5):461–465PubMedCrossRef Orban JC, Giunti C, Levraut J, Grimaud D, Ichai C (2003) Metformin-associated lactic acidosis remains a serious complication of metformin therapy. Ann Fr Anesth Reanim 22(5):461–465PubMedCrossRef
23.
go back to reference Bronstein AC, Spyker DA, Cantilena LR Jr, Rumack BH, Dart RC (2012) 2011 annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 29th annual report. Clin Toxicol (Phila) 50(10):911–1164CrossRef Bronstein AC, Spyker DA, Cantilena LR Jr, Rumack BH, Dart RC (2012) 2011 annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 29th annual report. Clin Toxicol (Phila) 50(10):911–1164CrossRef
24.
go back to reference Perrone J, Phillips C, Gaieski D (2011) Occult metformin toxicity in three patients with profound lactic acidosis. J Emerg Med 40(3):271–275PubMedCrossRef Perrone J, Phillips C, Gaieski D (2011) Occult metformin toxicity in three patients with profound lactic acidosis. J Emerg Med 40(3):271–275PubMedCrossRef
25.
go back to reference Bronstein AC, Spyker DA, Cantilena LR Jr, Green JL, Rumack BH, Dart RC (2011) 2010 annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 28th annual report. Clin Toxicol (Phila) 49(10):910–941CrossRef Bronstein AC, Spyker DA, Cantilena LR Jr, Green JL, Rumack BH, Dart RC (2011) 2010 annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 28th annual report. Clin Toxicol (Phila) 49(10):910–941CrossRef
26.
go back to reference Bronstein AC, Spyker DA, Cantilena LR Jr, Green JL, Rumack BH, Giffin SL (2010) 2009 annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 27th annual report. Clin Toxicol (Phila) 48(10):979–1178CrossRef Bronstein AC, Spyker DA, Cantilena LR Jr, Green JL, Rumack BH, Giffin SL (2010) 2009 annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 27th annual report. Clin Toxicol (Phila) 48(10):979–1178CrossRef
27.
go back to reference Arroyo AM, Walroth TA, Mowry JB, Kao LW (2010) The MALAdy of metformin poisoning: is CVVH the cure? Am J Ther 17(1):96–100PubMedCrossRef Arroyo AM, Walroth TA, Mowry JB, Kao LW (2010) The MALAdy of metformin poisoning: is CVVH the cure? Am J Ther 17(1):96–100PubMedCrossRef
28.
go back to reference Barrueto F, Meggs WJ, Barchman MJ (2002) Clearance of metformin by hemofiltration in overdose. J Toxicol Clin Toxicol 40(2):177–180PubMedCrossRef Barrueto F, Meggs WJ, Barchman MJ (2002) Clearance of metformin by hemofiltration in overdose. J Toxicol Clin Toxicol 40(2):177–180PubMedCrossRef
29.
go back to reference Bismuth C, Gaultier M, Conso F, Assan R, Heuclin C (1976) Lactic acidosis induced by excessive ingestion of metformin. Eur J Toxicol Environ Hyg 9(1):55–57PubMed Bismuth C, Gaultier M, Conso F, Assan R, Heuclin C (1976) Lactic acidosis induced by excessive ingestion of metformin. Eur J Toxicol Environ Hyg 9(1):55–57PubMed
30.
go back to reference Assan R, Heuclin C, Ganeval D, Bismuth C, George J, Girard JR (1977) Metformin-induced lactic acidosis in the presence of acute renal failure. Diabetologia 13(3):211–217PubMedCrossRef Assan R, Heuclin C, Ganeval D, Bismuth C, George J, Girard JR (1977) Metformin-induced lactic acidosis in the presence of acute renal failure. Diabetologia 13(3):211–217PubMedCrossRef
31.
go back to reference Ortega Carnicer J, Ambrós Checa A, Martín Rodríguez C, Ruiz Lorenzo F, Portilla Botelho M, Gómez Grande L (2007) Overdose of metformin secondary to acute renal insufficiency: a report of six cases. Med Intensiva 31(9):521–525PubMedCrossRef Ortega Carnicer J, Ambrós Checa A, Martín Rodríguez C, Ruiz Lorenzo F, Portilla Botelho M, Gómez Grande L (2007) Overdose of metformin secondary to acute renal insufficiency: a report of six cases. Med Intensiva 31(9):521–525PubMedCrossRef
32.
go back to reference Dell’Aglio DM, Perino LJ, Todino JD, Algren DA, Morgan BW (2010) Metformin overdose with a resultant serum pH of 6.59: survival without sequelae. J Emerg Med 39(1):e77–e80PubMedCrossRef Dell’Aglio DM, Perino LJ, Todino JD, Algren DA, Morgan BW (2010) Metformin overdose with a resultant serum pH of 6.59: survival without sequelae. J Emerg Med 39(1):e77–e80PubMedCrossRef
33.
go back to reference Kosmalski M, Drozdowska A, Sliwinska A, Drzewoski J (2012) Inappropriate metformin prescribing in elderly type 2 diabetes mellitus (T2DM) patients. Adv Med Sci 57(1):65–70PubMedCrossRef Kosmalski M, Drozdowska A, Sliwinska A, Drzewoski J (2012) Inappropriate metformin prescribing in elderly type 2 diabetes mellitus (T2DM) patients. Adv Med Sci 57(1):65–70PubMedCrossRef
34.
go back to reference Tschöpe D, Hanefeld M, Meier JJ, Gitt AK, Halle M, Bramlage P, Schumm-Draeger PM (2013) The role of co-morbidity in the selection of antidiabetic pharmacotherapy in type-2 diabetes. Cardiovasc Diabetol 12:62PubMedCentralPubMedCrossRef Tschöpe D, Hanefeld M, Meier JJ, Gitt AK, Halle M, Bramlage P, Schumm-Draeger PM (2013) The role of co-morbidity in the selection of antidiabetic pharmacotherapy in type-2 diabetes. Cardiovasc Diabetol 12:62PubMedCentralPubMedCrossRef
35.
36.
go back to reference Devetzis V, Passadakis P, Panagoutsos S, Theodoridis M, Thodis E, Georgoulidou A, Vargemezis V (2011) Metformin-related lactic acidosis in patients with acute kidney injury. Int Urol Nephrol 43(4):1243–1248PubMedCrossRef Devetzis V, Passadakis P, Panagoutsos S, Theodoridis M, Thodis E, Georgoulidou A, Vargemezis V (2011) Metformin-related lactic acidosis in patients with acute kidney injury. Int Urol Nephrol 43(4):1243–1248PubMedCrossRef
37.
go back to reference Boulagnon C, Garnotel R, Fornes P, Gillery P (2011) Postmortem biochemistry of vitreous humor and glucose metabolism: an update. Clin Chem Lab Med 49(8):1265–1270PubMedCrossRef Boulagnon C, Garnotel R, Fornes P, Gillery P (2011) Postmortem biochemistry of vitreous humor and glucose metabolism: an update. Clin Chem Lab Med 49(8):1265–1270PubMedCrossRef
38.
go back to reference Zilg B, Alkass K, Berg S, Druid H (2009) Postmortem identification of hyperglycemia. Forensic Sci Int 185(1–3):89–95PubMedCrossRef Zilg B, Alkass K, Berg S, Druid H (2009) Postmortem identification of hyperglycemia. Forensic Sci Int 185(1–3):89–95PubMedCrossRef
39.
go back to reference Palmiere C, Sporkert F, Vaucher P, Werner D, Bardy D, Rey F, Lardi C, Brunel C, Augsburger M, Mangin P (2012) Is the formula of Traub still up to date in antemortem blood glucose level estimation? Int J Legal Med 126(3):407–413PubMedCrossRef Palmiere C, Sporkert F, Vaucher P, Werner D, Bardy D, Rey F, Lardi C, Brunel C, Augsburger M, Mangin P (2012) Is the formula of Traub still up to date in antemortem blood glucose level estimation? Int J Legal Med 126(3):407–413PubMedCrossRef
Metadata
Title
Fatal metformin overdose: case report and postmortem biochemistry contribution
Authors
Alessandro Bonsignore
Fulvia Pozzi
Giulio Fraternali Orcioni
Francesco Ventura
Cristian Palmiere
Publication date
01-05-2014
Publisher
Springer Berlin Heidelberg
Published in
International Journal of Legal Medicine / Issue 3/2014
Print ISSN: 0937-9827
Electronic ISSN: 1437-1596
DOI
https://doi.org/10.1007/s00414-013-0927-3

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