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01-11-2015 | Original Article

Post-mortem analysis of lactate concentration in diabetics and metformin poisonings

Authors: T. Keltanen, T. Nenonen, R. A. Ketola, I. Ojanperä, A. Sajantila, K. Lindroos

Published in: International Journal of Legal Medicine | Issue 6/2015

Abstract

Lactate is produced in carbohydrate metabolism under anaerobic conditions. Lactic acidosis occurs when the production of lactate exceeds its removal. In post-mortem (PM) context, the lactic acidosis is difficult to interpret due to unknown pathophysiological factors prior to death and PM changes that may affect the lactate levels. We evaluated 1865 medico-legal autopsy cases where the quantitation of glucose, lactate, and ketone bodies was performed as a part of the cause of death (CoD) investigation. Lactate was shown to ascend in a logarithmic manner as the PM interval increased until a plateau was achieved approximately after 8–10 days PM, and the elevation was caused mainly by PM changes. The lactate level was higher than the mean in cases where the CoD was diabetes mellitus type 2 (DM2) or metformin poisoning. Although there was a correlation between metformin and lactate levels, our findings suggest the DM2 and its complications were the cause for elevated lactate levels rather than metformin, since the lactate levels were similar in DM2-associated deaths where no metformin was detected. Elevated lactate levels in PM samples rather referred to metabolic disturbances often caused by DM2. An assay to detect D-lactate in PM samples was described.

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Luft D, Deichsel G, Schmulling RM, Stein W, Eggstein M (1983) Definition of clinically relevant lactic acidosis in patients with internal diseases. Am J Clin Pathol 80(4):484–489PubMed

Boulagnon C, Garnotel R, Fornes P, Gillery P (2011) Post-mortem biochemistry of vitreous humor and glucose metabolism: an update. Clin Chem Lab Med 49(8):1265–1270. doi:10.1515/CCLM.2011.638 CrossRefPubMed

Hess C, Musshoff F, Madea B (2011) Disorders of glucose metabolism-post mortem analyses in forensic cases: part I. Int J Legal Med 125(2):163–170. doi:10.1007/s00414-010-0509-6 CrossRefPubMed

Sippel H, Mottonen M (1982) Combined glucose and lactate values in vitreous humour for postmortem diagnosis of diabetes mellitus. Forensic Sci Int 19(3):217–222CrossRefPubMed

Traub F (1969) Method for the detection of lethal glucose metabolism disorders in the corpse (diabetes mellitus and hypoglycemia). Zentralbl Allg Pathol 112(4):390–399PubMed

Hess C, Wollner K, Musshoff F, Madea B (2013) Detection of diabetic metabolism disorders post-mortem--forensic case reports on cause of death hyperglycaemia. Drug Test Anal 5(9–10):795–801. doi:10.1002/dta.1479 CrossRefPubMed

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):407–413. doi:10.1007/s00414-011-0659-1 CrossRefPubMed

Zilg B, Alkass K, Berg S, Druid H (2009) Postmortem identification of hyperglycemia. Forensic Sci Int 185(1–3):89–95. doi:10.1016/j.forsciint.2008.12.017 CrossRefPubMed

Brinkmann B, Fechner G, Karger B, DuChesne A (1998) Ketoacidosis and lactic acidosis--frequent causes of death in chronic alcoholics? Int J Legal Med 111(3):115–119CrossRefPubMed

10.

Keltanen T, Sajantila A, Palo JU, Partanen T, Valonen T, Lindroos K (2013) Assessment of Traub formula and ketone bodies in cause of death investigations. Int J Legal Med 127(6):1131–1137. doi:10.1007/s00414-013-0917-5 CrossRefPubMed

11.

Vivero G, Vivero-Salmeron G, Perez Carceles MD, Bedate A, Luna A, Osuna E (2008) Combined determination of glucose and fructosamine in vitreous humor as a post-mortem tool to identify antemortem hyperglycemia. Rev Diabet Stud 5(4):220–224PubMedCentralCrossRefPubMed

12.

Fall PJ, Szerlip HM (2005) Lactic acidosis: from sour milk to septic shock. J Intensive Care Med 20(5):255–271. doi:10.1177/0885066605278644 CrossRefPubMed

13.

De Letter EA, Piette MH (1998) Can routinely combined analysis of glucose and lactate in vitreous humour be useful in current forensic practice? Am J Forensic Med Pathol 19(4):335–342CrossRefPubMed

14.

Bailey CJ, Turner RC (1996) Metformin. N Engl J Med 334(9):574–579CrossRefPubMed

15.

Lalau JD (2010) Lactic acidosis induced by metformin: incidence, management and prevention. Drug Saf : Int J Med Toxicol Drug Experience 33(9):727–740. doi:10.2165/11536790-000000000-00000 CrossRef

16.

Salpeter SR, Greyber E, Pasternak GA, Salpeter EE (2010) Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev 4, CD002967. doi:10.1002/14651858.CD002967.pub4 PubMed

17.

Scale T, Harvey JN (2011) Diabetes, metformin and lactic acidosis. Clin Endocrinol (Oxf) 74(2):191–196. doi:10.1111/j.1365-2265.2010.03891.x CrossRef

18.

Stades AME, Heikens JT, Erkelens DW, Holleman F, Hoekstra JBL (2004) Metformin and lactic acidosis: cause or coincidence? A review of case reports. J Intern Med 255(2):179–187. doi:10.1046/j.1365-2796.2003.01271.x CrossRefPubMed

19.

Uribarri J, Oh MS, Carroll HJ (1998) D-lactic acidosis. A review of clinical presentation, biochemical features, and pathophysiologic mechanisms. Medicine 77(2):73–82CrossRefPubMed

20.

Felby S, Nielsen E (1994) Determination of Ketone-Bodies in Postmortem Blood by Headspace Gas-Chromatography. Forensic Sci Int 64(2–3):83–88CrossRefPubMed

21.

Felby S, Nielsen E, Thomsen JL (2008) The postmortem distribution of ketone bodies between blood, vitreous humor, spinal fluid, and urine. Forensic Sci Med Pathol 4(2):100–107. doi:10.1007/s12024-007-9018-4 CrossRefPubMed

22.

Thomsen JL, Felby S, Theilade P, Nielsen E (1995) Alcoholic ketoacidosis as a cause of death in forensic cases. Forensic Sci Int 75(2–3):163–171CrossRefPubMed

23.

Laffel L (1999) Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Res Rev 15(6):412–426. doi:10.1002/(sici)1520-7560(199911/12)15:6<412::aid-dmrr72>3.0.co;2-8 CrossRefPubMed

24.

Gergov M, Nenonen T, Ojanpera I, Ketola RA (2015) Compensation of matrix effects in a standard addition method for metformin in postmortem blood using liquid chromatography-electrospray-tandem mass spectrometry. J Anal Toxicol. doi:10.1093/jat/bkv020 PubMed

25.

Harper DR (1989) A comparative study of the microbiological contamination of postmortem blood and vitreous humour samples taken for ethanol determination. Forensic Sci Int 43(1):37–44CrossRefPubMed

26.

Lalau JD, Arnouts P, Sharif A, De Broe ME (2015) Metformin and other antidiabetic agents in renal failure patients. Kidney Int 87(2):308–322. doi:10.1038/ki.2014.19 CrossRefPubMed

27.

Cox K, Cocchi MN, Salciccioli JD, Carney E, Howell M, Donnino MW (2012) Prevalence and significance of lactic acidosis in diabetic ketoacidosis. J Crit Care 27(2):132–137. doi:10.1016/j.jcrc.2011.07.071 PubMedCentralCrossRefPubMed

28.

Kraut JA, Madias NE (2007) Serum anion gap: its uses and limitations in clinical medicine. Clin J Am Soc Nephrol 2(1):162–174. doi:10.2215/CJN.03020906 CrossRefPubMed

29.

Lu J, Zello GA, Randell E, Adeli K, Krahn J, Meng QH (2011) Closing the anion gap: contribution of D-lactate to diabetic ketoacidosis. Clin Chim Acta 412(3–4):286–291. doi:10.1016/j.cca.2010.10.020 CrossRefPubMed

30.

Sheikh-Ali M, Karon BS, Basu A, Kudva YC, Muller LA, Xu J, Schwenk WF, Miles JM (2008) Can serum beta-hydroxybutyrate be used to diagnose diabetic ketoacidosis? Diabetes Care 31(4):643–647. doi:10.2337/dc07-1683 CrossRefPubMed

31.

Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN (2009) Hyperglycemic crises in adult patients with diabetes. Diabetes Care 32(7):1335–1343. doi:10.2337/dc09-9032 PubMedCentralCrossRefPubMed

32.

Bonsignore A, Pozzi F, Fraternali Orcioni G, Ventura F, Palmiere C (2013) Fatal metformin overdose: case report and postmortem biochemistry contribution. Int J Legal Med. doi:10.1007/s00414-013-0927-3 PubMed

33.

Tolman KG, Fonseca V, Dalpiaz A, Tan MH (2007) Spectrum of liver disease in type 2 diabetes and management of patients with diabetes and liver disease. Diabetes Care 30(3):734–743. doi:10.2337/dc06-1539 CrossRefPubMed

34.

Suzuki T, Shinjo S, Arai T, Kanai M, Goda N (2014) Hypoxia and fatty liver. World J Gastroenterol 20(41):15087–15097. doi:10.3748/wjg.v20.i41.15087 PubMedCentralCrossRefPubMed

35.

Weidemann A, Johnson RS (2008) Biology of HIF-1alpha. Cell Death Differ 15(4):621–627. doi:10.1038/cdd.2008.12 CrossRefPubMed

36.

Xiao H, Gu Z, Wang G, Zhao T (2013) The possible mechanisms underlying the impairment of HIF-1alpha pathway signaling in hyperglycemia and the beneficial effects of certain therapies. Int J Med Sci 10(10):1412–1421. doi:10.7150/ijms.5630 PubMedCentralCrossRefPubMed

37.

Pawlyk AC, Giacomini KM, McKeon C, Shuldiner AR, Florez JC (2014) Metformin pharmacogenomics: current status and future directions. Diabetes 63(8):2590–2599. doi:10.2337/db13-1367 PubMedCentralCrossRefPubMed

38.

Talasniemi JP, Pennanen S, Savolainen H, Niskanen L, Liesivuori J (2008) Analytical investigation: assay of D-lactate in diabetic plasma and urine. Clin Biochem 41(13):1099–1103. doi:10.1016/j.clinbiochem.2008.06.011 CrossRefPubMed

Title: Post-mortem analysis of lactate concentration in diabetics and metformin poisonings
Authors: T. Keltanen
T. Nenonen
R. A. Ketola
I. Ojanperä
A. Sajantila
K. Lindroos
Publication date: 01-11-2015
Publisher: Springer Berlin Heidelberg
Published in: International Journal of Legal Medicine / Issue 6/2015
Print ISSN: 0937-9827
Electronic ISSN: 1437-1596
DOI: https://doi.org/10.1007/s00414-015-1256-5

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Post-mortem analysis of lactate concentration in diabetics and metformin poisonings

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