The postmortem diagnosis of alcoholic ketoacidosis.

AIMS: The aim of this article is to review the forensic literature covering the postmortem investigations that are associated with alcoholic ketoacidosis fatalities and report the results of our own analyses. METHODS: Eight cases of suspected alcoholic ketoacidosis that had undergone medico-legal investigations in our facility from 2011 to 2013 were retrospectively selected. A series of laboratory parameters were measured in whole femoral blood, postmortem serum from femoral blood, urine and vitreous humor in order to obtain a more general overview on the biochemical and metabolic changes that occur during alcoholic ketoacidosis. Most of the tested parameters were chosen among those that had been described in clinical and forensic literature associated with alcoholic ketoacidosis and its complications. RESULTS: Ketone bodies and carbohydrate-deficient transferrin levels were increased in all cases. Biochemical markers of generalized inflammation, volume depletion and undernourishment showed higher levels. Adaptive endocrine reactions involving insulin, glucagon, cortisol and triiodothyronine were also observed. CONCLUSIONS: Metabolic and biochemical disturbances characterizing alcoholic ketoacidosis can be reliably identified in the postmortem setting. The correlation of medical history, autopsy findings and biochemical results proves therefore decisive in identifying pre-existing disorders, excluding alternative causes of death and diagnosing alcoholic ketoacidosis as the cause of death.

Ketoacidosis and adrenocortical insufficiency.

We herein report an autopsy case involving a 27-year-old Caucasian woman suffering from chronic adrenocortical insufficiency with a background of a polyendocrine disorder. Postmortem biochemistry revealed pathologically decreased aldosterone, cortisol, and dehydroepiandrosterone levels in postmortem serum from femoral blood as well as decreased cortisol and 17-hydroxycorticosteroid in urine. Decreased vitreous sodium and increased 3-beta-hydroxybutyrate and C-reactive protein concentrations were observed. The cause of death was determined to be acute adrenocortical insufficiency. Fasting ketoacidosis was postulated to have precipitated the Addisonian crisis. Traumatic causes of death and third-party involvement were excluded. The case highlights the importance of systematically performing exhaustive postmortem biochemical investigations to formulate appropriate hypothesis regarding the pathophysiological mechanisms involved in the death process.

Unconsciousness and sedation as precipitating factors of diabetic ketoacidosis.

The aim of this study was to identify medico-legal situations characterized by increased vitreous glucose concentrations, potentially lethal blood 3-hydroxybutyrate levels and conditions that could either incapacitate or lead to death on their own. The above was investigated in order to verify whether prolonged states of unconsciousness may play a role in precipitating diabetic ketoacidosis. Six groups of medico-legal situations (corresponding to 206 autopsy cases) were identified. Among these, three cases were characterized by pathologically increased vitreous glucose and blood 3-hydroxybutyrate levels. In one case diabetic ketoacidosis coexisted with underlying features that might have potentially incapacitated or lead to death on their own, whereas in two cases it corresponded with potentially lethal or lethal drug concentrations. The results of this study highlight the usefulness of systematically performing biochemistry in order to identify diabetic ketoacidosis-related deaths, even when autopsy and toxicology results provide apparently conclusive findings.

Is the formula of Traub still up to date in antemortem blood glucose level estimation?

According to the hypothesis of Traub, also known as the 'formula of Traub', postmortem values of glucose and lactate found in the cerebrospinal fluid or vitreous humor are considered indicators of antemortem blood glucose levels. However, because the lactate concentration increases in the vitreous and cerebrospinal fluid after death, some authors postulated that using the sum value to estimate antemortem blood glucose levels could lead to an overestimation of the cases of glucose metabolic disorders with fatal outcomes, such as diabetic ketoacidosis. The aim of our study, performed on 470 consecutive forensic cases, was to ascertain the advantages of the sum value to estimate antemortem blood glucose concentrations and, consequently, to rule out fatal diabetic ketoacidosis as the cause of death. Other biochemical parameters, such as blood 3-beta-hydroxybutyrate, acetoacetate, acetone, glycated haemoglobin and urine glucose levels, were also determined. In addition, postmortem native CT scan, autopsy, histology, neuropathology and toxicology were performed to confirm diabetic ketoacidosis as the cause of death. According to our results, the sum value does not add any further information for the estimation of antemortem blood glucose concentration. The vitreous glucose concentration appears to be the most reliable marker to estimate antemortem hyperglycaemia and, along with the determination of other biochemical markers (such as blood acetone and 3-beta-hydroxybutyrate, urine glucose and glycated haemoglobin), to confirm diabetic ketoacidosis as the cause of death.

Blood, urine and vitreous isopropyl alcohol as biochemical markers in forensic investigations.

Isopropyl alcohol (IPA) is widely used as an industrial solvent and cleaning fluid. After ingestion or absorption, IPA is converted into acetone by alcohol dehydrogenase. However, in ketosis, acetone can be reduced to IPA. The aim of this study was to investigate blood IPA and acetone concentrations in a series of 400 medico-legal autopsies, including cases of diabetic ketoacidosis, hypothermia and alcohol misuse-related deaths, to illustrate the extent of ketosis at the time of death. Vitreous glucose, blood 3-β-hydroxybutyrate (3HB) and acetoacetate (AcAc) concentrations were also determined systematically. Additionally, vitreous and urine IPA, acetone, 3HB and AcAc concentrations as well as other biochemical markers, including glycated hemoglobin and carbohydrate-deficient transferrin (CDT) were also determined in selected cases. The results of this study indicate that ketosis is characterized by the presence of IPA resulting from the acetone metabolism and that IPA can be detected in several substrates. These findings confirm the importance of the systematic determination of IPA and acetone levels that is used to quantify biochemical disturbances and the importance of ketosis at the time of death.

Usefulness of postmortem biochemistry in forensic pathology: illustrative case reports.

The aim of this work is to present some practical, postmortem biochemistry applications to illustrate the usefulness of this discipline and reassert the importance of carrying out biochemical investigations as an integral part of the autopsy process. Five case reports are presented pertaining to diabetic ketoacidosis in an adult who was not known to suffer from diabetes and in presence of multiple psychotropic substances; fatal flecainide intoxication in a poor metabolizer also presenting an impaired renal function; diabetic ketoacidosis showing severe postmortem changes; primary aldosteronism presented with intracranial hemorrhage and hypothermia showing severe postmortem changes. The cases herein presented can be considered representative examples of the importance of postmortem biochemistry investigations, which may provide significant information useful in determining the cause of death in routine forensic casework or contribute to understanding the pathophysiological mechanisms involved in the death process.

Postmortem diagnosis of unsuspected diabetes mellitus.

Vitreous glucose, blood beta-hydroxybutyrate and glycated hemoglobin were systematically measured in a series of 500 medico-legal autopsies in order to characterize the glycemic control during the weeks preceding death and identify ketoacidosis as the cause of death in diagnosed and unsuspected diabetics. Unenhanced CT-scans, histology and toxicology were performed in all cases. 16 cases of diabetic ketoacidosis were identified based on the results of all investigations. Among those, 13 cases concerned individuals with pre-existing diagnoses of diabetes mellitus whereas 3 cases concerned individuals with undiagnosed diabetes. A recent cocaine use was observed in 2 cases. C-reactive protein, interleukin-6 and interleukin-10 were measured and proved to be increased in all cases of diabetic ketoacidosis, whereas markers of generalized, bacterial infection and sepsis were normal in most of these cases. The results of this study highlight the usefulness of systematically performing biochemistry to identify ketoacidosis in unsuspected diabetics. It also emphasizes the role of toxicology and biochemistry to support the diagnosis of diabetic ketoacidosis and delineate the pathophysiological mechanisms that may disrupt the metabolic balance and finally lead to death in diabetic individuals.

Postmortem distribution of 3-beta-hydroxybutyrate.

The concentrations of 3-beta-hydroxybutyrate (3HB) in femoral blood, urine, vitreous humor as well as pericardial and cerebrospinal fluids were retrospectively examined in a series of medico-legal autopsies, which included cases of diabetic ketoacidosis, hypothermia fatalities without ethanol in blood, bodies presenting mild decompositional changes, and sudden deaths in chronic alcoholics. Similar increases in 3HB concentrations were observed in blood, vitreous, and pericardial fluid, irrespective of the cause of death, suggesting that pericardial fluid and vitreous can both be used as alternatives to blood for postmortem 3HB determination. Urine 3HB levels were higher than blood values in most cases. Cerebrospinal fluid 3HB levels were generally lower than concentrations in blood and proved to be diagnostic of underlying metabolic disturbances only when significant increases occurred.

Preliminary results on the postmortem measurement of 3-beta-hydroxybutyrate in liver homogenates.

The concentrations of 3-beta-hydroxybutyrate (3HB) in blood and two liver samples were retrospectively examined in a series of medicolegal autopsies. These cases included diabetic ketoacidosis, nondiabetic individuals presenting moderate to severe decompositional changes and nondiabetic medicolegal cases privy of decompositional changes. 3HB concentrations in liver sample homogenates correlate well with blood values in all examined groups. Additionally, decompositional changes were not associated with increases in blood and liver 3HB levels. These results suggest that 3HB can be reliably measured in liver homogenates when blood is not available at autopsy. Furthermore, they suggest that metabolic disturbances potentially leading or contributing to death may be objectified through liver 3HB determination even in decomposed bodies.

Postmortem chemistry update part I.

Postmortem chemistry is becoming increasingly essential in the forensic pathology routine and considerable progress has been made over the past years. Biochemical analyses of vitreous humor, cerebrospinal fluid, blood and urine may provide significant information in determining the cause of death or in elucidating forensic cases. Postmortem chemistry may essentially contribute in the determination of the cause of death when the pathophysiological changes involved in the death process cannot be detected by morphological methods (e.g. diabetes mellitus, alcoholic ketoacidosis and electrolytic disorders). It can also provide significant information and useful support in other forensic situations, including anaphylaxis, hypothermia, sepsis and hormonal disturbances. In this article, we present a review of the literature that covers this vast topic and we report the results of our observations. We have focused our attention on glucose metabolism, renal function and electrolytic disorders.

Fatal metformin overdose: case report and postmortem biochemistry contribution.

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.

Postmortem biochemistry: mith or reality?

Postmortem biochemistry is becoming increasingly essential in the forensic casework and considerable progress has been made over the past years. Biochemical analyses of blood, postmortem serum, pericardial fluid, vitreous humor and urine may indeed provide significant information in identifying the cause of death as well as characterizing the precipitating conditions and the predisposing disorders. Postmortem biochemical analyses are decisive in determining the cause of death when the pathophysiological changes involved in the process cannot be otherwise ascertained by morphological investigations (mainly diabetic and alcoholic ketoacidosis). It can also provide significant information and useful support in numerous situations on forensic interest, including cold exposure-related deaths, fatal anaphylaxis, bacterial infection-related fatalities and hormonal disturbances. In this report we present an overview pertaining to the diagnostic performance of classical and novel biochemical markers in the forensic setting.

Schizophrénie, diabète et nouveaux neuroleptiques [Schizophrenia, diabetes and new neuroleptics].

Diabetes mellitus occurs more frequently in schizophrenic patients. The use of a novel antipsychotic drug seems to be concomitant to a further increase in imbalance of blood glucose homeostasis. Such cases have already been reported in the literature indicating that diabetes mellitus might be a real side effect of this novel class of neuroleptics. In conclusion, it seems that schizophrenic patients under such treatment would greatly benefit from a closer clinical and biological follow up regarding glucose metabolism. Further randomised studies would be needed.