Fatal Diabetic Ketoacidosis and Antipsychotic Medication

Hyperglycemia and new onset diabetes have been described with certain antipsychotic medications and some of the initial presentations are fatal diabetic ketoacidosis (DKA). We report 17 deaths due to DKA in psychiatric patients treated with second generation antipsychotic medications. Death certificates and toxicology data were searched for DKA and hyperglycemia. We reviewed the medical examiner records which included the autopsy, toxicology, police, and medical examiner investigators' reports. The decedents ranged in age from 32 to 57 years (average 48 years). There were 15 men and two women. The immediate cause of death was DKA in all. The psychiatric disorders included: 10 schizophrenia, three bipolar/schizophrenia, two bipolar, and two major depression. The most frequent atypical antipsychotic medications found were quetiapine and olanzapine followed by risperidone. In 16 deaths, we considered the medication as primary or contributory to the cause of death.     

Utility of Postmortem Vitreous Beta-Hydroxybutyrate Testing for Distinguishing Sudden from Prolonged Deaths and for Diagnosing Ketoacidosis

A retrospective, cross-sectional analysis of vitreous beta-hydroxybutyrate (BHB) on 967 forensic cases over a two-year period was conducted. Cases were sorted into six categories of death: (i) sudden traumatic/non-natural (ST), (ii) sudden natural (SN), (iii) prolonged traumatic/non-natural (PT), (iv) prolonged natural (PN), (v) diabetic ketoacidosis (DKA), and (vi) alcoholic ketoacidosis (AKA). The mean BHB for all cases was 1.67 mmol/L (17.4 mg/dL; range: 0.11–18.02 mmol/L). The numbers of DKA, AKA, PN, PT, SN, and ST deaths were 21, 5, 155, 258, 275, and 253, respectively. Their mean vitreous BHBs were as follows: 11.04 mmol/L (DKA), 8.88 mmol/L (AKA), 1.56 mmol/L (PN), 1.55 mmol/L (PT), 1.26 mmol/L (SN), and 1.38 mmol/L (ST). There was a statistically significant difference between the mean BHBs of the PN and SN death groups (p < 0.001), as well as between those of the PT and ST death groups (p = 0.004). Given the overlapping ranges seen between the prolonged and sudden death groups, the identified differences did not hold clinical significance. In addition, we sought to determine a threshold value for vitreous BHB to definitely diagnose cases of ketoacidosis. BHB threshold concentrations between 2.5 and 5 mmol/L produced sensitivities >92% and specificities >96%. A receiver operator characteristic curve found 3.43 mmol/L to be the optimal cutoff value, demonstrating a specificity of 98.3% and a sensitivity of 96.2%.     

Fatalities Due to Failure of Continuous Subcutaneous Insulin Infusion Devices: A Report of Six Cases

Diabetes mellitus type 1 and type 2 are diseases characterized by impaired regulation of blood glucose due to decreased insulin production and insulin resistance, respectively. Management of diabetes mellitus often requires injection of exogenous insulin. Continuous subcutaneous insulin infusion (CSII or insulin pump) is a diabetes treatment modality utilizing a device to aid in regulation of glycemic control. Malfunctions in device components can have rare fatal consequences. Described in this report are six fatalities due to one such malfunction, the failure of plastic cannulas of CSII devices to penetrate the skin and deliver insulin, resulting in fatal diabetic ketoacidosis (DKA). The cases derive from four different death investigation systems. For each case, scene and autopsy findings are presented, as well as selected toxicology and histology findings. These cases illustrate the importance of careful examination of CSII devices in death investigations and introduce a discussion on discrepant manner of death classifications.     

Investigation of markers to indicate and distinguish death due to alcoholic ketoacidosis, diabetic ketoacidosis and hyperosmolar hyperglycemic state using post-mortem samples

Data from 191 post-mortem cases where post-mortem blood beta-hydroxybutyrate (βHB) and acetone concentrations and vitreous humor glucose concentrations (where available) had been measured were retrospectively investigated to determine the markers required to identify and distinguish between Alcoholic Ketoacidosis (AKA), Diabetic Ketoacidosis (DKA) and Hyperosmolar Hyperglycemic State (HHS). Blood βHB concentrations above 250 μg/mL were considered significant and it was shown to be the preferred marker of ketoacidosis. All cases with significant βHB detected also had acetone present (greater than 2mg/dL) demonstrating that acetone can be used as a marker to identify ketoacidosis and can be used to indicate when βHB measurement is necessary. Vitreous humor glucose concentrations above 6.9 mmol/L were considered high and indicative of hyperglycemia prior to death. Vitreous humor glucose concentrations can be used to distinguish between DKA and ketoacidosis from other causes and to identify deaths due to HHS. The data showed that ketoacidosis can occur without a history of alcoholism or diabetes. Many diabetics are undiagnosed for many years. Therefore, DKA or HHS should be considered in sudden or unexplained deaths and glucose should be routinely measured especially in cases with risk factors for diabetes including obesity, old age, a history of mental health problems or treatment with atypical antipsychotic drugs including clozapine, olanzapine, quetiapine and risperidone.     

Beta-hydroxybutyric acid--an indicator for an alcoholic ketoacidosis as cause of death in deceased alcohol abusers

We analyzed the postmortem blood of a total of 100 fatal cases for beta-hydroxybutyric acid (BHBA). In 25 cases of sudden and unexpected death of alcoholics we found pathologically increased levels of BHBA of 1260 to 47200 (median 8000) micromol/L. This led us to the diagnosis of an alcoholic ketoacidosis (AKA) as cause of death in these cases. The control group of 69 postmortem cases revealed that BHBA concentrations below 500 can be regarded as normal, and values up to 2500 micromol/L as elevated. Our study shows that BHBA values over 2500 micromol/L could lead to death, if no medical attention is sought. During storage we did not find any indication of postmortem formation or decomposition of BHBA in blood in vitro or in the corpses. In our opinion, BHBA should be considered the diagnostic marker of choice for the postmortem determination of alcoholic ketoacidosis (AKA) as the cause of death. The classical indications of such deaths are: unexpected death of a chronic alcoholic; none or only traces of ethanol in the blood; increased acetone blood concentration; and neither autopsy, histology, microbiology, nor toxicology reveal the cause of death. In six further cases a diabetic ketoacidosis (DKA) was diagnosed as the cause of death.     

Sudden and unexpected deaths after the acute onset of diabetes mellitus.

Four cases of sudden and unexpected death caused by the acute onset of diabetes mellitus are reported. Three are examples of acute juvenile diabetes while the fourth demonstrated the aketotic form of diabetic coma. Such instances can present a diagnostic problem to the forensic pathologist. The usefulness of vitreous humor glucose analysis to diagnose such a condition is stressed.     

Pharmaceutical error resulting in fatal diabetic ketoacidosis

A 41-year-old male with a 25-year history of diabetes mellitus requiring 25 to 30 units of neutral protamine hagedorn (NPH) insulin daily was found dead at home. Recent history revealed that he was well until the last four days of life when he had the onset of nausea, vomiting, and anorexia coinciding with procurement of a new bottle of insulin from his pharmacist. Pertinent autopsy findings included coronary and aortic atherosclerosis, a peptic ulcer, and diabetic glomerulopathy. Chemical analysis of the vitreous humor, including glucose (813 mg/dL) and acetone (40 mg/dL), revealed that he died of diabetic ketoacidosis. Further investigation revealed that the pharmacist had accidentally substituted regular insulin, with a duration of action of up to 6 h as opposed to 24 to 28 h, for NPH. Cultures of blood and of the regular insulin yielded no growth. Analysis of this case emphasizes the importance of obtaining a careful medical and medication history and the usefulness of vitreous electrolytes when investigating a sudden death in a diabetic.     

Postmortem detection of isopropanol in ketoacidosis

Isopropanol (IPA) detected in deaths because of diabetic ketoacidosis (DKA) or alcoholic ketoacidosis (AKA) may cause concern for IPA poisoning. This study addressed this concern in a 15-year retrospective review of 260 deaths in which concentrations of acetone and IPA, as well as their ratios, were compared in DKA (175 cases), AKA (79 cases), and IPA intoxication (six cases). The results demonstrated the frequency of detecting IPA in ketoacidosis when there was no evidence of IPA ingestion. IPA was detectable in 77% of DKA cases with quantifiable concentrations averaging 15.1 ± 13.0 mg/dL; 52% of AKA cases with quantifiable concentrations averaging 18.5 ± 22.1 mg/dL; and in cases of IPA intoxication, averaging 326 ± 260 mg/dL. There was weak correlation of IPA production with postmortem interval in DKA only (r = -0.48). Although IPA concentrations were much higher with ingestion, potentially toxic concentrations were achievable in DKA without known ingestion.     

Biochemical measurements of glucose metabolism in relation to cause of death and postmortem effects

This study was performed to examine the relationship between postmortem biochemical values and cause of death. The follow samples were taken from 399 corpses: cerebrospinal fluid (CSF; n = 376, suboccipital), blood (n = 158, femoral vein), and urine (n = 101, at autopsy). (See Table 1 for causes of death) All samples were stored at -80 degrees C. A further 100 samples of blood were later taken and stored at +4 degrees C before testing. Biochemical determinations made were: glucose in CSF, blood, and urine (hexokinase method); lactate (LDH/GPT) and free acetone (HS-gas chromatography) in CSF; hemoglobin A1 in blood (microcolumn technique). In 34 cases fatal diabetic coma was considered verified by morphological and chemical findings. One hundred cases of sudden cardiac death were chosen as the main control group. In 32 of the 34 cases defined above, the value of the formula of Traub (glucose + lactate in CSF) exceeded 415 mg/dl. It is not influenced significantly by hyperglycemia or hyperlactatemia due to factors other than diabetes (i.e., carbon monoxide, asphyxia). After death the value rose till the 30th hpm, then remained stable for at least 1 week. Fatal coma was defined as the ketoacidotic form if free acetone in CSF ranged above 21 mg/l. In these cases, CSF glucose and free acetone correlated positively. Hemoglobin A1 remained stable after death. Its amount was independent from postmortem blood glucose, postmortem interval and total hemoglobin. Furthermore, the manner of storage (-80 degrees or +4 degrees C) had no significant influence on its values. In 29 of 34 cases of fatal coma, Hb A1 exceeded 12.1%. Analysis of urine glucose showed elevated levels (over 500 mg/dl) in diabetic comas. On conclusion, fatal diabetic coma seems indicated as the cause of death if measured values of postmortem biochemistry exceed the following limits: CSF-Traub 415 mg/dl, free acetone (CSF) 21 mg/l; Hb A1 12.1%; urine glucose 500 mg/dl. Most important are the Traub formula and hemoglobin A1. Usually, in fatal coma both values are elevated. If both of them are normal, diabetic coma can nearly be excluded. Combined evaluation of all values is absolutely necessary. Morphology must also always be taken into account. Consequently, a diagnosis of fatal coma can be obtained by a process of elimination.     

Unsuspected hereditary hemochromatosis at forensic autopsy: its presentation, confirmation, and implications

Hereditary hemochromatosis (HH) is one of the most common genetic disorders and may present clinically in a variety of ways. The most common presentation is micronodular cirrhosis with possible associated diabetes. However, HH may also present with cardiac dysfunction and sudden death. The confirmation of unsuspected HH at autopsy is complicated by the growing number of genetic abnormalities, which are not detected by current commercial genetic testing for C282Y and H63D mutations. Consequently, quantitative liver iron studies on fresh or paraffin embedded liver is recommended in confirming HH. The importance of detection and confirmation of HH cannot be overemphasized given the need to screen surviving family members in preventing organ damage of asymptomatic individuals. We present a case of a 38-year-old white woman with micronodular cirrhosis secondary to unsuspected HH that was confirmed by a quantitative liver iron study. The possible presentation of cardiac sudden death from HH, confirmation issues and implications of a HH diagnosis for surviving family members are also discussed.     

Sudden death due to undiagnosed Wilms' tumor in an adult

Sudden unexpected deaths due to natural causes constitute a large number of cases encountered by the forensic pathologist. In a majority of such cases, heart disease is responsible for sudden death. Rare disease entities resulting in sudden death are occasionally encountered and may not fit the classic epidemiological profile. We present a case of sudden death due to a previously undiagnosed Wilms' tumor (WT) in an adult. The pathology of WT is discussed, as is the topic of sudden death due to previously unrecognized malignancy.     

Is there progress in the autopsy diagnosis of sudden unexpected death in adults?

Sudden death is now currently described as natural unexpected death occurring within 1h of new symptoms. Most studies on the subject focused on cardiac causes of death because most of the cases are related to cardiovascular disease, especially coronary artery disease. The incidence of sudden death varies largely as a function of coronary heart disease prevalence and is underestimated. Although cardiac causes are the leading cause of sudden death, the exact incidence of the other causes is not well established because in some countries, many sudden deaths are not autopsied. Many risk factors of sudden cardiac death are identified: age, gender, heredity factors such as malignant mutations, left ventricular hypertrophy and left ventricle function impairment. The role of the police surgeon in the investigation of sudden death is very important. This investigation requires the interrogation of witnesses and of the family members of the deceased. The interrogation of physicians of the rescue team who attempted resuscitation is also useful. Recent symptoms before death and past medical history must be searched. Other sudden deaths in the family must be noted. The distinction between sudden death at rest and during effort is very important because some lethal arrhythmia are triggered by catecholamines during stressful activity. The type of drugs taken by the deceased may indicate a particular disease linked with sudden death. Sudden death in the young always requires systematic forensic autopsy performed by at least one forensic pathologist. According to recent autopsy studies, coronary artery disease is still the major cause of death in people aged more than 35 years. Cardiomyopathies are more frequently encountered in people aged less than 35 years. The most frequent cardiomyopathy revealed by sudden death is now arrhythmogenic right ventricular cardiomyopathy also known simply as right ventricular cardiomyopathy (RVC). The postmortem diagnosis of cardiomyopathies is very important because the family of the deceased will need counseling and the first-degree relatives may undergo a possible screening to prevent other sudden deaths. In each case of sudden death, one important duty of the forensic pathologist is to inform the family of all autopsy results within 1 month after the autopsy. Most of the recent progress in autopsy diagnosis of sudden unexpected death in the adults comes from molecular biology, especially in case of sudden death without significant morphological anomalies. Searching mutations linked with functional cardiac pathology such as long-QT syndrome, Brugada syndrome or idiopathic ventricular fibrillation is now the best way in order to explain such sudden death. Moreover, new syndromes have been described by cardiologists, such as short-QT syndrome and revealed in some cases by a sudden death. Molecular biology is now needed when limits of morphological diagnosis have been reached.     

Lipids in the proximal tubules of the kidney in diabetic coma

Vacuolization of the renal tubular epithelial cells (the Armanni-Ebstein lesion) associated with diabetic hyperglycemia is usually regarded as an accumulation of glycogen. In a case of death of diabetic coma, the vacuoles were stained strongly for lipids. This observation may have both clinical and therapeutic consequences, and may increase our knowledge of the metabolism in diabetes.     

A comparison of respiratory symptoms and inflammation in sudden infant death syndrome and in accidental or inflicted infant death

Upper respiratory infection and pulmonary inflammation are common in sudden infant death syndrome, but their role in the cause of death remains controversial. Controlled studies comparing clinical upper respiratory infection and inflammation in sudden infant death syndrome with sudden infant deaths caused by accidents and inflicted injuries (controls) are unavailable. Our aim was to compare respiratory inflammation and upper respiratory infection within 48 hours of death and postmortem culture results in these two groups. A retrospective analysis of upper respiratory infection and pathologic variables in the trachea and lung of 155 infants dying of sudden infant death syndrome and 33 control infants was undertaken. Upper respiratory infection was present in 39% of sudden infant death syndrome cases and 40% of control cases. Upper respiratory infection was more likely to have occurred in association with more severe lymphocytic interstitial pneumonitis when sudden infant death syndrome cases and control cases were combined ( P=.04). Proximal and distal tracheal lymphocytic infiltration was more severe in control cases than in sudden infant death syndrome cases ( P=.01 and.01, respectively). Lymphocytic infiltrations of the bronchi, bronchioles, and pulmonary interstitium were similar between groups. Bronchial associated lymphoid tissue was more prominent in control cases ( P=.04). Cultures were positive in 80% of sudden infant death syndrome cases, 78% of which were polymicrobial. Among control cases, 89% were positive, with 94% being polymicrobial. This study confirms that microscopic inflammatory infiltrates in sudden infant death syndrome are not lethal.     

Sudden infant death with anomalous origin of the left coronary artery.

Autopsy of a 3-month-old girl, an apparent case of sudden infant death syndrome, revealed anomalous origin of the left coronary artery from the right aortic sinus. Acute angulation of the left coronary artery along the aortic root, as well as a focal intramyocardial course within the ventricular septum, may have contributed to episodic luminal narrowing. Anomalous coronary origins of similar type have been associated with sudden death in children, teenagers, and young adults, but have not necessarily been associated with sudden death in older adults. Somewhat similar malformations have been reported in sudden infant death; two cases involved the left coronary artery and six involved the right.     

Postmortem diagnosis of diabetes mellitus. Quantitation of fructosamine and glycated hemoglobin

Fructosamine and glycated hemoglobin were determined in samples from 52 cadavers autopsied in the Forensic Pathology Institute of the University of Copenhagen (Denmark). The population studied comprised 15 adult subjects with history of diabetes mellitus and 37 adult non-diabetic subjects. The fructosamine/total protein ratio was 1.7 times higher in diabetic than in non-diabetic subjects, as was the case for glycated hemoglobin. Measurement of glycated serum protein appears to be a useful tool for the postmortem diagnosis of fatal diabetic coma and glucose concentration before death.     

Enzyme chemical studies of pericardial fluid

The authors examined the enzyme activities of LDH, CK, GOT, GPT and gamma-GT in blood-free pericardial fluid. The cases were divided into seven groups: a shot in the head with instant death, sudden cardiac death, poisoning, brain death with a long survival time, sudden infant death syndrome, and asphyxia. Taking all five enzymes into consideration, the cases of cardiac death differed significantly on the 1% level from the head shooting. However, concerning CK sudden cardiac death differed on the 5% level from the deaths as a result of poisoning. The wide range of the results, however, does not permit any reliable association of one single value with any of the respective groups.     

Oronasal blood in sudden infant death.

Oronasal secretions are observed frequently in sudden infant death syndrome (SIDS), but overt blood is uncommonly reported. The literature on oronasal blood in sudden infant death is limited. The goal of this study was to determine the frequency of oronasal blood in sudden infant deaths and to examine possible causative factors. Oronasal blood was described in 28 (7%) of 406 cases of sudden infant death. Oronasal blood could not be attributed to cardiopulmonary resuscitation in 14 cases, including 10 (3%) of 300 cases of SIDS, 2 (14%) of 14 accidental suffocation cases, and 2 (15%) of 13 undetermined cases. Eight of the 10 infants in cases of sudden infant death were bedsharing: 5 with both parents, 2 between both parents. The infant in 1 SIDS case was from a family that had had three referrals to Child Protective Services. Oronasal blood not attributable to cardiopulmonary resuscitation occurs rarely in SIDS when the infant is sleeping supine in a safe environment. Bedsharing may place infants at risk of suffocation from overlaying. Oronasal blood observed before cardiopulmonary resuscitation is given is probably of oronasal skin or mucous membrane origin and may be a sign of accidental or inflicted suffocation. Sanguineous secretions that are mucoid or frothy are likely of remote origin, such as lung alveoli. The use of an otoscope to establish the origin of oronasal blood in cases of sudden infant death is recommended.     

过敏性和冠心病猝死者心肌组织中肥大细胞类胰蛋白酶、脑利钠肽的表达

目的探讨肥大细胞类胰蛋白酶、脑利钠肽(brain natriuretic peptide,BNP)在过敏性猝死和冠心病猝死鉴别诊断中的意义。方法选取山西医科大学法医病理学教研室2010—2015年尸检案例心肌标本共30例,分为颅脑损伤致死组、过敏性猝死组、冠心病猝死组,每组各10例。采用免疫荧光染色和Western印迹法分析各组心肌组织肥大细胞类胰蛋白酶和BNP的表达。结果过敏性猝死组、冠心病猝死组心肌组织内肥大细胞类胰蛋白酶免疫荧光染色均出现阳性染色;三组间两两比较,表达差异均具有统计学意义(P0.05)。冠心病猝死组心肌组织内BNP的表达量高于过敏性猝死组、颅脑损伤致死组(P0.05),过敏性猝死组与颅脑损伤致死组之间差异无统计学意义(P0.05)。结论联合检测心肌组织内肥大细胞类胰蛋白酶、BNP有望为过敏性猝死和冠心病猝死的法医学鉴别诊断提供帮助。     

The spectrum of intramyocardial small vessel disease associated with sudden death

Intramyocardial small vessel abnormalities are not commonly recognized. The best known abnormality is fibromuscular dysplasia involving the sinoatrial or atrioventricular nodal arteries. Small vessel disease has been reported as an isolated cardiac anomaly in individuals with sudden death, and may also be associated with other cardiac conditions including hypertrophic cardiomyopathy and mitral valve prolapse. The nature of the association is unknown, and the mechanism causing sudden death is sometimes obscure. We describe pathological changes of the intramyocardial small vessels of three individuals with sudden death. Abnormalities involved small vessels at different levels. In all the cases, the abnormalities were thought to have caused or contributed to the individual's death. The possible mechanisms of this are discussed.