Postmortem diagnosis of unsuspected diabetes mellitus

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Abstract

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.

Introduction

In forensic pathology routine, postmortem biochemical analyses are generally recommended to investigate fatalities where the pathophysiological changes responsible for death cannot be detected by morphological methods (necropsy, histology and immunohistochemistry) as well as to better characterize contributing conditions, predisposing disorders and pathological processes prior to death [1], [2], [3], [4], [5]. The postmortem diagnosis of diabetic ketoacidosis is one of the most representative examples of a medico-legal situation in which the role and contribution of postmortem biochemical analyses are decisive in determining the cause of death. Elevated vitreous glucose and ketones in biological fluids sampled during autopsy have been indicated by several authors as appropriate and sufficient laboratory findings in order to reliably reach this diagnosis [6], [7], [8], [9], [10], [11], [12], [13]. The concomitant determination of glycated hemoglobin levels in blood specimens collected during autopsy has also been reported as a suitable tool for assessing the glycemic control of known diabetic patients just before death as well as diagnosing previously unsuspected cases of diabetes mellitus [1], [7], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23].

Diabetic ketoacidosis is the most common cause of death in children and adolescents with type 1 diabetes and accounts for half of all deaths in diabetic patients younger than 24 years of age [24]. Depending on the reports, ketoacidosis at the clinical diagnosis of type 1 diabetes in the pediatric population may range from 15% to more than 77% of cases [25]. Data on the changes in diabetic ketoacidosis frequency at disease onset in children vary among the published studies performed in different parts of the world. While some of them showed a decrease in frequency upon diagnosis, others found no change [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43].

Recent epidemiological studies have indicated that hospitalization for diabetic ketoacidosis in the United States is increasing. In the decade from 1996 to 2006, there was a 35% increase in the number of cases, for a total of 136.510 cases with a primary diagnosis of diabetic ketoacidosis in 2006 – a rate of increase perhaps more rapid than the overall increase in the diagnosis of diabetes. Most patients with diabetic ketoacidosis were between the ages of 18 and 44 years (56%) and 45 and 65 years (24%), with only 18% of patients younger than 20 years of age. Two-thirds of diabetic ketoacidosis patients were considered to have type 1 diabetes and 34% to have type 2 diabetes [24].

Imagawa et al. [44], [45] have recently identified a subtype of type 1 diabetes mellitus, called fulminant type 1 diabetes mellitus. This type is characterized by a rapid onset, markedly rapid hyperglycemia progression and ketoacidosis, normal or near-normal glycated hemoglobin level at onset and complete pancreas beta-cell destruction [46]. A nationwide survey in Japan found that fulminant diabetes mellitus accounted for 15–20% of Japanese type 1 diabetes mellitus cases with ketosis or ketoacidosis at onset [47]. In Korea, the prevalence of fulminant type 1 diabetes mellitus has been reported to be 7.1% among all patients newly diagnosed with type 1 diabetes mellitus and 30.4% among patients with adult-onset diabetes [48].

Several papers have been published in the medico-legal literature pertaining to the postmortem diagnosis of ketoacidosis in both unsuspected diabetic adults and children. Despite their decisive role in diagnosing some specific metabolic disturbances responsible for death, such as ketoacidosis in diabetics and unsuspected diabetics, biochemical investigations are still not extensively and systematically applied in forensic pathology routine.

The aim of this study was to systematically measure vitreous glucose, blood beta-hydroxybutyrate (β-HB) and glycated hemoglobin levels in a series of 500 medico-legal autopsies as a means of assessing the glycemic control during the weeks preceding death and identifying ketoacidosis as the cause of death in unsuspected diabetes mellitus cases. Additionally, so as to obtain a more complete biochemical profile of ketoacidosis, markers of inflammation and bacterial infection were also measured in these cases.

Section snippets

Forensic autopsy cases

During 2007–2012, vitreous humor samples were systematically collected from consecutive deceased subjects after their arrival at the morgue (1–48 h after death). Blood samples were also collected from the same cases during autopsy (3–51 h after death). In total, 500 cases were included in this study (388 males and 112 females), with a mean age of 59.6 years. Samples from severely decomposed bodies and from bodies with severe cranial destruction were rejected. Only cases with both vitreous humor

Results

16 fatal diabetic ketoacidosis cases were identified after having performed all postmortem investigations. Among those, 13 cases (all males) concerned individuals with pre-existing diagnoses of insulin-requiring type 1 diabetes mellitus. According to medical records as well as the information given by the families, diabetes mellitus had gone undiagnosed in 3 other cases (1 male and 2 females). Blood, urine, vitreous, pericardial and cerebrospinal fluids were available during autopsy in 15 cases

Discussion

Diabetic ketoacidosis results from absolute or relative deficiency of circulating insulin and the combined effects of increased levels of the counterregulatory hormones. Absolute insulin deficiency typically occurs in previously undiagnosed type 1 diabetes mellitus and when patients on treatment deliberately or inadvertently do not take insulin. Relative insulin deficiency occurs when the concentrations of counterregulatory hormones increase under major stressful conditions, such as trauma or

Financial disclosures

The authors declare no financial interests and/or conflict of interest related to this study.

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