Postmortem diagnosis of unsuspected diabetes mellitus
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.
References (114)
- et al.
Forensic biochemistry for functional investigation of death: concept and practical application
Leg. Med. (Tokyo)
(2011) - et al.
Usefulness of postmortem biochemistry in forensic pathology: illustrative case reports
Leg. Med. (Tokyo)
(2012) - et al.
Postmortem identification of hyperglycemia
Forensic Sci. Int.
(2009) Postmortem diagnosis of diabetes mellitus. Quantitation of fructosamine and glycated hemoglobin
Forensic Sci. Int.
(1988)- et al.
Glycated hemoglobin: a useful post-mortem reference marker in determining diabetes
Forensic Sci. Int.
(2002) - et al.
Interleukin-6 and C-reactive protein serum levels in sepsis-related fatalities during the early postmortem period
Forensic Sci. Int.
(2001) C-reactive protein (CRP), a comparison of pre- and postmortem blood levels
Forensic Sci. Int.
(2001)- et al.
Serum C-reactive protein levels in postmortem blood—an analysis with special reference to the cause of death and survival time
Forensic Sci. Int.
(2002) - et al.
Significance of levels of IL-6 and IL-8 after trauma: a study of 11 cytokines post-mortem using multiplex immunoassay
Injury
(2007) Postmortem diagnosis of sepsis
Forensic Sci. Int.
(2007)
The routine use of C-reactive protein in forensic investigations
Forensic Sci. Int.
Active use of cocaine: an independent risk factor for recurrent diabetic ketoacidosis in a city hospital
Endocr. Pract.
Diabetic ketoacidosis and cocaine use
Med. Clin. (Barc)
Diabetic ketoacidosis and cocaine use
Med. Clin. (Barc)
Abnormal glucose metabolism in patients treated with antipsychotics
Diabetes Metab.
Olanzapine-induced hyperglycemic ketoacidosis and corresponding acetone concentrations post-mortem: a forensic interpretation
Forensic Sci. Int.
Diagnosis of fulminant type 1 diabetes mellitus in an autopsy case with postmortem changes
Leg. Med. (Tokyo)
Investigation of markers to indicate and distinguish death due to alcoholic ketoacidosis, diabetic ketoacidosis and hyperosmolar hyperglycemic state using postmortem samples
Forensic Sci. Int.
Plasma high sensitivity C-reactive protein and its relationship with cytokine levels in children with newly diagnosed type 1 diabetes and ketoacidosis
Clin. Biochem.
Glycated haemoglobin and glycated protein and glucose concentrations in necropsy blood samples
J. Clin. Pathol.
Is postmortem biochemistry really useful? Why is it not widely used in forensic pathology?
Leg. Med. (Tokyo)
Significance of postmortem biochemistry in determining the cause of death
Leg. Med. (Tokyo)
Postmortem chemistry update. Emphasis on forensic application
Am. J. Forensic Med. Pathol.
Postmortem diagnosis of unsuspected diabetes mellitus established by determination of decedent's hemoglobin A1c level
J. Forensic Sci.
Postmortem diagnosis of diabetes mellitus and diabetic coma: a comparison of HbA1, glucose, lactate and combined glucose and lactate values in vitreous humor and in cerebrospinal fluid
Diagnostic values of combined glucose and lactate values in cerebrospinal fluid and vitreous humor—our experiences
Forensic Sci. Int.
Postmortem biochemistry of vitreous humor and glucose metabolism: an update
Clin. Chem. Lab. Med.
Postmortem chemistry update part I
Int. J. Legal. Med.
Is the formula of Traub still up to date in antemortem blood glucose level estimation?
Int. J. Legal. Med.
Initial results of postmortem diagnosis of diabetes mellitus by Hb A1 determination
Z. Rechtsmed.
Post-mortem glycosylated hemoglobin (HbA1c): evidence for a history of diabetes mellitus
Ann. Clin. Lab. Sci.
The diagnostic value of glycated haemoglobin levels in post-mortem blood
Ann. Clin. Biochem.
Serum fructosamine after death
Diab. Med.
Glycated haemoglobin and glycated protein and glucose concentrations in necropsy blood samples
J. Clin. Pathol.
Analysis of glycated albumin in postmortem blood samples as the diagnostic parameters of diabetes mellitus
Nihon. Hoigaku Zasshi.
HbA1c as a postmortem tool to identify glycemic control
J. Forensic Sci.
Measuring postmortem glycated hemoglobin—a comparison of three methods
Leg. Med. (Tokyo)
Hyperglycemic crises in adult patients with diabetes
Diabetes Care
Decrease in frequency of ketoacidosis at diabetes onset over the past two decades—perspectives of a paediatric tertiary care centre
Diabet. Med.
Ketoacidosis at onset of type 1 diabetes mellitus in pediatric age in Spain and review of the literature
Pediatr. Endocrinol. Rev.
Pediatric diabetes consortium diabetic, ketoacidosis at diabetes onset: still an all too common threat in youth
J. Pediatr.
Factors associated with the presence of diabetic ketoacidosis at diagnosis of diabetes in children and young adults: a systematic review
BMJ
Reduced prevalence of diabetic ketoacidosis at diagnosis of type 1 diabetes in young children participating in longitudinal follow-up
Diabetes Care
Frequency and clinical characteristics of ketoacidosis at onset of childhood type 1 diabetes mellitus in Northwest Saudi Arabia
Saudi Med. J.
Regional differences in incidence and clinical presentation of type 1 diabetes in children aged under 15 years in Croatia
Croat. Med. J.
Clinical profile of diabetic ketoacidosis in Indian children
Indian J. Pediatr.
Incidence and modes of presentation of childhood type 1 diabetes mellitus in Malta between 2006 and 2010
Pediatr. Diabetes
Diabetic ketoacidosis in children and adolescent with diabetes
Pediatr. Diabetes
Europe and diabetes, geographical variation of presentation at diagnosis of type 1 diabetes in children: the EURODIAB study. European and diabetes
Diabetologia
DPV Initiative and the German BMBF Competency Network for diabetes mellitus, ketoacidosis at diabetes onset is still frequent in children and adolescents: a multicenter analysis of 14,664 patients from 106 institutions
Diabetes Care
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2021, Journal of Forensic and Legal MedicineCitation Excerpt :For example, Hindle et al. studied blood glucose levels from the subclavian vein, femoral vein, right atrium, and left ventricle and found the following average values: 43.2, 32.4, 477, and 46.8 mg/dl, respectively.5 This variability has led some authors to search for other markers useful to diagnose hyperglycemia/diabetes after death, of which the most promising were found to be glucose, lactate, and beta-hydroxybutyrate in the cerebrospinal fluid (CSF)6,9–11 or vitreous humor, but also glycosylated hemoglobin.3,6,12,13 Vitreous humor is more protected from postmortem degradation than other bodily fluids and is easy to harvest after death, even before the actual autopsy.7,14
Fourier-transform infrared microspectroscopy of pulmonary edema fluid for postmortem diagnosis of diabetic ketoacidosis
2021, Spectrochimica Acta - Part A: Molecular and Biomolecular SpectroscopyCitation Excerpt :Nevertheless, nearly one-third of all deaths from DKA occurred in individuals with an unknown diabetes condition because it is usually overlooked until there are symptoms and/or complications [7,8]. Biochemical analyses, in such cases, may complement postmortem investigations and provide useful information for determining a conclusive cause of death [9]. In recent decades, vitreous glucose and acetone concentrations and blood glycated hemoglobin (HbA1c) and acetone concentrations have been studied as a potential postmortem diagnostic basis for DKA [3,8,10].