Establishing vitreous glucose and beta-hydroxybutyrate thresholds to assist in the diagnosis of hypothermia.

The post-mortem diagnosis of hypothermia is challenging to establish due to the lack of pathognomonic findings and the confounding problem that any comorbidity may account for death. A 4-year retrospective case-control study was performed to compare the vitreous glucose and beta-hydroxybutyrate (BHB) concentrations between hypothermia deaths and controls. Over the study period 34 cases of hypothermia and 39 controls were analyzed. Hypothermia deaths versus controls had higher mean vitreous glucose (2.93 mmol/L vs. 1.14 mmol/L; p < 0.0001), BHB (1.89 mmol/L vs. 1.35 mmol/L; p = 0.01), and combined glucose+BHB (4.83 mmol/L vs. 2.46 mmol/L; p < 0.0001). Receiver operating characteristic (ROC) curves showed that the best model for predicting hypothermia in all cases was a combined vitreous glucose+BHB threshold of 2.03 mmol/L (sensitivity 88.2 %; specificity 56.4 %). A sub-group analysis broken down by detectable levels of blood ethanol showed that cases of hypothermia with and without ethanol maintained higher median vitreous glucose relative to the controls (2.05 vs. 0.35 mmol/L and 2.70 vs. 0.65 mmol/L; p = 0.02), however median BHB was only significantly elevated when ethanol was absent (1.88 vs. 1.42 mmol/L; p < 0.0001). Subsequent ROC curve analysis demonstrated that a better model for predicting hypothermia was in cases when blood ethanol was absent. In those deaths vitreous BHB alone had the best area under the curve, with an optimum threshold of 1.83 mmol/L (sensitivity 83.3 %; specificity 96.3 %). This study shows that post-mortem vitreous glucose and BHB are useful ancillary studies to assist in the diagnosis of hypothermia. Ethanol however is a confounder and can alter the utility of vitreous BHB when diagnosing hypothermia in those who have consumed alcohol prior to death.

Deaths From Alcoholic and Diabetic Ketoacidosis at Autopsy-A Comparison Study.

Diabetes mellitus and alcoholism are common disorders that may result in sudden death. Ketoacidosis may occur in both conditions. Diagnosis is based on history, and post-mortem findings including biochemistry and toxicology. This study compares deaths from alcoholic and diabetic ketoacidosis from two centres with large autopsy workloads. In the study period 9332 deaths were autopsies with 151 deaths diagnosed as ketoacidosis (1.6%) with 82 (0.9 %) being diabetic ketoacidosis (DKA) and 48 (0.5%) alcoholic ketoacidosis (AKA) deaths. There were more male deaths in each group. The median age for DKA deaths was 51 years (range 19-79). The median age for AKA deaths was 55 years (range was 34-78). The BMI range in DKA deaths was 12.5 to 40.4 kg/m2, with a median of 21.9. The comparative figures for AKA deaths was a range of 11.3 - 38.3 with a median of 20.2. Acetone concentrations were statistically higher in diabetic compared with alcoholic deaths, mean of 33.7 mg/100 mL in DKA cases versus mean of 16.9 mg/100 mL in AKA cases. Both DKA and AKA deaths are seen more commonly in males than female and are typically people with low BMIs in their 50s.

Ballooned neurons in semi-recent severe traumatic brain injury.

Traumatic brain injury (TBI) is now recognized as an insult triggering a dynamic process of degeneration and regeneration potentially evolving for years with chronic traumatic encephalopathy (CTE) as one major complication. Neurons are at the center of the clinical manifestations, both in the acute and chronic phases. Yet, in the acute phase, conventional neuropathology detects abnormalities predominantly in the axons, if one excludes contusions and hypoxic ischemic changes. We report the finding of ballooned neurons, predominantly in the anterior cingulum, in three patients who sustained severe TBI and remained comatose until death, 2 ½ weeks to 2 ½ months after the traumatic impact. All three cases showed severe changes of traumatic diffuse axonal injury in line with acceleration/deceleration forces. The immunohistochemical profile of the ballooned neurons was like that described in neurodegenerative disorders like tauopathies which were used as controls. The presence of αB-crystallin positive ballooned neurons in the brain of patients who sustained severe craniocerebral trauma and remained comatose thereafter has never been reported. We postulate that the co-occurrence of diffuse axonal injury in the cerebral white matter and ballooned neurons in the cortex is mechanistically reminiscent of the phenomenon of chromatolysis. Experimental trauma models with neuronal chromatolytic features emphasized the presence of proximal axonal defects. In our three cases, proximal swellings were documented in the cortex and subcortical white matter. This limited retrospective report should trigger further studies in order to better establish, in recent/semi-recent TBI, the frequency of this neuronal finding and its relationship with the proximal axonal defects.

Postmortem survey of haemoglobin A1c, non-alcoholic steatohepatitis and liver fibrosis within a general population.

AIMS: Non-alcoholic steatohepatitis (NASH), fatty liver disease and fibrosis are associated with diabetes mellitus and obesity. Previous autopsy series have reported prevalence of fatty liver disease to be 11%-24%. Recent studies, using imaging and serology, suggest a prevalence of 20%-35%, NASH of 5% and advanced fibrosis of 2%-3%. We examined the prevalence of NASH and liver fibrosis in a general autopsy population. METHODS: A cross-sectional study of consecutive, adult, medicolegal autopsies over a 1-year period was conducted. Liver sections were scored for fibrosis, inflammation and steatosis using a modified NASH scoring system. Stepwise logistic regression was used to identify associations between NASH or moderate/severe fibrosis and several clinicopathological parameters, including postmortem haemoglobin A1c (HbA1c). RESULTS: Of 376 cases, 86 (22.9%) were classified as NASH. Prevalence of diabetes mellitus, body mass index (BMI) and postmortem HbA1c were significantly higher in NASH cases (39.5%, 32.3 kg/m2 and 6.88%) than non-NASH cases (12.1%, 27.0 kg/m2 and 5.73%). Decedents with moderate/severe fibrosis (6.9%) had higher prevalence of diabetes, BMI and HbA1c (50%, 31.4 kg/m2 and 6.7%) compared with those with no/mild fibrosis (16%, 28 kg/m2 and 5.9%). HbA1c ≥7% was found to be an independent predictor of NASH (OR 5.11, 95% CI 2.61 to 9.98) and advanced fibrosis (OR 3.94, 95% CI 1.63 to 9.53). CONCLUSIONS: NASH and advanced fibrosis were higher in our general adult autopsy population compared with previously published estimates. This is a large series with histological evaluation showing that HbA1c >7.0% is independently associated with NASH and advanced fibrosis.

Evaluating small vessel neutrophils as a marker for sepsis.

A retrospective case-control study of 100 sepsis autopsy cases and 103 controls over a 9-year period was conducted to analyze patterns of neutrophils in small caliber vessels of the liver, heart, and lungs in relation to sepsis as the cause of death. Data extracted included demographics of the decedent, cause of death, presence of conditions that could interfere with an inflammatory response, history of hospitalization, and results of microbiology cultures. Histologic sections of the liver, heart, and lungs were assessed. Organs were scored for neutrophilic inflammation based upon a predetermined grading system. Scores of 0, 1, and 2 were assigned according to mild, moderate, and florid neutrophilic presence, respectively; a total score was also assigned based on the sum of the scores from all three organs. Comparing the histologic grading between cases and controls found a statistical difference with the neutrophil grading in the liver (p < 0.001), lung (p < 0.001), and heart (p < 0.001) and between the combined total scores (p < 0.001). Combined neutrophilic scores of 4 and greater showed high specificities (90% to 100%) for sepsis-related deaths. Examining the percentage of sepsis cases as the histologic neutrophilic score increased found a positive slope in all three organs. However, only the linear regression looking at the lung (p = 0.03) and the combined score (p = 0.001) were statistically significant. Despite the above results, sepsis cases with low scores and controls with moderate and florid neutrophilic infiltrates were also seen.

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%.

Fat Embolism, Fat Embolism Syndrome and the Autopsy.

Fat embolism is common following trauma and is a common autopsy finding in these cases. It may also be seen in non-traumatic cases and is seen in children as well as adults. In comparison fat embolism syndrome (FES) only occurs in a small number of trauma and non-trauma cases. Clinical diagnosis is based on characteristic clinical and laboratory findings. Fat embolism exerts its effect by mechanical blockage of vessels and/or by biochemical means including breakdown of fat to free fatty acids causing an inflammatory response. Fat embolism can be identified at autopsy on microscopy of the lungs using fat stains conducted on frozen tissue, including on formalin fixed but not processed tissue. With FES fat emboli can be seen in other organs including the brain, kidney and myocardium. Fat can also be identified with post-fixation staining, typically with osmium tetroxide. Scoring systems have been developed to try and determine the severity of fat embolism in lung tissue. Fat embolism is also common following resuscitation. When no resuscitation has taken place, the presence of fat on lung histology has been used as proof of vitality. Diagnosis of fat embolism syndrome at autopsy requires analysis of the history, clinical and laboratory findings along with autopsy investigations to determine its relevance, but is an important diagnosis to make which is not always identified clinically. This paper reviews the history, clinical and laboratory findings and diagnosis of fat embolism and fat embolism syndrome at autopsy.

Opioid-Related Deaths in Eastern Ontario from 2011 to 2016.

There has been a growing opioid crisis in the United States and Canada. The aim of this study was to analyze trends in opioid-related deaths from the Eastern Ontario Regional Forensic Pathology Unit so that prevention strategies for these deaths can be developed. The analyses included examining the opioids involved and demographic characteristics of the individuals in these deaths so that possible risk factors for opioid-related deaths could be identified. A retrospective cross-sectional analysis of the full autopsy and toxicology data between 2011 and 2016 was conducted. Trends regarding the opioids involved in the death, all opioids reported in the toxicology reports and certain nonopioid drugs reported in the toxicology reports were examined. The distribution of opioid-related death by age-group and manner of death was also conducted. Two hundred seventy-four opioid-related deaths met the inclusion criteria and were examined. The majority of individuals overdosing were male. The most frequent age range for opioid-related deaths was 45 to 54 years with increasing deaths among individuals aged 55 years and older over the period studied. Fentanyl was responsible for most deaths overall when single or multiple opioids were involved. However, hydromorphone involvement was the only opioid to have a statistically significant increase over the time period. Analysis of nonopioid-related drugs revealed extensive use of antidepressants, benzodiazepines, and their metabolites. Accident was the most common manner of death throughout all age groups except for those aged 65 years or older, where suicide was most common.

The Utility and Scope of Forensic Histopathology.

Forensic histopathology is the use of histology to aid in the identification of disease and injuries in forensic pathology practice. The value of routine microscopy has been challenged in various studies and discussions have taken place in forensic journals about how useful microscopic diagnosis is in medicolegal autopsies. This paper reviews the literature on the value of histological examination in forensic practice and discusses routine histochemical stains that can be used in postmortem examinations to aid in the diagnosis and add value by confirming or refuting macroscopic findings.

Histologic Changes In Recreational Drug Misuse.

Use of recreational drugs is associated with a number of histologic changes. These may be related to the method of administration or due to systemic effects of the drugs. This paper reviews the histopathological features seen following recreational drug use. With injection, there may be local effects from abscess formation and systemic effects may result in amyloidosis. Injections have been associated with necrotizing fasciitis, anthrax, and clostridial infections. Systemic effects include infective endocarditis, with the risk of embolization, and abscesses may be seen in organs in the absence of infective endocarditis. Viral complications of injection include hepatitis and human immunodeficiency virus (HIV) infection. Injecting crushed tablets can result in intravascular granulomata in the lungs. Smoking drugs is associated with intraalveolar changes, including blackand brown-pigmented macrophages in crack cocaine and cannabis smoking, respectively. Snorting may result in intraalveolar granulomata forming when crush tablets are used and there may be systemic granulomata. Stimulants are associated with cardiovascular and cerebrovascular pathology, including contraction band necrosis and myocardial fibrosis, as well as coronary artery dissection. Stimulants may cause hyperpyrexia and rhabdomyolysis, which may be associated with changes in multiple organs including myoglobin casts in the kidney. Opioids cause respiratory depression and this can be associated with inhalational pneumonia and hypoxia in other organs if there is resuscitation and a period of survival. Ketamine use has been associated with changes in the urothelium and the liver. This paper reviews histology changes that may be seen in drug-related deaths using illustrative cases.

Liver Pathology in First Presentation Diabetic Ketoacidosis at Autopsy.

Diabetes mellitus is an enormous health burden on developed and developing nations. Eight percent of people in the United States are stated to have diabetes mellitus and 79 million people have impaired glucose tolerance. Sudden death from diabetic ketoacidosis (DKA) is common and nonalcoholic fatty liver disease (NAFLD) is a frequent finding in patients with diabetes mellitus and impaired glucose tolerance. Diabetic ketoacidosis accounts for around 1% of autopsy cases in our units and 25% of these cases did not have a previous diagnosis of diabetes mellitus. We have analyzed for the presence of NAFLD in 16 patients dying on first presentation of DKA. Some degree of NAFLD was present in all cases, with all but one case having some degree of steatosis and some degree of fibrosis was present in 14 out of 16 cases, though none where cirrhotic. Inflammation was present in nine of 13 cases and glyogenated nuclei in five of 13 cases. NAFLD can be well established in patients dying of DKA who were not known to be diabetic before death. The pathology shares features with alcoholic liver disease. They should not be mistakenly diagnosed as dying of other causes of ketoacidosis based upon the liver pathology present.

Sudden Death and an Extra-Adrenal Paraganglioma.

Pheochromocytomas and paragangliomas are a rare cause of sudden death. We present the case of a 34-year-old male who died suddenly. He had been diagnosed as having diabetes mellitus five days previously and was hypertensive. At autopsy he had a 3.5 cm extra-adrenal mass. Histology of the tumor showed it to be a paraganglioma with the characteristic histological appearance. Postmortem biochemistry revealed a vitreous glucose of 5.9 mmol/L (106 mg/dL) with negative ketones. Urinary catecholamines were measured and revealed raised metanephrine:creatinine and normetanephrine:creatinine ratios. There may be genetic implications in patients with pheochromocytomas and paragangliomas as they are associated with a number of hereditary syndromes.

Alcoholism and the Armanni-Ebstein lesion.

The Armanni-Ebstein lesion is a histological change in the kidney consisting of sub-nuclear vacuolation of the proximal tubules. It has been most associated with diabetic ketoacidosis. The vacuoles have been reported to contain glycogen. More recent studies show them to contain fat. Recent papers have associated the Armanni-Ebstein lesion with non-diabetic ketoacidosis. We present 11 cases of alcoholic ketoacidosis where the Armanni-Ebstein lesion was identified. None had a history of diabetes mellitus and none showed any changes of diabetic nephropathy. All 11 cases had raised acetone levels (3-67 mg/100 mL (mean 17.9 mg/100 mL and median value of 16 mg/100 mL). In addition a case of isopropanol poisoning was found to have the Armanni-Ebstein lesion. Isopropanol is converted to acetone but is not associated with acidosis. These results indicate that the Armanni-Ebstein lesion is not specific to diabetes mellitus.

The histopathology of drugs of abuse.

The use of drugs for recreational purposes is widespread. The drugs used can be divided into groups including stimulants (cocaine, amphetamines, etc.), opiates and opioids (heroin, oxycodone, methadone, fentanyl, etc.), sedatives (benzodiazepines and related substances) and miscellaneous drugs, including ketamine and cannabis (marijuana). These drugs can have profound effects on all organ systems in the body. The method of administration, whether by injection or inhalation, can cause localized and systemic effects, including the transmission of infection and granulomata at the site of injection and in the lungs. Suppurative abscesses from injection can result in systemic amyloidosis. Stimulants have profound effects on the cardiovascular and cerebrovascular systems, with enlarged hearts with fibrosis seen microscopically and cerebral infarction and haemorrhage. Crack cocaine use is also associated with changes in the pulmonary system, including carbon pigmented intra-alveolar macrophages, emphysema and pulmonary arterial changes. Cannabis use is associated with brown pigmented macrophages in the lung as well as changes in the respiratory tract epithelium. Opiates/opioids are associated with inhalational pneumonitis and hypoxic brain damage due to their respiratory depressant effects. Heroin use has been associated with focal segmental glomerulonephritis (heroin-associated nephropathy: HAN). 3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) use is associated with changes in the cardiovascular system. Its use can lead to hyperpyrexia, which results in systemic changes. Ketamine abuse has been associated with cystitis. Drugs of abuse may affect testicular function. In analysing the effects of drugs at autopsy a systematic approach to sampling of histology is required.

Pseudo-gunshot wound injury from perforating rib fracture: a cautionary case report.

We report a case of a young woman who was found unresponsive in a garbage dumpster beneath the balcony of her 9th floor apartment residence. Initial investigations by the police and coroner raised concerns regarding the circumstances of the death. Initial examination of the body, revealed a single penetrating injury on the chest with a wide abrasion collar--the injury pattern was similar to a gunshot entry wound or a shored exit wound. Autopsy revealed the abraded skin perforation along with major chest injuries with bruising of the chest wall, extensive comminuted rib fractures, and pleural and lung lacerations. These injuries were consistent with the effects of a fatal descent from height. The penetrating injury with the abrasion collar was due to a fractured end of a rib protruding through the skin mimicking a gunshot wound. The involvement of a firearm was further excluded by postmortem radiography (no projectile in situ), detailed external examination of the clothing, and scene investigation revealing that the decedent had descended from a balcony into the dumpster. This case underscores the concept that all round penetrating wounds with abrasion collars are not gunshot injuries.

The validity of the certification of manner of death by Ontario coroners.

PURPOSE: The aim of the study is to examine the validity of manner of death (MOD) certification of unnatural adult deaths by Ontario coroners. METHODS: A census of 306 active coroners practicing in Ontario was performed, with data collection occurring in 2002. Mailed self-administered questionnaires contained 14 fictitious clinicopathologic scenarios and questions regarding demographic information of the coroner. Crude and adjusted odds ratios of correct MOD certification were calculated by using responses of two deputy chief coroners as the gold standard. RESULTS: Nearly 74% of coroners responded to the survey. Deaths from hanging, drowning, and carbon monoxide had better odds of being certified correctly; whereas deaths from heroin, over-the-counter medication, and injuries from a descent had decreased odds of being certified correctly. Scenarios including a prior suicide attempt or a note had greater odds of correct MOD certification than those with only depression. Accidental deaths were underreported when injury resulted in a "natural" lethal complication and when there was a delay between injury and death. CONCLUSIONS: In detailing which deaths are likely to be misclassified and how they may be misclassified, this study will allow future research to more accurately assess suicidal and accidental deaths.