Autopsy & forensics

Heroin

• Category: opioid, CNS depressant
• Metabolism:
  • Rapidly (t1/2: 2 - 6 min) metabolized into 6-monoacetylmorphine (MAM) - in vivo or in vitro
  • Slower (t1/2: 6 - 25 min) metabolism into morphine
    • Will generally be detected as morphine in postmortem toxicology
• Mechanism of death: respiratory depression (StatPearls: Heroin Toxicity [Accessed 24 February 2022], Br J Anaesth 2008;100:747)
  • Binds to and activates specific receptors in the brain:
    • Mu: stimulation causes respiratory depression, analgesia (supraspinal and peripheral) and euphoria
    • Kappa: analgesic effects, disassociation, hallucinations and dysphoria
    • Delta: analgesic effects, modulate mu receptors and are thought to influence mood
    • Tolerance to respiratory depression is less than complete and may be slower than tolerance to euphoria and other effects
    • Produce inhibition at the chemoreceptors via mu opioid receptors and in the medulla via mu and delta receptors causing respiratory depression
• Best samples at autopsy
  • Urine (screening)
  • Blood (quantification)
  • Vitreous humor (extended window of detection for 6-acetylmorphine [6AM]) (Forensic Sci Int 2013;226:152, J Forensic Sci 2020;65:570)
• Autopsy findings
  • Needle marks
    • Local dissection of the skin may show underlying soft tissue hemorrhage in doubtful cases
  • Pulmonary edema
  • Association with endocarditis (from use of unclean needles)
    • Septic emboli can travel to diverse regions of the body
• Histopathology findings
  • No specific histologic findings
• Toxicology (Forensic Sci Int 2012;215:18, Pharmazie 2003;58:447)
  • Therapeutic levels (for morphine)
    • 10 mg IV dose = plasma concentration 0.01 - 0.1 mg/L
  • Lethal levels (heavily dependent on decedents history of use)
    • Morphine: 0.04 - 5.5 mg/L
    • 6-MAM: 0.01 median; 0.06 mg/L (97th percentile) (blood)

Cocaine

• Category: CNS stimulant
• Metabolism: rapidly (t1/2: 0.7 - 1.5 h) metabolized into benzoylecgonine
  • When coadministered with alcohol = cocaethylene (produced in the liver whether cocaine and alcohol are both metabolized)
• Mechanism of death: arrhythmias and cardiotoxic effects
  • Binds to and activates specific receptors
    • Stimulation of adrenergic receptors: vasoconstriction in both cardiac and peripheral vasculature, tachycardia
    • Inhibition of CNS serotonin and dopamine: euphoria and addictive effects
    • Sodium (Na+) channel blockade - slow Na+ current in cardiac myocytes and local anesthetic properties
  • Increases cardiac rate, blood pressure and cardiac contractility (all of which increase myocardial oxygen demand), while causing vasoconstriction, platelet adherence, thrombus formation and coronary spasm (all of which simultaneously decreases oxygen supply), resulting in myocardial ischemia and infarction (Cureus 2021;13:e14594)
  • Effect on Na+ channels lead to prolongation of QRS complex, which is arrhythmogenic
• Best samples at autopsy
  • Urine (screening)
  • Blood (quantification)
  • Vitreous (for screening) (J Anal Toxicol 2000;24:59)
• Autopsy findings (possible but not required)
  • Myocardial infarction
    • Spontaneous coronary artery dissection is a potential complication of cocaine use (Cardiovasc Pathol 2001;10:141)
  • Cerebrovascular accidents
• Histopathology findings (possible but not required)
  • Myocarditis
  • Contraction band necrosis
  • Alveolar hemorrhages from airway injury (if smoked)
  • Eosinophilic pneumonia (if smoked)
  • Overall ischemia related changes (from vasoconstriction / thrombus formation)
• Toxicology
  • Cocaine may exhibit postmortem redistribution
  • Lethal levels (Am J Forensic Med Pathol 2011;32:71)
    • Cocaine: 0.01 - 78 mg/L
    • Benzoylecgonine: 0.02 - 90 mg/L
    • Dependent on dose, method of administration, period of survival and combination with other substances

Methamphetamine / amphetamine

• Category: CNS stimulant
• Metabolism: amphetamine
• Mechanism of death: cardiovascular complications
  • Interacts with monoamine transport proteins in the CNS to enhance the release and prevent reuptake and degradation of monoamine neurotransmitters such as serotonin, dopamine and norepinephrine (Front Neuroanat 2019;13:48)
  • Results in a surge of adrenergic stimulation
  • Stimulated alpha and beta adrenergic receptors produce hypertension, tachycardia, hyperthermia and vasospasm that can lead to multiple cardiovascular complications, including cardiac arrhythmias, acute coronary syndrome and cerebrovascular accidents
• Best samples at autopsy
  • Urine (screening)
  • Blood (quantification)
• Autopsy findings
  • Needle marks
    • Local dissection of the skin may show underlying soft tissue hemorrhage in doubtful cases
  • Myocardial infarction
  • Complications from increased blood pressure
    • Cerebrovascular pathology (especially hemorrhagic strokes and aneurysm ruptures)
    • Aortic rupture
• Histopathology findings (Addiction 2008;103:1353)
  • Cardiovascular pathology
    • Cardiomegaly, hypertrophy, atherosclerosis, ischemic heart disease, etc.
    • Methamphetamine use may cause the premature and accelerated development of cardiovascular disease and exacerbate pre-existing pathology
• Toxicology (Forensic Sci Int 2007;170:163, CUNY Academic Works: Investigation of Postmortem Methamphetamine Cases Submitted to the New York City Office of Chief Medical Examiner [Accessed 25 February 2022], J Occup Environ Med 2002;44:435)
  • May exhibit postmortem redistribution
  • Therapeutic levels
    • Amphetamine: 0.02 - 0.1 mg/L
  • Toxic levels
    • Amphetamine: > 0.2 mg/L
  • Lethal levels
    • Amphetamine: 0.24 - 11 mg/L
    • Methamphetamine: 0.02 - 15 mg/L
• Other
  • Illicit methamphetamine will consist of a racemic mixture (d and l enantiomers)
  • Certain inhalers, decongestants and prescription drugs can metabolize or contain a specific enantiomer of methamphetamine and since standard confirmatory assays are unable to differentiate between the 2 chiral molecules, postmortem toxicology results will show up as methamphetamine (J Occup Environ Med 2002;44:435)
  • Common examples include Vicks inhalers, selegiline, famprofazone

Ethanol (EtOH)

• Category: CNS depressant
• Metabolism: primarily metabolized in the liver (by alcohol dehydrogenase) into acetaldehyde
• Mechanism of death:
  • Acute ethanol intoxication: respiratory depression (J Intensive Care Med 2004;19:183)
    • Binds to GABA and glycine receptors: potentiating release of inhibitory neurotransmitters
    • Interacts with N-methyl-D-aspartate (NMDA) receptors: inhibiting glutamate release (primary CNS excitatory neurotransmitter)
    • Directly suppresses the respiratory center in the medulla oblongata (dose dependent), leading to respiratory depression
    • Induces metabolic abnormalities: including lactic acidosis, hypoglycemia, hypokalemia, hypomagnesemia, hypocalcemia and hypophosphatemia, which can lead to atrial and ventricular tachydysrhythmias, metabolic (keto) acidosis and seizures
  • Chronic ethanolism - complications of chronic liver disease
    • Chronic ethanol use is known to induce many neuroadaptive changes in the CNS involving both glutamatergic and GABAergic synaptic transmission
    • Number of GABA receptors increases, as well as the function of NMDARs and in NMDAR mediated glutamatergic synaptic transmission, requiring more and more alcohol to create the same level of inhibition
    • Increased ethanol consumption levels lead to increased hepatotoxicity, mediated through metabolism to acetaldehyde, a well known hepatotoxic molecule (Clin Liver Dis 2019;23:71)
    • Ketoacidosis can also develop in chronic alcoholics with poor nutritional intake
    • High levels of ketone bodies in body fluids, namely acetone, acetoacetate and particularly b-hydroxybutyrate
    • Most ultimately succumb to systemic complications of chronic liver disease
  • Withdrawal (StatPearls: Delirium Tremens [Accessed 25 February 2022])
    • After discontinuation of chronic alcohol consumption, there is loss of the GABA inhibitory effect with potentiation of NMDA excitatory effects, leading to CNS hyperstimulation
    • Delirium tremens is the most severe form, leading to significant autonomic dysfunction and vital sign abnormalities that can result in cardiovascular collapse and seizures
• Best samples at autopsy
  • Urine (screening)
  • Blood (quantification)
  • Vitreous (more stable in decomposing or embalmed bodies) (Forensic Sci Int 2007;165:10)
• Autopsy findings
  • Acute ethanol intoxication
    • Acute pancreatitis
    • Pulmonary edema
    • May have no specific findings
  • Chronic ethanolism
    • Hepatic steatosis / cirrhosis
    • Dilated cardiomyopathy
    • Ascites
    • Jaundice
    • Ecchymosis
    • Lower extremity edema
    • Cerebellar vermis atrophy
    • Atrophy / infarction of mammillary bodies (Wernicke-Korsakoff syndrome)
• Histopathology findings
  • Acute ethanol intoxication
    • Acute hepatitis / pancreatitis
    • Pulmonary edema
    • Central pontine demyelination (can be seen with rapid correction of hyponatremia during attempted resuscitation of decedents that die after presenting to the emergency department)
  • Chronic ethanolism
    • Cirrhosis - hepatic nodular fibrosis
    • Macrovesicular steatosis
    • Periportal chronic inflammation
    • Atrophy / infarction of mammillary bodies (Wernicke-Korsakoff syndrome)
• Toxicology - all levels heavily dependent on tolerance
  • Does not exhibit significant postmortem redistribution
  • Therapeutic levels
    • 100 - 150 mg/dL
    • Ensures saturation of alcohol dehydrogenase in ethylene glycol and methanol poisonings in order to prevent conversion into toxic metabolites (formic acid or formate anions) (Clin Toxicol (Phila) 2015;53:797)
  • Toxic levels (Eur J Intern Med 2008;19:561)
    • > 50 mg/dL
  • Lethal levels (Leg Med (Tokyo) 2013;15:122, Forensic Sci Int 2003;135:206)
    • Acute ethanol toxicity: 74 - 680 mg/dL (mean: 364 mg/dL)
• Other
  • Alcohol can be endogenously produced in decomposing bodies from microbial activity and fermentation of glucose (Forensic Sci Int 2007;165:10)
  • Low concentrations (usually < 30 mg/dL)
  • Supporting evidence of alcohol in urine and vitreous humor proves useful for comparison in such cases
    • Ethanol > 10 mg/dl in blood or in chest fluid but < 10 mg/dl in vitreous or urine should be considered as endogenous production (Leg Med (Tokyo) 2013;15:122, J Forensic Sci 1982;27:549)

Fentanyl

• Category: synthetic opioid, CNS depressant
• Metabolism: norfentanyl
• Mechanism of death: respiratory depression (Br J Anaesth 2008;100:747)
  • Binds to and activates specific receptors in the brain:
    • Mu: stimulation causes respiratory depression, analgesia (supraspinal and peripheral) and euphoria
    • Kappa: analgesic effects, disassociation, hallucinations and dysphoria
    • Delta: analgesic effects, modulate mu receptors and are thought to influence mood
    • Fentanyl rapidly crosses the blood brain barrier, resulting in greater analgesic potency than natural opioids
    • Street heroin is often contaminated with unknown amounts of fentanyl, making it dangerous to unsuspecting users
    • Fundamental drive to breathe is generated in the brainstem and modulated by inputs from the cortex, brainstem and peripheral (carotid and aortic bodies) chemoreceptors that sense changes in the chemical constituents of blood
    • Inhibition of the chemoreceptors, via mu opioid receptors and in the medulla via mu and delta receptors, causes respiratory depression
• Best samples at autopsy
  • Screening
    • Urine
    • Vitreous humor
    • Brain tissue (high affinity / higher than circulating levels) (Forensic Sci Int 2019;305:109999)
  • Blood (currently preferred)
  • Liver tissue
    • Higher levels but less prone to postmortem redistribution (Clin Biochem 2013;46:598)
• Autopsy findings
  • Needle marks
    • Local dissection of the skin may show underlying soft tissue hemorrhage in doubtful cases
    • Pulmonary edema / congestion
• Histopathology findings
  • Pulmonary edema / congestion
• Toxicology
  • May exhibit postmortem redistribution
  • Therapeutic levels (Drugs 2017;77:747)
    • Opioid naïve patients experience rapid and effective analgesia at minimum plasma concentrations between 0.6 - 1.5 μg/L
    • Used for pain control, primarily in postsurgical and cancer patients
  • Toxic levels
    • Blood: 3 - 20 μg/L
    • Liver: 23 - 56 μg/kg (Clin Biochem 2013;46:598)
  • Lethal levels
    • Blood: 3 - 383 μg/L (mean 25 μg/L) (J Anal Toxicol 2006;30:603)
    • Liver: > 56 μg/kg (Clin Biochem 2013;46:598)

A 43 year old man with a history of metastatic lung cancer has a cardiac arrest in the ambulance during transportation to the hospital. Cardiopulmonary resuscitation was started and continued in the emergency department, where he eventually expired. His family requested an autopsy. At autopsy, multiple rib fractures with recent soft tissue hemorrhage were observed. An ill defined mass was found in the right lung. Multiple ill defined masses were present in distant organs, consistent with metastatic disease. The gastric content showed 50 mL of undigested food mixed with numerous intact and partially digested white round pills. What is the best next step?

1. Collect blood and liver samples to run toxicology studies before signing out the case
2. Rib fractures are evidence of blunt force trauma; stop the examination and contact the medical examiner's office
3. Document all the findings and sign out the case as a natural death
4. Take a photo of the pills found in the gastric content, collect them with blood and liver samples and contact the medical examiner's office
5. Document all the findings and contact the medical examiner's office

D. Take a photo of the pills found in the gastric content, collect them with blood and liver samples and contact the medical examiner's office. The evidence of numerous pills in the stomach is suspect for acute intoxication. In a patient with late stage cancer, acute intoxication may indicate suicide or accident. Thus, this death must be reported to the local medical examiner / coroner's office. It is critical to document all the findings (including photos), and collect blood and other organ samples if antemortem blood is unavailable. Answer B is incorrect: there is evidence of cardiopulmonary resuscitation before death. The case must be reported to the medical examiner but not because of the rib fractures. Answer C is incorrect: despite the evidence of metastatic disease consistent with the medical history, the gastric finding isn't compatible with natural death. Answers A and E are only partially correct: this case requires both documentation and samples collection, and must be reported.

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Reference: Forensic toxicology

A 25 year old man is found unresponsive on the bedroom floor of his secure residence. He is brought to the nearest emergency department. He has shallow breathing and a respiratory rate of 5 breaths per minute. He has pinpoint pupils and multiple needle tracks on his right arm. He eventually dies despite treatments. What is the most likely cause of death?

1. Accidental air embolism following intravenous drug injection
2. Acute subarachnoid hemorrhage
3. Benzodiazepines toxicity
4. Cocaine intoxication
5. Opiate overdose

E. Opiate overdose. Respiratory depression, pinpoint pupils, decreased or loss of consciousness and multiple needle tracks are consistent with opiate overdose. Cocaine intoxication generally results in tachycardia, hypertension and dilated pupils. Acute subarachnoid hemorrhage typically causes severe headaches, dilated or asymmetric pupils and neck stiffness. Air embolism due to intravenous injection is rare and generally does not cause respiratory depression. Although benzodiazepines toxicity must be considered, they are associated with a low incidence of respiratory depression due to the low density of binding sites in the brainstem, which controls the respiratory center.

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Reference: Forensic toxicology