7. Sudden and Unespected Deaths.docx

**Sudden & Unexpected Death: Cardiovascular** **[Acute MI]** - **Synonyms**: Myocardial ischemia, heart attack, acute coronary syndrome - **Definitions**: irreversible myocardial muscle damage caused: prolonged ischemia, resulting from sustained **imbalance** of **perfusion**, sup...

**Sudden & Unexpected Death: Cardiovascular** **[Acute MI]** - **Synonyms**: Myocardial ischemia, heart attack, acute coronary syndrome - **Definitions**: irreversible myocardial muscle damage caused: prolonged ischemia, resulting from sustained **imbalance** of **perfusion**, supply, & demand - **Etiology/Pathogenesis** - Coronary Artery **[Atherosclerosis ]** - Risk Factors - Smoking - HTN - Elevated low-density lipoprotein cholesterol - Diabetes - Increasing age - **Nonatherosclerotic Coronary Disease**: Coronary artery vasculitis, Coronary artery amyloidosis, Coronary artery dissection, Coronary artery spasm, Coronary artery embolus (endocarditis), myocardial bridging - **Other Causes of Mismatched Perfusion and Myocardial Demand** - LT ventricular hypertrophy (cardiomyopathy, hypertensive heart disease) - Congenital heart disease - Cardiac arrest (from nonischemic causes) - Metabolic, neurogenic, arrhythmia - Impaired oxygen delivery (respiratory failure, **severe** **anemia**) **AMI -- [Epidemiology]** - Incidence - Annual incidence of new MI in US has been estimated at 610,000 cases - **Recurrent** MI accounts for 325,000 additional episodes - Age: Avg: **64.5**y (men) & **70.3**y (women) - Gender: **M** \> F - Women thought to be "protected" from **coronary** **atherosclerosis** in **reproductive** years - Ethnicity - Prevalence is highest in **developed** **nations**, presumably due to comparatively high-calorie diet, more sedentary lifestyle, & longer life expectancy - Significant variation in incidence across developed nations (lowest in Japan & high in US) **Pathophysiology -- Myocardial Bridging** - Systolic compression - Delayed diastolic flow - "Branch Steal" - Proximal atherosclerosis - Functional disorders of coronary epithelium - **Presentation** - Cardiac arrest without recognized antecedent sx - **Typical** **sx**: Chest pain (**angina**) on exertion or rest, mandibular, upper arm, or **epigastric** discomfort; usually lasts **\> 20 min**, associated nausea, diaphoresis, syncope - No sx - In elderly, women, diabetic, postoperative, & critically ill - **Treatment** - Surgical approaches - Coronary artery bypass grafting - Percutaneous coronary intervention (PCI) - Usually reserved for acute ST elevation MI (salvageable myocardium) - Balloon angioplasty with coronary artery stenting - Drugs - Sublingual nitroglycerin: vasodilator - Antiplatelet therapy (aspirin, clopidogrel) - Morphine: pain relief - Thrombolytic agents (effective **only** in **1^st^ hour** **[after]** acute coronary thrombosis) - 1^st^ generation: Streptokinase, urokinase, acetylated plasminogen streptokinase activator complex (APSAC) - 2^nd^ generation: t-PA, tenecteplase **AMI -- [Prognosis]** - Median 30-day mortality: 16.6% (Median 30-day readmission: 19.9%) - Complications - Acute - Cardiogenic shock - Rupture of myocardium (tamponade, acquired ventricular septal defect, ruptured papillary muscle) - Ventricular pseudoaneurysm (contained rupture) - Pericarditis (Dressler syndrome) - Arrhythmias - **Sudden death** - Long term - Congestive heart failure - Ischemic dilated cardiomyopathy - Ventricular true aneurysms (often w mural thrombus) - Mitral regurgitation (scar retraction of papillary muscle) - Recurrent ventricular arrhythmias - Risk of 2^nd^ MI **AMI-- Macroscopic Features** - **General Features** - Initial few **minutes** to **hours** (up to 8-12 hours), w no grossly apparent abnormality Thereafter: - 12-24 hours: No change or subtle mottling & regional stiffness - 1-3 days: Mottling w **yellow**-**tan** **center** - 3-7 days: Yellow-tan center with **hyperemic edges** - 7-10 days: Grossly softened & depressed w **more** **prominent** hyperemic edges - 10-14 days: Edges become more **gray** in color - 3-8 weeks: **Gray-white** **scar** begins to form at edges & progresses to center - 8-12 weeks: Gray-white scar w **early** **remodeling** (wall thinning & chamber dilatation) - **Hemorrhagic Infarct** - After revascularization (durable or failed), **restoration** of bl flow to damaged tissue may result in **hemorrhagic infarction** - **Dark red-brown** in color due to **hemorrhage** into ischemic tissues - **Vital Staining of Fresh Heart Tissue (Autopsy)** - **Triphenyltetrazolium** **chloride** (TTC) or nitro blue tetrazolium (NBT) dye test - Redox indicator catalyzed by dehydrogenase enzymes in viable myocardium (but not infarcted myocardium) - TTC will stain **viable** myocardium **brick red** (infarcted myocardium will remain unchanged) - NBT will stain viable myocardium **dark blue-purple** (IM will remain unchanged) **AMI --Histologic Features** - After 4 hrs (variable), myocytes may appear **wavy** & **elongated**, interstitial edema - Within 24 hrs, interstitial edema, focal hemorrhage, **myocyte contraction bands**, & **infiltration** of **neutrophils** (margination) - Staining for **C4d** may be **positive** in acutely ischemic myocytes due to complement activation - 1-3 days: Coagulative necrosis with loss of nuclei, contraction bands, & heavy neutrophilic infiltration - 3-7 days: Myocyte loss, karyorrhexis of neutrophils ("**nuclear dust**"), early **phagocytosis** by macrophages at infarct border - 7-10 days: Well-developed phagocytosis with distended macrophages, granulation tissue at infarct border - 10-14 days: Well-established granulation tissue with new bl vessels & fibroblast infiltration - 2-8 weeks: **↑collagen** deposition w decreased cellularity - \> 2 months: Dense collagenous **scar** - Caveat: sequence of changes assumes no revascularization (no reversal of ischemia) - Spontaneous or interventional reperfusion must be taken into account - Reperfusion injury (after revascularization) - Prominent coagulative necrosis - Marked erythrocyte extravasation/hemorrhage - Small vessels may show small thrombi or atheroemboli **Cardiomyopathy** - Definitions: complex **set** of **disorders** often posing dx **challenges** - Bases for Classification - Etiology: **Primary**, **Secondary**, Alcoholic, Peripartum - Morphology: Dilated, Hypertrophic & Restrictive - Physiology - Systolic heart failure - Diastolic: Preserved ejection fraction heart failure **Cardiomyopathy -- Primary** - Genetic - Hypertrophic cardiomyopathy - Arrhythmogenic cardiomyopathy - LT ventricular noncompaction/hypertrabeculation - Mitochondrial myopathies - Ion channel disorders - Acquired - Inflammatory (myocarditis) - Stress provoked (Takotsubo/apical ballooning) - Tachycardia induced - Peripartum - Mixed - Dilated cardiomyopathy - Primary restrictive cardiomyopathy **Cardiomyopathy -- Secondary** - **Amyloidosis**: Primary (AL, AH), Senile (ATTR) & Familial (numerous) - Other infiltrative disease: Gaucher, Hurler & Hunter - **Storage** **disease**: Fabry & Hemochromatosis - Eosinophilic endomyocardial disease - Sarcoidosis - **Endocrine**: Diabetic cardiomyopathy & Thyroid dysfunction (hyper or hypo) - **Cardiofacial**: Noonan syndrome & Lentiginosis - **Neuromuscular**: Friedrich ataxia & Muscular dystrophy - Nutritional: Beriberi and Pellagra - **Autoimmune**/collagen vascular: Lupus & Rheumatoid - Electrolyte imbalance - Consequence of cancer therapy - Radiation induced - Anthracycline toxicity **Cardiomyopathy - [Findings]** - **External Examination** - Lower extremity edema - Ascites (abdominal distension) - Pacemaker, implanted defibrillator - Ventricular assist device - **Internal Examination** - Cardiothoracic ratio - Heart: chest diameter in situ - Pulmonary edema & congestion - Pleural effusions - Liver enlargement (early) or "cardiac cirrhosis" (late) - Nephrosclerosis - Possible indicator of **hypertensive** heart disease **Cardiomyopathy -- [Organ Findings]** - **LT ventricular hypertrophy** - Heart **weight** **\> 150-175%** of expected weight = moderate to severe hypertrophy - Ratio of septal: free wall thickness **\>** **1.3** **cm** = **asymmetric** septal hypertrophy - **Exclude** **papillary** **muscles** when **measuring** free wall - **LT ventricle dilatation** - Short axis LT ventricle internal diameter - **\>** **5 cm** = severely dilated - **Other** **chambers** usually **enlarged** due to congestion from **systolic** **failure** - Dilated cardiomyopathy shows **both** dilatation & hypertrophy (by heart weight criteria) - **Right-sided effects** - Pulmonary venous HTN - Secondary to elevated LT atrial pressure/congestion - Dilated & tortuous vein branches in lobular septa - Septal edema & widening, prominent septal lymphatics - Intraalveolar hemosiderophages (**heart failure cells**) - RT ventricle enlargement - Complex chamber geometry precludes criteria for dilatation using width - "Gestalt" sense more useful - RT ventricle thickness (excluding trabeculation) **\> 0.6** **cm** = hypertrophy **Cardiomyopathy -- Ventricular Assist Devices & other hardware** - Evaluate for pump thrombus, position and patency of cannulas - Evaluate anastomotic connections for kinking, bending, extrinsic compression - Deactivate implantable defibrillators - Coordinate with pacemaker nurse for institution, manufacturer - Potential for electric shock to autopsy prosector **Cardiomyopathy -- Idiopathic Dilated Cardiomyopathy** - Features - Moderate-severe LV dilatation (LVISD **\> 4 cm**) - Moderate-severe LV hypertrophy (heart weight **\> 150%** of expected weight) - Myocyte hypertrophy and interstitial fibrosis - Etiology - Presumed to be late **post** myocarditis (viral or post viral) in most case - Termed "**idiopathic**" due to **lack** of definitive **causation** - Wide age range (congenital to elderly) - Rare forms: Familial, alcoholic, peripartum, hemochromatosis, tachycardia induced - Differential dx - Mainly valvular disease, regurgitant valves (volume hypertrophy) **Cardiomyopathy -- Hypertrophic Cardiomyopathy** - Features - Thick LT ventricle walls, especially septum (septum to free wall ratio **\> 1.3 cm**) - Small LT ventricle chamber volume - Moderate to severe LVH (heart **weight \> 150%** of expected) - Myocyte hypertrophy, interstitial fibrosis, myocyte disarray - LT atrium & RT chambers also enlarged - Etiology - Mutations in sarcomeric or sarcomere-associated genes - Genetic testing: **MYH7**, **MBPC**, others - May manifest at any age - Common cause of sudden death in **young people** - Differential dx - Hypertensive heart disease - Aortic stenosis (pressure hypertrophy) - Storage disease (LAMP2-Danon) - Athlete's heart **Cardiomyopathy -- Restrictive Cardiomyopathy** - Features - Normal heart weight or mild hypertrophy **(\< 150%** of expected heart weight) - LT atrial enlargement with normal-sized left ventricle & normal valves - RT chambers may be enlarged chronically - Etiology - **Primary**: Mid to late adulthood, possible association with **troponin I mutations** - **Secondary**: Infiltrative, storage disease - Differential dx - Mitral stenosis - Constrictive pericarditis - Eosinophilic endomyocardial disease **Cardiomyopathy -- Arrhythmogenic Cardiomyopathy** - Features - Often **normal** heart **weight**, only **mild** **dilatation** (right or left ventricle) - Fibrofatty transmural replacement of ventricular wall - **Diverticular** **outpouchings** from ventricles in areas of wall thinning - **RT** **\>** LT ventricle involvement - **F** **\>** M, young adults - Etiology - Viral & genetic factors are implicated in pathogenesis (possibly complex interaction of environment &genetic predisposition) - Screening for cell junction protein defects (desmoplakin, plakoglobin, plakophilin) by immunofluorescence - Monomorphic ventricular tachycardia on EKG - **Sudden cardiac death in young patients** - Differential dx - Normal mural fat, especially in RT ventricle wall - Fatty degeneration/replacement of myocardium in dilated cardiomyopathy **Cardiomyopathy** - **Clinically Relevant Pathologic Features** - Exclude valvular, ischemic, & hypertensive heart disease - Correlate with antemortem imaging (echocardiogram), EKG - Systolic or diastolic (preserved ejection fraction) failure - Chamber dilatation, enlargement - Wall thickness - High or low voltage EKG - **Pathologic Interpretation Pearls** - Special stains for fibrosis, glycogen, iron, & amyloid - Selection can be guided by H&E appearance - Autopsy examination approximates end systolic dimensions in clinical imaging - **Rigor** causes near maximal ventricular contraction - Subject to decomposition changes - **Autopsy Considerations** - In cases of cardiomyopathy with potential heritability, consider storing frozen samples - Blood, myocardium, spleen - **Gross Examination** - **Accurate** heart **weight** (great vessels, pericardium, blood removed) - **Accurate** wall **thickness** (mid ventricle, exclude papillary muscles) - LT ventricle internal **short** axis **diameter** - **Microscopic Examination** - Degree & extent of fibrosis, hypertrophy - Special stains to **exclude** iron, amyloid, glycogen storage disease - Disarray in hypertrophic cardiomyopathy - Severe myocyte vacuolization in storage disease **Cardiomyopathy -- Histologic Features** - Interstitial fibrosis - Myocyte hypertrophy - Binucleation of myocytes (mild, early) - Enlarged, hyperchromatic "boxcar" nuclei (moderate, severe) - **Primary cardiomyopathy is a diagnosis of exclusion**; must rule out the following: - Chronic valvular disease - Hypertensive heart disease - Ischemic heart disease - Etiology specific findings - Myocyte disarray: Hypertrophic cardiomyopathy - Hemosiderin: Hemochromatosis - Amyloid: Amyloidosis - Marked transmural myocyte vacuolization: Storage disease - Foamy macrophages: Gaucher **[Myocarditis]** - **Definition:  **Inflammatory process involving myocardium with degeneration &/or necrosis of myocytes secondary to infection or autoimmune response - **Etiology** - Viral -- coxsackie, influenza, adenovirus, Herpesviridae, poxvirus - Bacterial -- gram positive cocci, rickettsia, borrelia - Fungal -- candida, aspergillus, zygomycosis - Parasitic -- toxoplasma gondii, trypanosoma cruzii (chagas) - Postviral/postinfectious sequela - Giant cell myocarditis - Eosinophilic myocarditis - **Macroscopic Pathology** - Pericarditis may also be present (myopericarditis) - **No** gross **abnormalities** (**most common**) - **Microscopic Pathology** - Dallas criteria - No myocarditis: No inflammation or myocardial abnormalities - Borderline myocarditis: Inflammatory without myocyte damage - Myocarditis: Significant inflammation with myocyte damage - Lymphocytic - T cells predominate - Neutrophils and rare eosinophils may also be seen (mixed) - Eosinophilic - Prominent interstitial/perivascular eosinophils - Eosinophilic granulomas - Giant cell - Diffuse myocardial infiltration and infarct-like damage - No recognizable granulomas - Prominent eosinophils in background **[Cardiac Conduction System]** - **Sinoatrial (SA) Node -- Right atrium** - Subepicardial structure near superior vena cava, overlying terminal crest (vertical crest on interior wall of right atrium that separates sinus of vena cava from rest of right atrium) - Found at union of smooth-walled "sinus venosus" portion and trabecular portion of right atrium - Supplied by sinus node artery (usually a branch from right coronary) - **Atrioventricular (AV) Node -** within tricuspid annulus near atrioventricular (membranous) septum - Subendocardial structure found within Koch triangle, an anatomic area defined by these 3 vertices - Membranous septum - Roof of coronary sinus ostium - Tricuspid annulus at a point directly below coronary sinus ostium - Supplied by AV nodal artery (usually from posterior descending artery) - **Bundle of His and Purkinje cells** - Strategies for Processing and Examining Conduction System - Given small size of these structures - It is difficult to grossly cut tissue blocks thinly enough to evaluate different segments in a single histologic section - Serial sectioning of paraffin blocks is necessary to identify structures and evaluate abnormalities - Some authors advocate exhaustive sectioning of paraffin blocks (1,200-1,600 total slides) to evaluate every conduction system cell **Cardiac conduction system -- Indications for Examination** - **SA Node - Documented sinus node electrocardiographic abnormalities** - Tachycardia-bradycardia syndrome, Sick sinus syndrome, Sinus arrest, Not atrial fibrillation or atrial flutter (in most cases, SA node is normal) - Previous ablation procedure - Sudden unexpected death without other cardiac cause(s) (pathologist's discretion) - **AV Node -** Atrioventricular block - 1st degree - 2nd degree (Mobitz type 1 or Wenckebach type) - 2nd degree (Mobitz type 2) - 3rd degree - Junctional arrhythmias - Previous ablation procedure - **His Bundle and Bundle Branches -** Variable, generally not indicated (Very difficult to localize pathways of interest) - Previous ablation procedure - **Preexcitation Electrocardiographic Changes -** Classic example is Wolff-Parkinson-White syndrome - Anomalous connecting band of contractile myocardium between atria and ventricle - Bypassing normal conduction delay coordinated in AV node - Careful examination of entire coronary groove can be undertaken to identify a "myocardial bridge" - **Transient Antemortem Conduction Disturbances** - Usually not associated with identifiable structural abnormality **Cardiac conduction system -- Major Diseases** - Congenital Atrioventricular Block - Usually "**benign**" clinically, but eventual pacemaker therapy - Lack of connection to atrial myocytes with fatty replacement of AV nodal structures & increased fibrosis - Sarcoidosis - Predilection for subendocardium & conduction pathways - Myocarditis - Conduction disturbance may occur in acute or chronic phase - Cystic Tumor of AV Node - Biologically indolent - Slow growing &vnever metastasizes - Sudden death may be presenting sign - Lenègre Disease - Idiopathic fibrosis of AV node - Amyloid -- associated with ischemic heart disease - Metastasis - Any primary site possible **[Aortic Dissection]** - Clinical Issues - If younger, ↑suspicion for syndromic or nonsyndromic connective tissue disorder - Imaging Findings - Widening of aortic silhouette or abnormal aortic contour on chest radiograph - May be normal in 12-15% of patients with aortic dissection - Macroscopic Pathology - **Marfan Syndrome**: thin habitus, long limbs (arm span \> height), long digits (arachnodactyly) - **Loeys Dietz**: marfan features **plus** **craniofacial** **abnormalities**: - Craniosynostosis, hypertelorism, bifid uvula &/or cleft palate - **Loeys-Dietz Syndrome**: Type 2 overlaps with vascular Ehlers-Danlos syndrome and Marfan syndrome - Fewer craniofacial abnormalities (only bifid uvula), pectus, joint laxity and arachnodactyly but no marfanoid body habitus, easy bruising (may see bruises), soft velvety translucent skin - **Vascular Ehlers-Danlos Syndrome**: Fewer overall physical findings; small joints with mild hypermobility, soft velvety translucent skin and easy bruising (may see bruises on body) - Turner syndrome: Short stature, shield-like chest, webbed neck, short 4th metacarpal **Aortic Dissection -- Gross Findings** - Cardiac tamponade - Hemothorax - Intimal tears **Aortic aneurism** - Aortic dissection (cross) - Ascending aorta dissection - Histology of dissection **[Abdominal Aortic Aneurysm]** - **Definitions** - Aneurysm: Localized permanent pathologic dilatation of vessel wall with diameter at least 50% \> normal - Normal diameter ↑with age, varies with aortic location and body habitus - Abdominal aortic diameter \< 3 cm - **Macroscopic Pathology** - Describe shape, length, position in relation to renal artery ostia (supra-/juxta-/infrarenal) and diameter - Rupture risk ↑ with ↑ diameter; 4-5 cm 1% per year, 5-6 cm 11% per year, 6 cm 25% per year: Repair usually at 5.5 cm - Abdominal or aorta x-ray highlights endografts - Look for rupture if hemoperitoneum or retroperitoneal hematoma present - Most common site: **Left lateral infrarenal** - **Microscopic Pathology** - Complications: Atheroemboli ± thrombosis/vasculitis, infarcts (kidney, intestine, brain, spleen) - Saccular aneurysm - Stent **Sudden and Unexpected Death: Respiratory** **[Pulmonary Thromboembolism] (PTE, VTE)** - **Terminology** - Thromboemboli in pulmonary arterial circulation, virtually all arising from **deep veins** of **lower** extremity - **Macroscopic Pathology** - Signs of deep venous thrombosis include swollen red lower extremity; measure bilateral calf circumference to reveal subtle swelling - Risk factors: Recent surgery, hip fracture, atrophy of lower extremities suggesting paralysis, trauma - Remove heart and lung block together to avoid disruption of pulmonary thromboembolus, open pulmonary artery anteriorly - Check for presence of thromboembolus either proximal within bifurcation (saddle embolus) or distal vasculature - True thromboembolus has shape of vessel of origin, has venous valve markings on exterior - **Presentation** - Wells criteria: Clinical risk score for PTE (0-1 = low, 2-6 = intermediate, \> 6 = high) - Clinical signs/symptoms of PTE (3) - PTE/VTE favored clinical diagnosis (3) - Heart rate \> 100 (1.5) - Surgery/immobilization in last 30 days (1.5) - Prior VTE (1) - Hemoptysis (1) - Active or treated malignancy in last 6 months (1) - **Laboratory Tests** - D dimer elevation - High negative predictive value - Nonspecific - Postmortem utility not proven - **External Examination** - Deep venous thrombosis - Swollen red lower extremity: Bilateral calf and thigh circumference - **Internal Examination** - Often unremarkable or findings related to trauma, recent surgery, underlying malignancy - After incising iliac veins, lower extremities elevated and "milked" - Free-flowing blood from iliacs = no obstruction - **Organ Examination** - Cardiovascular system - Remove heart as previously described - Right ventricular dilatation, thromboembolus in transit - Patent foramen ovale (potential for paradoxical embolization) - IVC filter (postmortem radiograph helpful) - Respiratory system - Pulmonary vasculature opened completely to identify PTE (may be multiple) - Webs within pulmonary artery indicate organized and recanalized thromboemboli - Pulmonary edema may indicate preexistent congestive heart failure, a contributory cause of PTE - Hepatobiliary system - Liver congestion from acute cor pulmonale - Malignancy: Occult tumor - **Differential Diagnosis** - Postmortem Blood Clot - "Chicken fat" (yellow gelatinous) - "Currant jelly" (dark red) - Random arrangement of coagulated serum and red blood cells - Not adherent to wall - **Reporting Criteria** - Presence and Location of Thromboembolus - Cause of death or contributor? - Underlying risk factors identified from chart review or postmortem **Pulmonary Edema** Pulmonary edema is accumulation of fluid in alveolar spaces - **Etiology** - Pulmonary edema divided into cardiogenic and noncardiogenic causes - Diffuse alveolar damage is the prototypical example of noncardiogenic, permeability edema - Major histologic pattern associated with clinical syndrome of acute respiratory distress syndrome (ARDS) - In hospitalized patients, etiology of pulmonary edema or diffuse alveolar damage is often multifactorial - **Clinical Issues** - Significant cause of morbidity and mortality in hospitalized patients and is a common finding at autopsy - **Macroscopic Pathology** - Heavy and fluid-filled lungs - Diffuse alveolar damage results in airless and firm lungs - **Microscopic Pathology** - Nonpermeability pulmonary edema - Fluid accumulation within alveolar spaces - Diffuse alveolar damage - Hyaline membranes (early) and fibroblastic proliferation (late) **External Examination** - Pulmonary edema often occurs in setting of congestive heart failure - Pitting edema and venous stasis changes may be present - Severe edema (anasarca) noted in hypoalbuminemic states - Rapid infusion of fluids may result in iatrogenic volume overload and subsequent acute pulmonary edema - Note IV access and other central lines and correlate with clinical history of fluid administration as well as transfusions - Sternal incision from recent coronary artery bypass graft surgery, valve surgery, ventricular assist device - Burns (not encountered in hospital autopsy practice) - Gastric contents in mouth (aspiration) - Recent cesarean section scar (eclampsia-related pulmonary edema) **Internal Examination** - Absence or presence and character/quantitation of pleural effusions - Pleural effusion occurs when reserve capacity of lymphatic system to drain fluid from pulmonary extravascular spaces is exceeded and it is a good indicator of excess fluid in lungs - Cardiac disease is the major cause of nonpermeability pulmonary edema - Special attention should be paid to examination of the 4 heart chambers, cardiac valves, coronary vessels, and major vessels for any abnormality - Renal disease or renal artery stenosis can also cause noncardiogenic, nonpermeability pulmonary edema **Organ Examination** - Increased lung weights are a sensitive indicator of pulmonary disease and, in absence of another etiology such as infection or malignancy, reflect severity of fluid accumulation within lung - Prominent interstitial markings are often present on pleural surface and reflect accumulation of fluid within lobular interstitium - Sectioning of unfixed lung will result in exudation of fluid from cut surface - Assuming no other underlying pulmonary disease or longstanding cardiac disease resulting in chronic passive congestion, lungs in cardiogenic and noncardiogenic, nonpermeability pulmonary edema are fairly compliant - By contrast, lungs with evolving diffuse alveolar damage are airless and firm - Presence of frothy fluid exuding into trachea and bronchi prior to fixation is another indication of pulmonary edema **[Pulmonary Hemorrhage]** Diffuse alveolar hemorrhage is accumulation of intraalveolar red blood cells that originate from pulmonary microcirculation **Etiology** - Result of injury to pulmonary microcirculation - Pathogenesis varies according to etiology - Differential diagnosis includes seropositive systemic vasculitides and autoimmune disorders, coagulation disorders, drug toxicity, and infections **Clinical Issues** - Patients often (but not always) present with hemoptysis, diffuse radiographic pulmonary infiltrates, and hypoxemic respiratory failure **Macroscopic Pathology** - Diffusely heavy and blood-filled lungs with exclusion of localized sources of bleeding **Microscopic Pathology** - Intraalveolar red blood cells and fibrin with accumulation of hemosiderin-laden macrophages and organizing pneumonia in later phase. 3 major histologic patterns: - Pulmonary capillaritis - Bland hemorrhage - Diffuse alveolar damage **Diagnostic Checklist** - Clinical history and ancillary studies are essential for diagnostic interpretation - Diffuse alveolar hemorrhage - Coagulopathy **[Tension Pneumothorax]** **Terminology**: Pneumothorax is defined as presence of **air** in **pleural space** - Tension pneumothorax is progressive accumulation of entrapped air within pleural space that results in pressure-induced displacement of mediastinum and heart, resulting in potentially fatal hemodynamic compromise **Etiology** - Extensive number of underlying lung diseases, as well as traumatic and iatrogenic injury **Clinical Issues** - Differences in presentation and outcome based on whether patient is spontaneously breathing or on mechanical ventilation, with the latter being more difficult to recognize and more likely to result in mortality **Macroscopic Pathology** - **Tracheal** **deviation**, mediastinal shift, and pneumomediastinum - **Unilateral** lung **collapse** with positive test for air in pleural space - Signs of prior intervention **Microscopic Pathology** - Findings consistent with specific underlying lung disease predisposing to pneumothorax or recent lung injury - Collapsed Lung = atelectasis - Air bubbles - Bullae - Atelectasis due to CPR **Sudden and unexpected death: Gastrointestinal** **[Upper Gastrointestinal Hemorrhage]** **Etiology** - Predictors of poor outcome: **Age \> 60**, onset while inpatient, comorbid conditions, shock/orthostasis, coagulopathy, multiple transfusions, endoscopically visible vessel, or arterial bleedings **Top Differential Diagnoses** - *Peptic ulcer disease*: Most common cause of severe UGI hemorrhage - Typical gross appearance: Sharply punched-out gastric or duodenal ulcers with non-raised edges and clean ulcer base - Histology is crucial to exclude malignancy - *Esophageal varices*: 2nd most common cause of severe UGI hemorrhage - Esophageal varices collapse after death and are notoriously difficult to demonstrate - Eversion of unopened esophagus is a simple means of demonstrating esophageal varices - *UGI tumors* (primary and metastatic): 7% of UGI hemorrhage - Usually in late-stage disease with poor prognosis **Diagnostic Checklist** - Gross findings may be subtle - Clinical presentation, age, and premortem diagnostic studies should guide dissection - Other significant history of (NSAID use, gastritis, cirrhosis, trauma, aortic surgery, etc.) may lead to **index of suspicion** - Acuity and volume of blood influence the differential diagnosis - Esophageal tear - Peptic ulcer **[Lower Gastrointestinal Hemorrhage]** **Terminology -** Lower GI hemorrhage - Traditional: Blood loss from GI tract **distal** to **ligament of Treitz** - Recent: Blood loss from colon or anorectum **Etiology** - Diverticular disease 30-40% - Meckel diverticulum - Ischemic enterocolitis - Neoplasia - IBD (ulcerative colitis, Crohn disease), usually bloody diarrhea (severe LGIB \< 1%) **Clinical Issues** - LGIB accounts for 20% of all GI bleeding - Exact location of bleed not identified clinically in 10% of cases - Important elements of chart review - Type of bleeding, frequency, severity, duration - Factors affecting coagulation (cirrhosis, medications) - Medications (NSAIDs, sodium polystyrene) - Underlying GI disease - Prior therapy **Top Differential Diagnoses** - Postmortem autolysis occurs rapidly in luminal GI tract, may obscure diagnostic features of some diseases **[Intestinal ischemia]** - **Terminology** - Reduction in intestinal blood flow resulting in bowel injury ± infarction, necrosis, and perforation **Etiology** - Mesenteric artery embolism/thrombosis - Nonocclusive mesenteric ischemia (NOMI) - Mesenteric venous thrombosis - Secondary to mechanical obstruction - Ischemic colitis - Drugs, infections **Macroscopic Pathology** - Evaluate small and large intestine in situ for perforations, adhesions, volvulus, strangulated hernias, intussusception, masses - Examine aorta and branches for atherosclerosis, stenosis/occlusion, thrombi, status of stents - Examine branches of inferior vena cava for thrombi **Microscopic Pathology** - Epithelial degenerative/reactive changes with loss of cytoplasmic mucin and hyperchromatic nuclei, sloughing, necrosis, ulcers - Submucosal edema, congestion, lamina propria hemorrhage, transmural necrosis/hemorrhage, serositis - Vascular findings: Thromboemboli, cholesterol emboli, atherosclerosis, vasculitis, amyloid deposition, tumor thrombi, pylephlebitis **Top Differential Diagnoses** - Autolysis **Sudden and Unexpected Death: Hepatobiliary** **[Hepatic Hemorrhage]** Intraparenchymal with hematoma ± hemobilia or hepatic rupture with hemoperitoneum **Clinical Issues** - Incidence of hepatic hemorrhage is rare, differs depending on etiology - Mortality of hepatic rupture is high (30-75%) - Patient chart review - Cirrhosis/chronic liver disease, viral hepatitis, malignancy, pregnancy - Coagulopathy, medications, vasculitis/connective tissue disease - Recent hepatobiliary surgery, liver biopsy, or TIPS procedure **Macroscopic Pathology** - Examine Glisson capsule for disruption; check location and status of stents and drains - Assess presence of underlying liver disease - Common etiologies of hemorrhage: Tumors, Pregnancy related, Iatrogenic, Peliosis hepatis **Microscopic Pathology** - Submit representative sections of masses, hemorrhagic areas/hematomas, gross vascular lesions - Evaluate uninvolved liver with iron and trichrome ± reticulin stains for intrinsic disease - Very rarely, no underlying pathology identified **[Hemorrhagic Pancreatitis]** Acute hemorrhagic pancreatitis: Necrotizing pancreatitis with disruption of microvasculature, leading to severe systemic complications **Etiology** - Choledocholithiasis and alcohol related are most common - Metabolic disorders, infections, medications/toxins, obstruction, postoperative, ischemia, trauma **Clinical Issues** - Incidence of fatal hemorrhagic complications ∼ 2-15% - Overall mortality due to hemorrhage ∼ 20-50% **Macroscopic Pathology** - Signs of sepsis, Grey Turner or Cullen sign - Hemoperitoneum, ascites, peritonitis - Pancreatic/peripancreatic abscesses or pseudocysts - Indurated, edematous, red-black hemorrhagic parenchyma ± necrosis - Peripancreatic/mesenteric fat necrosis - Peripancreatic vascular lesions (thromboses, ruptures, pseudoaneurysms) - Gastric/esophageal varices, stress ulcers, perforations, fistulas, strictures **Microscopic Pathology** - Interstitial edema and hemorrhage - Acute inflammation ± necrosis involving acini, ducts, and islets of Langerhans - Other organs: Diffuse alveolar damage, bronchopneumonia, acute tubular injury/necrosis, hepatic centrilobular congestion/necrosis **[Acute Liver Failure]** **Terminology** - ALF: Coagulopathy (INR ≥ 1.5) and encephalopathy (any degree of mental alteration) resulting from liver injury for \< 26 weeks duration without preexisting liver disease/cirrhosis **Etiology** - Drug-/toxin-induced viral hepatitis: Most common - Ischemic/hemodynamic causes (shock liver, severe congestive heart failure, heat stroke, drug related, Budd-Chiari syndrome) - Autoimmune hepatitis - Metabolic disorders (Wilson disease, acute fatty liver of pregnancy) - Malignancy - Indeterminate etiology (∼ 15% of cases) **Clinical Issues** - ∼ 2,000 cases/year in USA, usually young patients, mortality ∼ 30% - Common immediate causes of death: Cerebral edema/herniation, multiorgan failure, infection/sepsis **Macroscopic Pathology** - Wrinkled capsule, nodular surface, necrosis **Microscopic Pathology** - Findings may differ depending on cause of ALF - Varying degrees of necrosis, ± parenchymal collapse, ductular reaction, regeneration - Top Differential Diagnoses - Cirrhosis/chronic liver failure **Sudden and Unexpected Death: Genitourinary** **[Pregnancy Complications]** **Definitions** - Maternal mortality (WHO) - Death of a woman while pregnant or within 42 days of termination of pregnancy (delivery) - Irrespective of gestational duration or site (e.g., ectopic) - Any cause related to or aggravated by pregnancy or its management - Not from accidental or incidental causes - Late maternal mortality - **From 42 days to 1 year after termination** **Pregnancy Complications -- [Presentation]** **Direct obstetric death** - Result from obstetric complications (pregnancy, labor, and puerperium). Examples: - Amniotic fluid embolism - Uterine rupture - Peripartum cardiomyopathy **Indirect obstetric death** - Result from preexisting disease or disease that developed during pregnancy - Not directly due to obstetric cause, but aggravated by pregnancy. Examples: - Congenital heart defect - Idiopathic pulmonary hypertension - Aortic dissection in Marfan syndrome **Coincidental maternal death** - Result from diseases or injuries not related to pregnancy -- Homicide, accidents **Risk factors associated with maternal death** - Inadequate maternal care - Substance abuse - Medical comorbidities - Previous pregnancy problems - Hypertensive disorders of pregnancy **Clinical Information** - Current pregnancy history - Gravida/para status, Mode of delivery - Delivery procedures (cesarean section, vacuum assisted, forceps) - APGAR scores - Infection serologies - TORCH, group B Streptococcus **Past Medical History** - Heart or lung disease, anemia, hypertension, thrombophilia/coagulopathy - Medications **Autopsy, Mother -** Per normal routine - Extensive sampling of lungs - Photograph liberally - Consider fixing pelvic organs en bloc and examining with obstetrician present **Autopsy, Fetus -** Per normal routine - Cultures (blood, CSF) **Surgical Specimens** - Obtain placenta, hysterectomy, or other organs removed in proximity to death - After surgical report is finalized **Pregnancy Complications -- [Findings]** **Amniotic Fluid Embolism** - Amniotic fluid, fetal cells, lanugo hair, and other debris enter maternal blood stream causing cardiorespiratory collapse and disseminated intravascular coagulation (DIC) - Can occur during active labor, delivery, or post delivery (Mortality rate: 11-44%) - Risk factors include - Maternal age ≥ 35 years - Cesarean section - Placenta previa - Multiparity - Pathophysiology poorly understood as fetal cells often found in asymptomatic women - Immunologic mechanisms, amniotic fluid-dependent anaphylactic reaction, and complement activation have been proposed as potential pathophysiologic mechanisms - Amniotic "squames" within pulmonary arterioles and capillaries, parauterine vessels - Cytokeratin staining used to highlight - Other supplemental stains may be used - PAS or Alcian blue to visualize mucus - Sudan III to show fatty substances **Postpartum Hemorrhage** - Uterine atony - Uterine rupture or genital tract trauma - Risk factors include prior cesarean section, connective tissue disorders, instrumentation - Retained placenta **Pregnancy Complications -- [Findings]** **Prepartum Hemorrhage** - Ectopic pregnancy - Those occurring in intramural portion of tube (cornual ectopic) and cesarean section scar are covered by myometrium and grow to larger size than typical tubal ectopic before symptomatic - Rupture later than tubal ectopic - More likely to cause catastrophic bleeding and death - Unskilled abortion - Placenta previa - Placental abruption **Placenta Accreta** - Placental invasion of myometrium - Villi in direct contact with superficial myometrial smooth muscle (no intervening decidua). Accreta, increta and percreta - Associated with previous uterine surgical scar sites, especially cesarean section scars - Risk increases with number of prior cesarean sections - Most associated with placenta previa - Maternal death: 4-7% - Hemorrhage with cardiovascular collapse (loss of most blood) - Secondary causes of death include DIC, renal failure, acute respiratory distress - **Others** -- Preeclampsia/Eclampsia, HELLP syndrome, fetal complications, pregnancy-associated hematologic disorders, spontaneous coronary dissection, peripartum cardiomyopathy **[Acute renal failure]** Sudden sustained decline of glomerular filtration rate (GFR) associated with uremia, fall in urine output, and serum creatinine (SCr) increase **Etiology** - Crescentic glomerulonephritis: ANCA-related small vessel vasculitis, anti-GBM crescentic glomerulonephritis, immune complex-related glomerulonephritis - Acute postinfectious glomerulonephritis - Thrombotic microangiopathy (TMA) - Hypersensitivity reaction: Antibiotics, nonsteroidals, protein supplements, proton pump inhibitors - Systemic disorders: Hypotension, hypovolemia, sepsis, rhabdomyolysis, post surgery - Vascular: Renal vein or artery thrombosis, atheroembolic disease - Infections: Acute pyelonephritis **Clinical Issues** - Prerenal causes: 55-60% - Renal parenchymal diseases: 35-40% - Postrenal causes: \< 5% - AKI in hospitalized patient: 3-7% - All ages are affected, and etiology varies according to age **Microscopic Pathology** - Microscopic findings vary according to processes causing renal failure - Renal vein thrombosis - Tubular necrosis - IgA nephropathy