hd1 pathology notes

8/19/2019 HD1 Pathology Notes

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HD1 – Pathology

Atherosclerosis and Ischemic Heart Disease

I) Atherosclerosis

A) General properties

1) A pathologic change that affects large and medium sized arteries

2) Characterized by intimal lesions called atheromas (or atheromatous plaques)

(a) These are raised lesions covered by a white fibrous cap and containing a soft, yellow, lipid core

3) Can obstruct blood flow, rupture, calcify, and/or weaken the underlying media

B) Risk factors for atherosclerosis

Risk Factors for Atherosclerosis

Major

Non-modifiable Potentially controllable

Increasing age Hyperlipidemia

Male gender Hypertension

Family history Cigarette smoking

Genetic abnormalities Diabetes

Lesser, Uncertain,

or Nonquantitated

Obesity High carbohydrate intake

Physical inactivity Alcohol

Stress Lipoprotein Lp(a)

Postmenopausal estrogen deficiency Chlamydia pneumoniae

Hardened (trans)unsaturated fat intake

1) Hypercholesteremia as a major risk factor

(a) LDL (“bad cholesterol”) delivers cholesterol to peripheral tissues

(b) HDL (“good cholesterol”) recycles cholesterol to the liver for excretion

2) Inflammation as a risk factor

(a) C-reactive protein, an acute-phase molecule, is a useful marker of risk for atherosclerosis and

ischemic heart disease

C) Pathogenesis

1) Endothelial injury or dysfunction produces a thrombogenic and/or adhesive cell surface

2) Adhesion of platelets and monocytes, which release growth factors

3) Smooth muscle cells migrate to the dysfunctional site and proliferate

4) Smooth muscle cells produce collagen, proteoglycans, and other ECM constituents

5) Macrophages digest lipid (e.g. LDL) and become foam cells

D) Stages of atheromatous plaques

1) Fatty streak

(a) Early lesions (may even be observed in children and adolescents)

(b) Often appear at branch points where flow is more turbulent

2) Fibrofatty plaque

3) Advanced plaque1


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(a) Stable plaque

(b) Vulnerable plaque

4) Complicated plaque

(a) Most serious stage

(b) Often have overlying thrombi that my have ruptured

(c) Calcifications in the necrotic centers are common

E) Complications of atheromas

1) Stenosis (especially of small arteries)

2) Ulceration of fibrous cap thrombosis athero-embolism

3) Intra-plaque hemorrhage

4) Aneurysm formation

5) Calcification

II) Ischemic Heart Disease

A) Angina pectoris

1) Chest pain resulting from ischemia without frank infarction

2) Three clinical patterns of angina

(a) Stable – caused by stenosis of major coronary vessels

(b) Prinzmetal – caused by vasospasm

(c) Unstable – caused by plaque disruption with variable mural thrombiB) Myocardial infarction (MI)

1) Leading cause of death in developed nations

2) Distribution of infarcts by vessel involvement

(a) Left anterior descending artery

(i) Anterior wall of left ventricle

(ii) Anterior part of interventricular septum

(b) Right coronary artery

(i) Posterior wall of left ventricle

(ii) Posterior part of interventricular septum

(c) Circumflex artery

(i) Lateral wall of left ventricle

3) Macroscopic dating of MI

(a) Appears normal up to 8 hours post-MI

(b) Appears mottled after 8 hours

(c) Appears yellow with a red edge after 36 hours

(d) Slight shrinkage is observed after 1 week

(e) Thinning is observed after 3 weeks

(f) Scarring is observed after 6-8 weeks

(g) A dense scar is formed after 3 months

4) Microscopic dating of MI

(a) 4-12 hours – coagulative necrosis and edema(b) 12-24 hours – nuclear pyknosis, increased eosinophilia, neutrophils at border

(c) 1-3 days – loss of striations and nuclei, neutrophils invade

(d) 3-7 days – loss of myocytes, neutrophils vanish, histiocytes appear

(i) It is during this period that the myocardium is most vulnerable to rupture

(e) 7-10 days – phagocytosis, early granulation tissue

(f) 10-14 days – advanced granulation tissue

(g) >2 months – dense scar

5) Results and complications of MI

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(a) No complications (10-20%)

(b) Cardiac failure (60%)

(i) Arrhythmias, heart block, sudden death

(c) Cardiogenic shock (10%)

(d) Mural thrombus and embolism (15-40%)

(e) Rupture (1-5%)

(f) Cardiac aneurysm

(g) Fibrinous pericarditis (Dressler syndrome)

III) Reperfusion and Reperfusion Injury

A) Reperfusion

1) Reperfusion can be accomplished by thrombolysis or placement of a stent

2) Earlier reperfusion is associated with better outcomes

(a) Reperfusion within 20 minutes usually prevents necrosis

(b) Reperfusion within the first 3-4 hours is critical, as reperfusion after this time will fail to limit the

size of the infarct

3) Reperfused myocardium is hemorrhagic

4) Contraction bands are seen in irreversibly injured myocytes due to exaggerated contraction of cells

during reperfusion (during which they are exposed to high concentrations of calcium)

B) Reperfusion injury1) Four types

(a) Stunned myocardium

(b) Impedance of microvascular blood flow (no-reflow phenomenon)

(c) Reperfusion arrhythmias

(d) Lethal reperfusion injury

(i) Independent mediator of cardiomyocyte death

(ii) Causes

o Increased intracellular calcium

o ROS

o pH changes

o Inflammation

(iii) Mediates cardiomyocyte death by opening mitochondrial permeability transition pores

(PTPs) and inducing myocardial hypercontracture

Patterns of Pulmonary Injury I

I) Atelectasis

A) Definition

1) Collapse (or incomplete expansion) of part or all of the lung

B) Several types depending on their mechanism of collapse

1) Resorptive – results from obstruction of airway(a) Secretions

(b) Aspiration of foreign bodies

2) Compressive – results from external compression of alveoli

(a) Hydro-, pneumo-, hemothorax

(b) Exudate in pleural cavity (pleural effusion)

(c) Tumor

II) Pulmonary Edema

A) Definition

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1) Buildup of fluid in the alveoli

B) Numerous causes

1) Increased hydrostatic pressure in pulmonary capillaries

(a) Left heart failure

(b) Mitral stenosis

(c) Increased blood volume

(d) Pulmonary vein obstruction

2) Decreased oncotic pressure in pulmonary capillaries

(a) Hypoalbuminemia

(b) Nephrotic syndrome

(c) Liver disease

(d) Protein-losing enteropathies

3) Pulmonary microvascular injury

(a) Infection

(b) Aspiration of foreign body

(c) Drugs

(d) Radiation

(e) Trauma

C) Two types, depending on cardiac involvement1) Cardiogenic, where heart pathology precipitates pulmonary edema

2) Non-cardiogenic, where other pathologies precipitate pulmonary edema

III) Diffuse Alveolar Damage

A) Definition

1) Histological pattern of lung injury seen in acute respiratory distress syndrome

B) Mechanism

1) Injury to pneumocytes and endothelial cells is mediated by several factors

(a) Activation of neutrophils and macrophages

(i) Release of pro-inflammatory cytokines (IL-8, IL-1, and TNF) recruit neutrophils to the

alveolar space

(ii) Activated neutrophils subsequently release proteases and leukotrienes which contribute to

local tissue damage

(b) Chronic inflammation and imbalance of pro-/anti-inflammatory mediators

(c) Loss of surfactant

C) Numerous etiologies

1) Infections

2) Physical and chemical injury

3) Hematologic conditions

4) Medical/surgical conditions (e.g. transfusion associated lung injury, TRALI)

D) Phases

1) Exudative2) Proliferative (


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4) Bronchial asthma

V) Emphysema

A) Definition

1) Destructive enlargement of airspaces distal to the terminal bronchioles

B) Four types

1) Centriacinar emphysema

(a) Destruction of the central portion of the functional acinus with sparing of distal airways

(b) Upper lobes are typically affected more severely

(c) Associated with smoking

2) Panacinar emphysema

(a) Uniform injury across the diseased region

(b) Lower lobes are typically affected more severely

(c) Associated with smoking and α1-anti-trypsin deficiency

3) Paraseptal emphysema

(a) Areas of fibrosis and atelectasis are found adjacent to the pleura

(b) More frequently affects the upper lobes

4) Irregular emphysema

(a) Injury is observed adjacent to areas of fibrosis

C) Pathogenesis

1) Smoking damages the lungs through the generation of ROS and alteration of protease activity

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2) Tissue damage has several end results

(a) Loss of elastic recoil (due in part to neutrophil elastase)

(b) Inflammation

(c) Goblet cell metaplasia mucus plugging

(d) Thickening of the bronchiolar wallVI)Chronic Bronchitis/Bronchiolitis

A) Definition

1) Persistent cough with sputum production for at least 3 months in at least 2 consecutive years

B) Causes

1) Smoking and dust irritate the airways inflammation, squamous metaplasia, and injury to cilia

VII) Bronchiectasis

A) Definition

1) Dilation of bronchi and bronchioles secondary to chronic inflammation

B) Associated conditions

1) Obstruction

2) Cystic fibrosis

3) Ciliopathies

(a) Kartagener syndrome, where cilia lack dynein arms

4) Necrotizing pneumonia

VIII) Bronchial Asthma

A) Definition

1) Chronic inflammatory disorder of the airways that results in contraction of bronchial muscle

B) Types

1) Extrinsic (atopic, allergic)

(a) Mediated by IgE as a type I hypersensitivity reaction

(b) IgE and mast cells recruit eosinophils, which promote smooth muscle contraction2) Intrinsic (non-atopic)

(a) No allergen sensitization

Lung Cancer

I) Overview of Lung Cancer

A) Epidemiology

1) Leading cause of preventable death

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2) Third most common malignancy in the US, but most frequent lethal cancer (~29% of all cancer

deaths)

B) Risk factors

1) Smoking (including second-hand smoke)

2) Genetic predisposition

(a) CYP1A1 polymorphisms

(b) Glutathione S-transferase (GSTM1) polymorphisms

3) Radon gas

4) Asbestos

5) Air pollutants

6) Viruses (e.g. HPV, JCV, SV40, CMV, etc.)

7) Radiation

C) Oncogenic mutations

1) K-ras proto-oncogene

(a) Observed in 20-30% of non-small cell lung cancers

2) Epithelial growth factor receptor (EGFR) gene

3) ALK (anaplastic lymphoma kinase) translocations

(a) Associated with non-small cell lung cancers in light and non-smokers

D) Clinical presentation1) Early cancer is asymptomatic, making early detection difficult

2) Advanced tumors are associated with several symptoms

(a) Recurrent pneumonia

(b) Dyspnea

(c) Coughing and hemoptysis

(d) Weight loss

3) Special presentations

(a) Paraneoplastic syndromes

(b) Superior vena cava syndrome (obstruction of SVC)

(c) Pancoast tumor (tumor at very apex of lung)

(d) Horner’s syndrome (sympathetic symptoms of ptosis, miosis, ahidrosis, etc.)

E) Diagnosis

1) Imaging (CXR, CT, PET-CT, bone scans, etc.)

2) Tissue sampling

(a) Bronchial brushing/washing

(b) Bronchioalveolar lavage

(c) Biopsy

F) Metastasis

1) Lymphatic spread hilar lymph nodes mediastinal lymph nodes

(a) Mediastinal node involvement is a strong marker of distant spread and poor survival

2) Resident sites(a) Bone

(b) Brain

(c) Liver

(d) Adrenal glands

G) Classifications

1) Therapeutic classifications

(a) Small cell lung carcinoma (unresectable)

(b) Non-small cell lung carcinoma (resectable at early stages)

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(c) Metastatic carcinomas (from other sites)

2) Histologic classification

(a) Adenocarcinoma (40-50%)

(i) Bronchioalveolar carcinoma (special type of adenocarcinoma)

(b) Squamous cell carcinoma (20-30%)

(c) Large cell undifferentiated (5-10%)

(d) Small cell carcinoma (10%)

(e) Carcinoid

II) Adenocarcinoma

A) General

1) Malignant epithelial tumors with several growth patterns and mucus production

(a) Tubular

(b) Acinar

(c) Papillary

2) May appear as spiculated, star-shaped lesions on chest CT

3) Irregular growth pattern invades lung

B) Bronchioalveolar carcinoma

1) Non-invasive tumor with bland cytology

2) May be classified as “adenocarcinoma in situ”3) Types

(a) Mucinous

(b) Non-mucinous

III) Squamous Cell Carcinoma

A) General

1) Malignant epithelial tumor with morphologic evidence of keratinization and/or intercellular bridges

2) Highly linked to smoking

IV)Small Cell Carcinoma

A) General

1) Malignant epithelial tumor consisting of small cells with several features

(a) Minimal cytoplasm

(b) Finely granular nuclear chromatin

(c) Absent or inconspicuous nucleoli

(d) Prominent nuclear molding

(e) High mitotic, apoptotic, and necrotic activity

2) Highly associated with smoking

3) Commonly causes paraneoplastic syndromes

(a) Ectopic ACTH secretion Cushing’s syndrome

(b) Inappropriate ADH secretion

(c) Encephalitis

B) Poor prognosis1) Long term survival


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2) No necrosis

3) 5-year survival rate >90%

C) Atypical carcinoid

1) 2-10 mitoses/10 HPF

2) Necrosis

3) 5-year survival rate of 50-70%

D) Treatment

1) Surgical resection with lymph node dissection

Myocardial Disease and Tumors

I) Cardiomyopathy

A) Four types

1) Dilated cardiomyopathy (DCM)

(a) Dilation of all four heart chambers (especially the left ventricle and atrium)

(b) Impairment of contractility systolic dysfunction

(c) Causes

(i) Most cases are idiopathic

(ii) Alcoholism and malnutrition(iii) Peripartum

(iv)Myocarditis

(v) Adriamycin therapy (DNA intercalator used for cancer chemotherapy)

o Acute DCM will resolve when adriamycin therapy is stopped

o Chronic DCM will persist regardless of adriamycin therapy

(vi)Genetic mutations in cytoskeletal proteins (including dystrophin)

(d) Diagnostic criteria

(i) Positive criteria (all four must be present)

o Generalized hypertrophy and dilation (large, globular heart)

o Mural thrombi

o Endocardial thickening

o Myocardial fibrosis

(ii) Negative criteria (none of these can be present)

o No major coronary artery disease/anomaly

o No valvular disease or anomaly

o No systemic hypertension

o No shunts within or outside the heart

(e) Histologic findings

(i) Dark, enlarged nuclei with blunted ends (rectangular shape)

(ii) Hypertrophic cardiomyocytes

2) Hypertrophic cardiomyopathy (HCM)(a) Hypertrophy of the left ventricle with left atrial enlargement

(b) Impairment of compliance diastolic dysfunction

(c) Causes

(i) Almost exclusively genetic (mutations in sarcomeric proteins)

(d) Diagnostic features

(i) Dynamic left ventricular outflow obstruction transient murmur

o The anterior leaflet of the mitral valve slaps against the ventricular septum fibrosis of

both the leaflet and septal wall (“mirror image plaque”) stenosis and murmur

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(ii) Dyspnea on exertion

(iii) Ventricular enlargement can be symmetric or asymmetric (ASH)

(e) Histologic findings

(i) Myocyte hypertrophy

(ii) Myofiber disarray

3) Restrictive cardiomyopathy (RCM)

(a) Mild hypertrophy of the left ventricle with left atrial enlargement

(b) Impairment of compliance diastolic dysfunction

(c) Causes

(i) Idiopathic

(ii) Amyloidosis

o Cardiac amyloidosis may occur as part of systemic amyloidosis (AL amyloidosis)

o Insoluble amyloid protein is deposited in beta-pleated sheets, which bind congo red dye

for visualization (appear green with luminescence)

(iii) Radiation-induced fibrosis

4) Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVCM)

(a) Hypertrophy of the right ventricular free wall is most common (though left ventricular and

biventricular forms exist)

B) Channelopathies1) Genetic mutations that affect myocardial ion channels

2) Examples

(a) QT syndrome

(b) Brugada syndrome

3) Patients have electrical abnormalities that predispose them to sudden cardiac death from fatal

arrhythmias

II) Myocarditis

A) Major causes of myocarditis

1) Infections

(a) Viruses (e.g., coxsackievirus, echo, influenza, CMV)

(b) Chlamydiae

(c) Rickettsiae

(d) Bacteria (e.g., Corynebacterium diphtheria, Neisseria meningococcus, Borrelia burgdorferi)

(e) Fungi

(f) Protozoa

(g) Helminths

2) Immune-mediated reactions

(a) Postviral

(b) Poststreptococcal (rheumatic fever)

(c) SLE

(d) Drug hypersensitivity(e) Transplant rejections

3) Unknown

(a) Sarcoidosis

(b) Giant cell myocarditis

B) Gross findings

1) Thin, mottled ventricular wall

C) Histologic findings

1) Neutrophil infiltration

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2) Isolated necrosis

3) Granuloma formation with giant cells

4) End-stage fibrosis with collagen deposition

III)Tumors

A) Primary tumors of the heart are rare

1) Myxoma

(a) Most common primary tumor in adults

(b) Clinically, mimic mitral stenosis or infective endocarditis

(c) Danger of embolism

(d) Histology reveals spindle-shaped myxoma cells in a gelatinous background that give rise to

capillary vessels

2) Rhabdomyoma

(a) Most common primary tumor in children

(b) Probably hamartomas (malformations)

(c) Associated with tuberous sclerosis

B) More commonly, tumors in the heart are metastases of other tumors

1) Breast

2) Lung

3) Lymphoma4) Melanoma

Laboratory Diagnosis of Heart Disease

I) Common Risk Biomarkers

A) Risk factors for ischemic heart disease

1) Elevated LDL (>100 mg/dL)

2) Low HDL (140/90)

5) Family history of premature CHD

(a) Male first-degree relative 55 years old

7) Obesity

8) Physical inactivity

9) Poor (atherogneic) diet

10) Elevated C-reactive protein (CRP, >1.0 mg/dL)

(a) The pathology of atherosclerosis has an inflammatory component(b) CRP is a non-specific marker of inflammation that is elevated in subjects with inflammation

(including atherosclerosis)

(c) Two assays for detection

(i) General assay will detect high levels

(ii) High sensitivity assay (hsCRP) will detect subtle increases

(d) Statin therapy was shown to be effective in patients with normal LDL levels, but elevated CRP

II) Markers of Myocardial Injury

A) Features of useful biomarkers

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1) Accurate and repeatable measurements are available

(a) Reasonable cost

(b) Rapid turnaround time

2) Provide information not obtainable by clinical assessment

3) Knowledge of the measured level aids clinical decision making

B) Cardiac troponins (I or T)

1) Preferred lab markers

(a) Rise within 2-3 hours

(b) Peak within 24 hours

(c) Remain elevated for 10-14 days (depends on assay)

2) Three isoforms

(a) TnC (binds calcium)

(i) Not cardiac specific, and thus not used for diagnosis

(b) TnI (inhibits actin/myosin interactions)

(i) Cardiac specific, and thus is used for diagnosis

(c) TnT (binds tropomyosin)

(i) Found primarily in myocytes, and may be used for diagnosis

(ii) Longer half-life

(iii) Rises in renal failure(d) Recommended to test at 0, 6, and 9 hours after presentation

3) Free cytolosic forms are released first, and complexed forms are released as necrosis persists

4) Presence of elevated troponin levels may alter treatment course

C) Creatine kinase (CK or CPK)

1) Largely replaced by troponin testing

2) Dimer of M and B subunits

D) Older biomarkers

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1) Increased white cell count

2) Myoglobin (rises and falls early)

3) Aspartate aminotransferase (AST)

4) Lactate dehydrogenase (“flipped pattern”)

III) Markers of Heart Failure

A) Atrial natriuretic peptide

1) Not used, due to short half life

B) B-type natriuretic peptide (BNP)

1) Synthesized by myocytes and fibroblasts in response to diastolic stretch

2) Effects of BNP

(a) Inhibits sympathetic activity

(b) Reduces secretion of some hormones

(i) Renin

(ii) Angiotensin II

(iii) Aldosterone

(c) Causes vasodilation

(d) Decreases blood pressure

(e) Increases sodium and water excretion

3) Physiological variations in BNP levels

(a) Age (increases with age)

(b) Sex (higher in females)

(c) BMI (Decreases with BMI)

4) Used to assess heart failure

(a) Very high negative predictive value

(i) I.e., a normal BNP level is a strong indicator that the patient does not have heart failure

Valvular Heart Disease

I) General Concepts

A) Insufficiency

1) Valve does not close completely, allowing reverse flow

2) Also called regurgitation or incompetence

B) Stenosis

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1) Valve does not open completely, restricting forward flow

C) Some diseases may have features of both insufficiency and stenosis

D) Left-sided valvular disorders are much more common

II) Aortic Pathology

A) Degenerative aortic valve stenosis

1) Progressive condition

(a) Deposition of lipoproteins chronic inflammation dystrophic calcification of valve cusps

(b) With senile-type calcific aortic valve stenosis, the individual typically becomes symptomatic

around age 70-80

2) Characteristics

(a) Scattered calcific nodules and areas of fibrosis appear

(b) Most prominent damage occurs at the base of the valve cusps on the aortic side

3) Complications

(a) Left ventricular hypertrophy

(b) Aortic root dilation

(c) Coronary insufficiency

(d) Mitral valve annular dilation

(e) Heart failure

B) Congenital anomalies

1) Bicuspid aortic valve(a) Most frequent cardiovascular malformation in humans

(b) May have raphe

(i) Fibrous attachments between the valve cusp and the aortic wall that inserts lower than the

commissure

2) Unicuspid aortic valve

(a) Very rare

(b) The central “hole” may be acommissural (does not extend to the aortic wall) or unicommissural

(makes one connection to the aortic wall)

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3) Bicuspid and unicuspid aortic valves predispose the individual to degenerative changes at an earlier

age

(a) Calcifications of bicuspid aortic valves typically become symptomatic around age 50-60

(b) Unicuspid aortic valves typically become symptomatic in childhood (


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1) Fusion of the commissures “fish mouth” appearance

2) Fusion of chordae tendinae

3) Aschoff bodies are diagnostic of rheumatic fever

(a) Regions of fibrinoid necrosis surrounded by lymphocytes, macrophages, plasma cells, andoccasional giant cells

(b) Contains caterpillar cells (or Anitschkow cells), macrophages with a wavy nucleus

D) Complications

1) Mitral stenosis left atrial dilation

2) Valve fibrosis and deformity

3) Valve stenosis and insufficiency

4) Ultimately, damage to the valve surface leads to the formation of vegetations

(a) Vegetations develop along the line of valve closure

(b) Vegetations develop on the side of blood flow

(i) Atrial side for atrioventricular valves

(ii) Ventricular side for semilunar valves

5) The mitral valve is affected most commonly, followed by the aortic valve, then the tricuspid valve,

and finally the pulmonic valve

V) Endocarditis

A) Endocarditis is observed under four main conditions

1) Rheumatic heart disease (RHDE)

2) Infectious endocarditis (IE)

3) Non-bacterial thrombotic endocarditis (NBTE)

4) Libman-Sacks endocarditis (LSE)

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B) Infectious endocarditis

1) Characteristics

(a) Bacterial vegetations forming on the surfaces of structural anomalies

(i) Ventricular septal defects

(ii) Atrial septal defects

(iii) Patent ductus arteriosus


(c) The vegetations my extend into the surrounding tissue, creating destructive abscesses

(d) Left-sided valves are affected more commonly

(i) Right-sided valves are affected in IV drug users

2) Etiologic agents

(a) Staphylococcus aureus

(b) Staphylococcus epidermidis

(c) Streptococcus viridans

(d) HACEK organisms

(i) Haemophilus

(ii) Actinobacillus

(iii) Cardiobacterium

(iv) Eikenella(v) Kingella

(e) Fungal

(i) Aspergillus and Candida species

(f) Other

(i) Enterococcus and Rickettsial organisms

3) Clinical presentation

(a) Fever, malaise, and flu-like symptoms

(b) Evidence of emboli to microvasculature

(i) Petechiae

(ii) Subungal splinter hemorrhages

(iii) Roth spots in the eyes

4) Histologic findings

(a) Acute

(i) Combination of fibrin, necrotic debris, organisms, and inflammatory cells (usually

neutrophils)

(b) Chronic

(i) Fibrous tissue

(ii) Granulation tissue

5) Complications

(a) Endocarditis abscess valvular insufficiency CHF

(b) Septic emboli(c) Cardiac abscesses (often in the valve ring)

(d) Mycotic aneurysms

(e) Arrhythmia

C) Non-bacterial thrombotic (marantic) endocarditis

1) Characteristics

(a) Fibrin thrombi attach to valve surface


2) More common in patients presenting with hypercoaguable states or DIC

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D) Libman-Sacks endocarditis

1) Exclusively affects patients with SLE

2) Sterile vegetations develop on either side of the valve or the chordae tendinae

3) May heal and scar deformation of the valve

VI)Prosthetic Valves

A) Bioprosthetic valves

1) Typically do not require anti-coagulation

2) May be sourced from human or porcine tissues

3) Shorter lifespan than mechanical valves

B) Mechanical valves

1) Require life-long anti-coagulation

2) Longer lifespan than bioprosthetic valves

Patterns of Pulmonary Injury II

I) Pulmonary Embolism

A) Most pulmonary emboli arise from veins in the legs

1) Large emboli (10%) can cause saddle obstruction and can cause sudden death

2) Medium emboli (20%) generally cause infarctions3) Small emboli (70%) have various fates

(a) Clinically silent

(b) Infarction

(c) Hemoptysis

B) Outcomes

1) Death

2) May resolve completely through thrombolysis

3) May leave eccentric arterial scars or webs

4) Chronic thromboemboli pulmonary hypertension

II) Pulmonary Hypertension

A) Medial hypertrophy of muscular and elastic arteries

1) Increases right heart pressures right heart failure cor pulmonale and death

B) Types

1) Primary (idiopathic)

(a) Mutation of BMPR2 in familial and some sporadic cases

2) Secondary (most common)

(a) COPD

(b) Chronic interstitial pulmonary disorders

(c) Chronic heart failure

(d) Recurrent pulmonary emboli

(e) Obstructive sleep apnea(f) Drugs

C) Localizing the lesion

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1) Pulmonary arteries (pulmonary embolism)

2) Pulmonary capillaries (COPD, interstitial pulmonary fibrosis, pulmonary arterial hypertension)

3) Pulmonary venules (Anomalous veno-occlusive disease)

4) Left atrium (myxoma)

5) Left ventricle (DCM, HCM)6) Aorta (hypertension)

III) Pulmonary Vasculitis

A) Can involve arteries, veins, or capillaries

B) Causes

1) Anti-neutrophil cytoplasmic antibodies (ANCA)

(a) Wegener’s vasculitis is an ANCA-related vasculitis

(i) Systemic involvement

o Upper respiratory tract

o Kidneys

o Lungs

(ii) Three key features

o Vasculitis in large and small vessels

o Necrosis (fibrinoid and regional)

o Granulomatous inflammation

2) Immune complex diseases (e.g., SLE)

3) Pulmonary hemorrhage

4) Systemic diseases

IV)Pulmonary Infections

A) Pneumonia

1) Alveolar pneumonia is most common

(a) Involves (fills) alveoli(b) Bacterial etiologies

(c) Types

(i) Lobar pneumonia occupies an entire lobe

o Four stages

• Congestion (swelling of vessels)

• Red hepatization (mild hemorrhage)

• Gray hepatization (organization)

• Resolution

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(ii) Bronchopneumoia infiltrates through upper airway

2) Interstitial pneumonia

(a) Involves tissue between alveoli

(b) Viral and atypical etiologies

3) Pathogenesis

(a) Inhalation of infectious air droplets

(b) Aspiration of infected secretions/objects

(c) Hematogenous spread (secondary to bacteremia)

4) Predisposing factors

(a) Decreased cough reflex

(b) Ciliary dysfunction/injury

(c) Decreased function of alveolar macrophages

(d) Edema/congestion (e.g., CHF)

(e) Retention of secretions

B) Abscess

1) Localized suppurative necrosis

(a) Highly virulent organisms are often the culprit(s)

2) Causes

(a) Aspiration(b) Pneumonia

(c) Septic emboli

(d) Tumors

(e) Direct infection

C) Histoplasmosis

1) Associated with pigeon and bat droppings

2) Calcified granulomas are often found after resolution

D) Blastomycosis

1) Associated with particular soils

E) Pulmonary tuberculosis

1) Caused by Mycobacterium tuberculosis

2) Stages of tuberculosis

(a) Primary

(i) Single granuloma within parenchyma

(ii) Infection typically does not progress resolution via calcification (Gohn nodule)

(iii) May disseminate to miliary TB

(b) Secondary

(i) Reactivation or infection of sensitized individual

(ii) Cavitary fibrocaseous lesions

(iii) Bronchopneumonia

(iv)Can disseminate to miliary TBF) Opportunistic pneumonias

1) Infections that affect immunosuppressed patients

(a) AIDS

(b) Iatrogenic

(i) Cancer patients

(ii) Transplant recipients

2) Organisms

(a) Pneumocystis

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(b) Aspergillus

(c) CMV

V) Pneumoconioses

A) General

1) Disorders caused by inhalation of inorganic elements (primarily metals)

2) Injury is determined by several features

(a) Length of exposure

(b) Physicochemical characteristics

(c) Host factors

B) Coal worker’s pneumoconiosis (carbon dust)

1) Anthracosis

2) Progression to massive fibrosis

C) Silicosis (silicon)

1) Small nodules inside swirling lesions

D) Asbestosis (asbestos)

1) Pulmonary fibrosis

2) Pleural disease (e.g., mesothelioma)

3) Lung carcinomas

VI)SarcoidosisA) Systemic granulomatous disorder of unknown etiology

1) Majority of cases involve lungs and hilar lymph nodes

B) Pathology

1) Noncaseating granulomas

2) Pulmonary fibrosis in ~20% of cases

VII) Chronic Interstitial Lung Diseases

A) Idiopathic pulmonary fibrosis (usual interstitial pneumonia)

1) Progressive fibrosis of unknown etiology

2) Respiratory and heart failure ensues within three years

3) “Honeycomb” appearance to lungs with thick walls

(a) Active fibrosis is observed at the boundary between healthy and scarred lung

(b) Strangely, there’s no inflammatory cell infiltrate that drives the fibrosis

B) Nonspecific interstitial pneumonia (NSIP)

1) Unknown etiology with diffuse lymphocytic infiltrate

C) Cryptogenic organizing pneumonia (bronchitis obliterans organizing pneumonia, BOOP)

1) Acute illness associated with prior respiratory infection

2) Restrictive pattern of fibrosis

3) Responsive to steroid therapy

VIII) Hypersensitivity Pneumonitis

A) Immune-mediated disorders affecting the airways and interstitium

B) Caused by prolonged exposure to inhaled antigensC) Examples

1) Farmer’s lung

2) Pigeon breeder’s lung

3) Air-conditioner lung

D) Characteristics

1) Bronchiolitis

2) Intersitial lymphocyte invasion

3) Small, vague granulomas

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E) Therapy

1) Avoid trigger

2) Steroids

Congenital Heart Disease

I) Overview

A) Statistics

1) CHD affects 0.25-1% of live births

2) 10% of cases also have a chromosomal abnormality

(a) The most common is trisomy 21 (Down syndrome)

(b) Turner syndrome (45, X)

(c) 22q11 deletions (velocardiofacial syndrome)

B) Very broad phenotypic spectrum

C) Anatomy determines the physiology, which determines the clinical presentation

1) Anatomy (and thus physiology and presentation) may change over time

II) Three Major Types of Lesion

A) Left to right shunt

1) Features(a) Oxygenated blood mixes into right-sided circulation

(b) Increased blood flow to pulmonary arteries

2) Sequelae

(a) Increased pulmonary blood flow pulmonary hypertension RV hypertrophy increased

RV pressure shunt reversal (now right to left) cyanosis

(b) Eisenmenger syndrome is often the final result

(i) Cyanosis

(ii) Exercise intolerance

(iii) Sudden death

(c) Cyanosis

(i) Acrocyanosis is cyanosis of the hands and feet

o Can be normal in infants

(ii) Perioral or central cyanosis is cyanosis of the lips, face, and/or trunk

o Pathological

3) Examples

(a) Ventricular septal defect (VSD)

(b) Atrial septal defect (ASD)

(c) Patent ductus arteriosus (PDA)

B) Right to left shunt

1) Features

(a) Deoxygenated blood mixes into systemic circulation2) Sequelae

(a) Cyanotic heart disease

(i) Failure to thrive

(ii) Polycythemia

(iii) Clubbing

(iv)Cerebral hypoxia

3) Examples (the “terrible T’s”)

(a) Transposition of the great arteries

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B) Presentation

1) Flow murmur due to the excess flow through the pulmonic valve

2) May be asymptomatic in adults

C) Associated with Down Syndrome (trisomy 21)

VI)Atrioventricular CanalA) Features

1) Endocardial cushion defect that involves incomplete formation of three components

(a) Lower atrial septum ASD

(b) Membranous ventricular septum VSD

(c) Atrioventricular valves AV canal

(i) Instead, there is a single, common, 5-leaflet valve that encircles the center of the heart

B) Presentation

1) 50% of cases are associated with trisomy 21 (Down syndrome)

2) Conversely, 50% of trisomy 21 cases are associated with some congenital heart defect

VII) Transposition of the Great ArteriesA) Features

1) The right ventricle is connected to the aorta

2) The left ventricle is connected to the pulmonary artery

3) Requires a shunt to remain viable

(a) VSD (40%)

(b) PFO or PDA (60%)

(i) These are unstable and require an atrial septostomy (surgical creation of an ASD) in the first

days of life

B) Presentation

1) Cyanotic heart disease

2) Association with 22q11 deletion(a) Autosomal dominant mutation with variable penetrance

(b) 3 MB deletion that may be detected by karyotype or FISH

(c) Includes a thymic hypoplasia/aplasia SCID

3) Also associated with maternal diabetes

C) Surgically corrected by switching the arteries and reimplanting the coronary arteries

VIII) Truncus Arteriosus

A) Features

1) The aorta and pulmonary artery share a common outflow tract overriding a single truncal valve

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2) Requires an underlying VSD for survival

B) Presentation

1) Many have other aortic arch or coronary artery anomalies

2) Early development of cyanosis

3) Late cyanotic heart disease

4) Increased pulmonary blood flow

5) Association with 22q11 deletion

IX)Tetralogy of Fallot

A) Most common congenital heart defect

B) Features (must know these)

1) Pulmonary outflow tract stenosis

2) Overriding aorta

3) VSD

4) RV hypertrophy

C) Presentation can depend on the degree of right ventricular outflow tract obstruction

1) Cyanotic episodes (“tet spells”) due to spasm of the right ventricular outflow tract

2) Mild obstruction has symptoms similar to an isolated VSD (e.g., murmur and Eisenmenger)

3) Severe obstruction will produce a right to left shunt and cyanotic heart disease

X) Aortic CoarctationA) Features

1) Abrupt narrowing at the level of the ductus arteriosus

B) Presentation

1) Heart failure in infancy

2) Variable blood pressure between the upper and lower extremities

C) Associations

1) Other congenital malformation

(a) Bicuspid aortic valve (40-50%)

(b) VSD (40-50%)

(c) Other lesions (25%)

2) Turner syndrome (45, X)

Summary of Congenital Heart Defects

Acyanotic Cyanotic

VSD (fetal alcohol syndrome) Transposition (diabetes, 22q11.2)

ASD (trisomy 21) Tetralogy of Fallot (22q11.2)

PDA (congenital rubella) Truncus arteriosus (22q11.2)

AV canal (trisomy 21) Tricuspid atresia

Coarctation of the aorta (Turner syndrome, bicuspid aortic valve)

Hypertension and Vascular Diseases

I) Systemic Hypertension

A) Introduction

1) Defined as consistent BP >140/90 mmHg

2) Predisposes individuals to atherosclerosis (leading to coronary heart disease, peripheral vascular

disease, and stroke), congestive heart failure, and renal failure

3) Serves as a silent killer that damages all organs

(a) May present with stroke, heart attack, aneurysm rupture, etc.

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4) BP varies with the circadian rhythm, which must be accounted for when taking BP measurements for

the sake of diagnosis

B) BP results from the combined effects of cardiac output and vascular resistance (set primarily by the

arterioles)

1) CO depends largely on blood volume, which depends on sodium homeostasis

2) The kidney thus plays an important role in blood pressure via the renin/angiotensin system

C) Classifications

1) Primary (essential) hypertension

(a) Idiopathic cause (may be familial)

(b) Onset typically occurs after age 40

(c) Usually responds well to treatment

(d) Represents 95% of all hypertension cases

2) Malignant (accelerated) hypertension

(a) A progression of benign hypertension that becomes rapidly symptomatic

(i) BP >200/120 mmHg

(b) Symptoms

(i) Headache

(ii) Blurred vision and retinopathy

(iii) Encephalopathy(iv)LV hypertrophy

(v) Hyperplastic arteriosclerosis

o Fibrinoid necrosis and intimal hyperplasia in small arterioles

o This can be so severe that the lumen is obliterated

3) Secondary hypertension

(a) Only represents 5% of cases, but is a very important diagnosis

(b) Treating the underlying pathology will typically cure the hypertension

(c) Causes

(i) Renal

(ii) Endocrine

(iii) Cardiovascular

(iv)Neurological

(v) Drug-induced

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II) Morphology of Hypertension

A) Hypertensive vascular changes are usually found in small arteries and arterioles

1) Hyaline arteriosclerosis (associated with benign hypertension)

(a) Accumulation of a homogenous, eosinophilic material thickens the vessel wall and narrows the

lumen

(b) Caused by leakage of plasma constituents across the vascular endothelium, leading to endothelial

damage, invasion of myointimal cells, and deposition of matrix proteins (hyaline)

2) Hyperplastic arteriosclerosis (associated with malignant hypertension)

(a) Fibrinoid necrosis of the vascular wall

(b) Intimal hyperplasia

(c) May be so severe that the lumen is actually obliterated/occluded

B) Effects on the heart

1) Concentric left ventricular hypertrophy (pressure overload)

2) LVH diastolic dysfunction left atrial enlargement

3) Heart failure

4) Treatment will reverse much of the hypertrophy

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1) Hyaline arteriosclerosis in response to benign hypertension

2) Hyperplastic arteriosclerosis in response to malignant hypertension

D) Effects on the brain

1) Infarction due to atherosclerosis and thrombosis

2) Cerebral hemorrhage

E) Effects on the lungs

1) Acute edema in response to LV failure

2) Infarction

3) Terminal bronchopneumonia

III) Aneurysms

A) Introduction

1) Defined as a localized, abnormal dilation of a blood vessel (usually an artery)

2) Two possible mechanisms of formation

(a) Weakening of the vessel wall

(b) Over-distention of the vessel

B) Classifications

1) True aneurysms

(a) Have remnants of the original artery wall

2) False aneurysms (pseudoaneurysms)(a) Breach in the vessel wall pulsating hematoma

C) Aneurysm morphology

1) Fusiform (cylindrical)

(a) Aneurysm is due to atherosclerosis

(b) The entire arterial circumference is dilated

(c) Most common aneurysm in the elderly

(d) Abdominal aortic aneurysms (AAA) below the renal arteries are most common

(e) May have familial predisposition in males

2) Saccular

(a) Results from weakening of a small portion of the artery wall

(b) A small ostium connects the aneurysm to the artery

(c) Causes/examples

(i) Syphilitic aortits (complication of tertiary syphilis which occludes vasa vasorum)

(ii) Berry aneurysm of the circle of Willis (focal defect in arterial media that may be associated

with some inherited diseases)

(iii) Arteritis

(iv)Mycotic aneurysm (caused by infection)

3) Dissecting (acute aortic dissection)

(a) An intramural hematoma within an arterial wall creates a false channel within the media

(i) Occurs between the inner 2/3 and outer 1/3 of the tunica media

(b) Causes(i) Medionecrosis

o Cystic medial necrosis may be associated with Marfan’s Syndrome

(ii) Hypertension

(iii) Pregnancy (very rarely)

(c) Complications

(i) Rupture into adjacent cavity (pericardial, pleural, or peritoneal)

(ii) Vascular obstruction (caused by extension of the dissection into branching arteries)

(iii) Aortic insufficiency (due to retrograde dissection of the aortic root)

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4) Micro-aneurysms

(a) Aneurysms of small vessels, typically 50 years of age)

2) Involves medium/large arteries in the head

(a) Granulomatous inflammation with focal destruction of internal elastic lamina

3) Clinical findings

(a) Abnormally tender temporal artery

(b) ESR elevation

(c) Headache, fever, fatigue

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4) Etiology may be T-cell mediated

D) Polyarteritis nodosa

1) Systemic vasculitis of small/medium muscular arteries

2) Immune complex disease (some patients have circulating Hepatitis B complexes)

3) Affects numerous organs

4) Fibrinoid necrosis of the vessel was is observed

E) Kawasaki disease

1) Inflammation of medium/large arteries

2) Most common cause of acquired heart disease in children

3) Delayed-type hypersensitivity reaction against an unknown antigen production of anti-endothelial

cell antibodies

ANGITIS VESSELS

INVOLVED

ORGAN OR TISSUE

AFFECTED

PRINCIPAL MORPHOLOGIC FEATURES

Polyarteritis

nodosa

Muscular

arteries

Gastrointestinal tract, mesentery,

liver, gallbladder, kidney,

pancreas, muscles, other sites

Lesions of varying ages: all layers of vessels with

acute fibrinoid necrosis and extensive periarterial

inflammation

Hypersensitivityangitis

Small venulescapillaries,

arterioles

All organs and tissues (skin,muscles, heart, kidneys, lungs)

Acute necrotizing vasculitis with fibrinoid necrosis of entire wall: often thrombosis of lumen

Giant cell arteritis

(temporal

arteritis)

Muscular

arteries

Usually temporal, ophthalmic,

and cranial arteries: may be

systemic

Disruption of elastic lamina with most intense

reaction in intimal medial layers: giant cells engulf

elastic fiber fragments: occasionally thrombosis of

lumen

Takayasu’s

arteritis

Aorta, arteries Extremities: head and neck;

viscera

Granulomatous arteritis with fibrosis and marked

narrowing − patients less than 50 years of age

Kawasaki’s

Disease

Arteries Generalized: coronary arteries Identical to polyarteritis (infantile polyarteritis);

Aneurysms

Wegener’s

granulomatosis

Small arteries

and veins

Lung, kidneys, upper respiratory

tract:

occasionally systemic

Acute necrotizing vasculitis with fibrinoid necrosis of

vessel wall: often proximate to granulomas in tissues

hd1 pathology notes

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