INTRODUCTION TO PATHOLOGY

Literally translated, pathology is the study (logos) of disease (pathos, suffering). It involves the investigation of the causes of disease and the associated changes at the levels of cells, tissues, and organs, which in turn give rise to the presenting signs and symptoms of the patient. There are two important terms that students will encounter throughout their study of pathology and medicine: 1. Etiology 2. Pathogenesis

Etiology

Etiology is the origin of a disease, including the underlying causes and modifying factors. It is now clear that most common diseases, such as hypertension, diabetes, and cancer, are caused by a combination of inherited genetic susceptibility and various environmental triggers. Understanding the genetic and environmental factors underlying the diseases is a major theme of modern medicine.

1-cause/etiology,

• The causes of a disease are known as etiological factors , these include:

• 1-biological agents: viruses, bacteria

• 2- physical forces (trauma, burns radiation).

• 3- nutritional excesses or deficit.

• 4- genetic mutations.

• Most of disease do not have single cause, most are multifactorial.

1-cause/etiology cont.

• Risk factors: are the multiple factors that predispose to a particular disease.

• Factors are grouped into categories based on whether they were present at birth or acquired later in life.

Pathogenesis

• Pathogenesis refers to the steps in the development of a disease. It describes how etiologic factors trigger cellular and molecular changes that give rise to the specific functional and structural abnormalities that characterize the disease.

• Whereas etiology refers to why a disease arises,

• pathogenesis describes how a disease develops.

CELLULAR RESPONSES TO STRESS AND NOXIOUS ّضارSTIMULI

• As cells encounter physiologic stresses or pathologic stimuli, they can undergo adaptation, achieving a new steady state and preserving viability and function.

• The principal adaptive responses are hypertrophy, hyperplasia, atrophy, and metaplasia.

• If the adaptive capability is exceeded or if the external stress is inherently harmful, cell injury develops.

• Hypertrophy: increased cell and organ size, often in response to increased workload; induced by growth

factors produced in response to mechanical stress or

other stimuli; occurs in tissues incapable of cell division

• Hyperplasia: increased cell numbers in response to hormones and other growth factors; occurs in tissues whose cells are able to divide or contain abundant tissue stem cells.

Atrophy

• Atrophy: decreased cell and organ size, as a result of decreased nutrient supply or disuse;

• Atrophy is associated with decreased synthesis of cellular building blocks and increased breakdown of cellular organelles

Metaplasia: change in phenotype of differentiated cells

• Metaplasia is a reversible change in which one adult cell type (epithelial or mesenchymal) is replaced by another adult cell type.

• In this type of cellular adaptation, cells sensitive to a particular stress are replaced by other cell types better able to withstand the adverse environment.

CAUSES OF CELL INJURY (Summery)

• The causes of cell injury range from the gross physical trauma of a motor vehicle accident to the single gene defect that results in a defective enzyme underlying a specific metabolic disease.

• Most injurious stimuli can be grouped into the following categories:

1. Oxygen Deprivation 2. Chemical Agents 3. Infectious Agents 4. Immunologic Reactions. 5. Genetic Defects

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CELL INJURY AND CELL DEATH • Injury may progress through a reversible stage and culminate

in cell death.

A-Reversible cell injury: In early stages or mild forms of injury the functional and morphologic changes are reversible if the damaging stimulus is removed. Morphologic Alterations include

1. cell swelling,

2. fatty change,

3. plasma membrane blebbing and

4. loss of microvilli,

5. mitochondrial swelling,

dilation of the ER, eosinophilia

At this stage, although there may be significant structural and functional abnormalities, the injury has typically not progressed to severe membrane damage and nuclear dissolution. 11

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The relationships between normal, adapted, and reversibly and irreversibly injured cells are well illustrated by the responses of the heart to different

types of stress

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B-Cell Death • With continuing damage, the injury becomes irreversible, the cell dies. • There are two types of cell death-necrosis and apoptosis-which differ in their

morphology, mechanisms, and roles in disease and physiology . 1. Necrosis: • When damage to membranes is severe, enzymes leak out of lysosomes, enter the

cytoplasm, and digest the cell, resulting in necrosis. Cellular contents also leak out through the damaged plasma membrane and elicit a host reaction (inflammation).

• Necrosis is the major pathway of cell death in many commonly encountered injuries, such as those resulting from ischemia, exposure to toxins, various infections, and trauma.

• increased eosinophilia; nuclear shrinkage, fragmentation, and dissolution; breakdown of plasma and organellar membranes; leakage and enzymatic digestion of cellular contents

2. Apoptosis • When a cell is deprived of growth factors or the cell's DNA or proteins are damaged

beyond repair, the cell kills itself by apoptosis, which is characterized by nuclear dissolution without complete loss of membrane integrity.

• Apoptosis is an active, energy-dependent, tightly regulated type of cell death that is seen in some specific situations. Whereas necrosis is always a pathologic process, apoptosis serves many normal functions and is not necessarily associated with pathologic cell injury.

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Acute and Chronic Inflammation • Inflammation is a defensive host response to foreign invaders and necrotic tissue, but it is itself capable of causing tissue damage.

• The main components of inflammation are:

1. a vascular reaction

2. a cellular response;

both are activated by mediators derived from plasma proteins and various cells.

• Although inflammation helps clear infections and other noxious stimuli and initiates repair, the inflammatory reaction and the subsequent repair process can cause considerable harm. It is itself capable of causing tissue damage.

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Steps of the inflammatory response

• The steps of the inflammatory response can be remembered as the five Rs:

(1) Recognition of the injurious agent,

(2) Recruitment of leukocytes

(3) Removal of the agent

(4) Regulation (control) of the response

(5) Resolution (repair).

Sequence of Events in Acute Inflammation : Vascular changes

1. The vascular changes in acute inflammation are characterized by increased blood flow secondary to arteriolar and capillary bed dilation (erythema and warmth).

2. Increased vascular permeability, as a consequence of

either widening of interendothelial cell junctions of the

venules or direct endothelial cell injury, results in an

exudate of protein-rich extravascular fluid (tissue edema).

Cellular events:

• Emigration of the leukocytes from the microcirculation and accumulation in the focus of injury (cellular recruitment and activation).

• The principal leukocytes in acute inflammation are neutrophils.

3. The leukocytes, initially predominantly neutrophils, adhere to the endothelium via adhesion molecules and then leave the microvasculature and migrate to the site of injury under the influence of chemotactic agents. 4. Phagocytosis, killing, and degradation of the offending agent follow. Genetic or acquired defects in leukocyte functions give rise to recurrent infections.

These leukocyte products (microbicidal substances) include lysosomal enzymes and reactive oxygen species ROS and nitrogen species NO.

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The outcome of acute inflammation

• The outcome of acute inflammation may be :

1. removal of the exudate with restoration of normal tissue architecture (resolution).

2. transition to chronic inflammation.

3. extensive destruction of the tissue resulting in scarring.

CHRONIC INFLAMMATION

• Chronic inflammation is inflammation of prolonged duration (weeks to months to years) in which active inflammation, tissue injury, and healing proceed simultaneously.

• Caused by Persistent infections: microbes that resist elimination, Autoimmune diseases: immune responses against self , Allergic diseases Immune responses against common environmental antigens, and Prolonged exposure to potentially toxic agents (e.g., silica).

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Chronic inflammation is characterized by

1. Infiltration with mononuclear cells, including macrophages, lymphocytes, and plasma cells.

2. Tissue destruction, largely induced by the products of the inflammatory cells.

3. Repair, involving new vessel proliferation (angiogenesis) and fibrosis.

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Repair by Scar Formation Tissues can be repaired by regeneration with complete

restoration of form and function, or by replacement with connective tissue and scar formation. 2. Repair by connective tissue deposition involves angiogenesis, migration and proliferation of fibroblasts, collagen synthesis, and connective tissue remodeling. 3.Repair by connective tissue starts with the formation of granulation tissue and culminates in the laying down of fibrous tissue. 4. Multiple growth factors stimulate the proliferation of the cell types involved in repair.

Hemodynamic Disorders, Thrombosis, and Shock

Hemodynamic Disorders, Thrombosis, and Shock

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Edema

Edema is the result of the movement of fluid from the vasculature into the interstitial spaces; the fluid may be:

a. protein-poor (transudate) or

b. protein-rich (exudate).

• Edema may be caused by:

1.increased hydrostatic pressure (e.g., heart failure)

2. increased vascular permeability (e.g., inflammation)

3.decreased colloid osmotic pressure, due to reduced

plasma albumin:

a. decreased synthesis (e.g., liver disease, protein

malnutrition)

b. increased loss (e.g., nephrotic syndrome)

4.lymphatic obstruction (e.g., inflammation or neoplasia).

5. sodium retention (e.g., renal failure)

• Although any organ or tissue in the body may be involved, edema is most commonly encountered in subcutaneous tissues, lungs, and brain.

• fluid collections in different body cavities are variously designated hydrothorax, hydropericardium, or hydroperitoneum (ascites).

• Anasarca is a severe and generalized edema with

profound subcutaneous tissue swelling.

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Subcutaneous Edema (Anasarca)

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Pitting edema

• Hyperemia versus congestion.

In hyperemia, increased inflow leads to engorgement with oxygenated blood, resulting in erythema.

In congestion, diminished outflow leads to a capillary bed swollen with deoxygenated venous blood and resulting in cyanosis.

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HYPEREMIA

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CONGESTION

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In both HYPEREMIA and CONGESTION there is an increased volume and pressure of blood in a given tissue with associated capillary dilation and a potential for fluid extravasation.

Hemorrhage (Bleeding Disorders)

• Hemorrhage is extravasation of blood from vessels into the extravascular space.

• An increased tendency to hemorrhage (usually with insignificant injury) occurs in a wide variety of clinical disorders collectively called hemorrhagic diatheses.

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Types of Hemorrhage

External Hemorrhage

Internal Hemorrhage

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Intra Cranial Hemorrhage Nail Hemorrhage

•Hematoma any accumulation of extravasated blood within a tissue (under skin or mucus membrane ) •Hematomas can be relatively insignificant (e.g., a bruise) or can involve so much bleeding as to cause death (e.g., a massive retroperitoneal hematoma resulting from rupture of a dissecting aortic aneurysm;

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Examples of Hemorrhage • Minute (1- to 2-mm) also called petechiae

• Purpura: Slightly larger (3- to 5-mm) hemorrhages

• Ecchymoses: Larger (1- to 2-cm)

• hemothorax, hemopericardium, hemoperitoneum, or hemarthrosis (in joints). Large accumulations of blood in one or another of the body cavities . Patients with extensive hemorrhages occasionally develop jaundice from the massive breakdown of red blood cells and systemic increases in bilirubin.

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Examples of Hemorrhage

1. Petechial hemorrhage is minute capillary bleeding into skin or mucus membranes or serosal surfaces

are typically associated with locally increased intravascular pressure, low platelet counts (thrombocytopenia), defective platelet function, or clotting factor deficiencies.

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• Punctate منقطpetechial hemorrhages of the colonic mucosa, a consequence of thrombocytopenia. B, Fatal intracerebral hemorrhage. Even relatively inconsequential volumes of hemorrhage in a critical location, or into a closed space (such as the cranium), can have fatal outcomes.

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purpura

• can be associated with many of the same disorders that cause petechiae; in addition, purpura can occur with trauma, vascular inflammation (vasculitis), or increased vascular fragility.

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3. Ecchymosis: Diffuse subcutaneous or sub mucous bleeding

subcutaneous hematomas (bruises) are called Ecchymosis. The erythrocytes in these local hemorrhages are phagocytosed and degraded by macrophages; the hemoglobin (red-blue color) is enzymatically converted into bilirubin (blue-green color) and eventually into hemosiderin (golden-brown), accounting for the characteristic color changes in a hematoma.

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hemothorax, hemopericardium, hemoperitoneum, or hemarthrosis

• Large accumulations of blood in one or another of the body cavities .

• E.g A hemothorax (or haemothorax) is a condition that results from blood accumulating in the pleural cavity.

• Patients with extensive hemorrhages occasionally develop jaundice from the massive breakdown of red blood cells and systemic increases in bilirubin.

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The clinical significance of hemorrhage depends on the volume, recurrence and site of blood loss

1. great loss of the blood can cause hemorrhagic (hypovolemic) shock.

2. The site of hemorrhage: bleeding that would be trivial in the subcutaneous tissues may cause death if located in the brain.

3. chronic or recurrent external blood loss (e.g., a peptic ulcer or menstrual bleeding) causes a net loss of iron, frequently culminating in an iron deficiency anemia.

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Thrombo-Embolism

Thrombosis

Embolism

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Pathological Thrombosis

Useful Thrombus leads

to Arrest Bleeding

Gradual Formation of Semi-Solid Mass from Blood Constituents

( Platelets + Fibrin )

Inside Cardio Vascular System

DURING LIFE

Harmful Thrombus leads to vascular occlusion 49

Acute arterial thrombosis of the right leg (note the blue discoloration)

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Thrombosis

There are three primary influences on thrombus formation (called Virchow's triad):

(1) endothelial injury,

(2) stasis or turbulence of blood flow (e.g., due to aneurysms, atherosclerotic plaque)

(3) blood hypercoagulability: either

a. primary (genetic): i.e. mutations in prothrombin gene .

(e.g. increased prothrombin synthesis, antithrombin III deficiency) or

b. secondary (acquired) (e.g., bed rest, tissue damage, malignancy).

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There are two distinct forms of thrombosis • Venous thrombosis: (phlebothrombosis) i.e Deep vein thrombosis

(DVT) is the formation of a blood clot within a Deep vein . It most commonly affects leg veins, such as the femoral vein.

• Arterial thrombosis is the formation of a thrombus within an artery.

arterial thrombi tend to grow in a retrograde direction from the point of attachment, while venous thrombi extend in the direction of blood flow (thus both tend to propagate toward the heart). The propagating portion of a thrombus tends to be poorly attached and therefore prone to fragmentation, generating an embolus.

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Fate of Thrombosis: • 1-Dissolution: Resolution by Fibrinolysis

• 2-Propagation. Thrombi accumulate additional

platelets and fibrin, eventually causing vessel

obstruction. Occlusion ( Gradual Process )

• 3-Embolism ( Sudden Process )

Thrombi dislodge or fragment and

are transported elsewhere in the

vasculature.

4-Organization and recanalization. Thrombi induce inflammation and fibrosis (organization). These can eventually recanalize (re-establishing some degree of flow), or they can be incorporated into a thickened vessel wall.

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• Thrombosis causes tissue injury by

• a. local vascular occlusion

• b. or by distal embolization.

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Embolism

Definition: An embolus is a solid, liquid, or gaseous mass carried by

the blood to a site distant from its origin; most are dislodged

thrombi.

Rare forms of emboli include fat droplets, bubbles of air or nitrogen, atherosclerotic debris (cholesterol emboli), tumor fragments, bits of bone marrow, or foreign bodies such as bullets.

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Effects of Embolisms:

• Sudden Arterial occlusion

• Sudden Tissue Ischemia followed by necrosis (Tissue Infarction ) of downstream tissue

• Embolism types are:

a. Pulmonary

b. Systemic ___________________________________________________

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Massive Pulmonary Embolism: Emergency Status

Embolectomy

Saddle حمل عبء سرج نتيجة التفرع Embolus Resulting in Arrest of Pulmonary Circulation.

Origin of Saddle Embolus: Massive DVT of Leg

Consequences may include right-sided heart failure, pulmonary hemorrhage, pulmonary infarction, or sudden death.

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Detached intravascular embolus (solid, liquid, or gaseous mass) is carried by the blood to a site distant from its point of origin. The clinical outcomes are best understood from the standpoint of whether emboli lodge in the pulmonary or systemic circulations.

Saddle Embolus derived from a lower extremity deep venous thrombosis and now impacted in a pulmonary artery branch.

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Systemic Embolisms:

1. Cerebral Embolism:

Origin: Left Atrial Thrombosis

Effects: * Cerebral artery Occlusion

* Cerebral Tissue Ischemia

* Cerebral Tissue Infarction

2. Renal Embolism:

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• A stroke, previously known medically as a cerebrovascular accident (CVA)

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Infarction

• Infarcts are areas of ischemic necrosis most commonly caused by:

a. arterial occlusion due to thrombosis

or embolization.

b. venous outflow

obstruction is a less

frequent cause.

Myocardial Infarction 62

Red and white infarcts. A, Hemorrhagic, roughly wedge-shaped pulmonary infarct (red infarct). B, Sharply demarcated pale infarct in the spleen (white infarct).

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Shock

• Shock is defined as a state of systemic tissue hypoperfusion due to reduced cardiac output and/or reduced effective circulating blood volume. The major types of shock are: 1. cardiogenic (e.g., myocardial infarction) 2.hypovolemic (e.g., blood loss) 3. and septic (e.g., infections). 4. Anaphylactic shock due to severe allergic condition. • Shock of any form can lead to hypoxic tissue injury if not corrected.