MedPox Rapid Review: Must-Know Step 1 Topics | Part-1|pathology|high-yield notes for USMLE Step 1

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Cell Injury and Death

In pathology, one of the foundational concepts is understanding how cells respond to injury. Cells are constantly adapting to changes in their environment, and they have mechanisms to handle mild stress. When stress or injury becomes too severe, the cell's capacity for adaptation is overwhelmed, leading to cell injury, and eventually, cell death.

Types of Cell Death

Cell death can occur in two major forms:

Necrosis — uncontrolled, typically due to severe injury, often leading to inflammation.
Apoptosis — a highly regulated, programmed form of cell death that doesn’t provoke an inflammatory response.

What is Apoptosis?

Apoptosis is often described as “programmed cell death” because it’s a deliberate, orderly process. Think of it as the cell’s self-destruction mechanism that is engaged when the cell is either damaged beyond repair or no longer needed. Unlike necrosis, where the cell bursts and releases its contents into the surrounding tissue (triggering inflammation), apoptosis involves the cell breaking apart into small, membrane-bound fragments called apoptotic bodies. These fragments are then phagocytosed by neighboring cells or macrophages without causing inflammation.

Physiological vs. Pathological Roles of Apoptosis

Physiological Apoptosis: Essential for development and maintenance, such as removing webbing between fingers in embryonic development or eliminating old, damaged, or dysfunctional cells.
Pathological Apoptosis: Triggered by factors like DNA damage, viral infections, or oxidative stress, which we’ll discuss further.

Key Players in Apoptosis

Several important molecules and signals control apoptosis, and understanding their roles is crucial:

1.Phosphatidylserine (PS)

Phosphatidylserine is a phospholipid normally located on the inner leaflet of the cell membrane.
During apoptosis, it flips to the outer leaflet, signaling to immune cells that the cell is ready for removal.
This “eat me” signal allows phagocytes to recognize and engulf the apoptotic cell, preventing leakage of cellular contents and subsequent inflammation.

2. Reactive Oxygen Species (ROS) and Oxidative Stress

Reactive oxygen species (ROS) are highly reactive molecules containing oxygen (like superoxide, hydrogen peroxide, and hydroxyl radicals).
While cells generate ROS during normal metabolism, particularly in the mitochondria, they usually keep ROS levels in check with antioxidants.
Oxidative stress occurs when ROS production exceeds the cell’s antioxidant defenses, leading to damage to DNA, proteins, and lipids, potentially triggering apoptosis.
High levels of ROS can damage the mitochondrial membrane, releasing pro-apoptotic signals (like cytochrome c) and initiating apoptosis through the intrinsic pathway.

Apoptosis Pathways

Apoptosis is controlled through two main pathways: intrinsic (mitochondrial) and extrinsic (death receptor). Let’s explore each:

1. Intrinsic (Mitochondrial) Pathway

•This pathway is triggered by internal cellular stressors such as DNA damage, oxidative stress, or a lack of growth factors.

•The mitochondria play a central role here. When a cell is damaged beyond repair, pro-apoptotic signals cause mitochondrial outer membrane permeabilization (MOMP).

•Key regulators include Bcl-2 family proteins:

Pro-apoptotic proteins (e.g., Bax and Bak) promote membrane permeabilization.
Anti-apoptotic proteins (e.g., Bcl-2, Bcl-xL) work to prevent apoptosis by blocking the release of apoptotic factors.

•Once the mitochondrial membrane is permeabilized, cytochrome c is released into the cytoplasm, where it binds to Apaf-1 to form the apoptosome.

•The apoptosome activates caspase-9, which triggers a cascade activating executioner caspases (caspase-3 and caspase-7), leading to cellular dismantling and formation of apoptotic bodies.

Pathoma Insight: Remember that p53, the “guardian of the genome,” plays a critical role here. In response to DNA damage, p53 can halt the cell cycle to allow repair or push the cell towards apoptosis if the damage is irreparable. Mutations in p53 are common in cancers, where cells escape apoptosis and accumulate mutations.

2. Extrinsic (Death Receptor) Pathway

The extrinsic pathway is activated by external signals binding to death receptors on the cell surface.
Examples of these receptors include Fas (CD95) and TNF receptor.
Binding of ligands (e.g., Fas ligand or TNF-α) to these receptors recruits adaptor proteins like FADD, forming the death-inducing signaling complex (DISC).
DISC activates caspase-8, which initiates a caspase cascade leading to apoptosis.
In certain cells, caspase-8 can also cleave Bid, a pro-apoptotic Bcl-2 family protein, linking the extrinsic pathway to the mitochondrial pathway.

Pathoma Insight: Disorders in the Fas-FasL system are associated with autoimmune diseases, where cells that should be eliminated are not, leading to excessive immune cell proliferation, as seen in autoimmune lymphoproliferative syndrome (ALPS).

Execution Phase of Apoptosis

Once either the intrinsic or extrinsic pathway is activated, both lead to the execution phase, which involves:

Executioner caspases (caspase-3, caspase-6, caspase-7) that break down cellular components.

DNA fragmentation: Cleavage of DNA between nucleosomes leads to characteristic DNA laddering.
Breakdown of the cytoskeleton and nuclear envelope, causing cell shrinkage and condensation.

The formation of apoptotic bodies, which are then phagocytosed, completing the cycle without triggering inflammation.

Key Clinical Correlations

Cancer: Mutations in apoptotic regulators (e.g., p53, Bcl-2) allow cells to escape apoptosis, leading to unregulated growth.
Follicular lymphoma: Characterized by Bcl-2 overexpression, which inhibits apoptosis and allows survival of abnormal B-cells.
Neurodegenerative Diseases: Oxidative stress plays a major role in diseases like Alzheimer’s and Parkinson’s, where accumulated ROS-induced damage contributes to neuronal death.
Autoimmune Conditions: Impaired apoptosis (e.g., Fas-FasL dysfunction) can lead to excessive immune cell survival and autoimmune disease.

Reversible Injury vs Irreversible Injury

Reversible Injury: Swelling and blebbing; recoverable if stress removed.
Irreversible Injury: Membrane rupture, nuclear breakdown → cell death.

Necrosis

Necrosis is a type of cell death resulting from irreversible injury, often due to factors such as ischemia, toxins, infection, or trauma.
It involves enzymatic degradation and denaturation of cell proteins, membrane rupture, and leakage of cellular contents, which elicit an inflammatory response in surrounding tissues.
Unlike apoptosis (programmed cell death), necrosis is typically uncontrolled and always pathological.
Most imp types for exam are Fat necrosis and coagulative necrosis

1.Coagulative Necrosis

Etiology: Most caused by ischemia or infarction, especially in solid organs like the heart, kidneys, and spleen.
Pathophysiology: Cell proteins, including enzymes, denature due to acid buildup (from hypoxia), which inhibits enzymatic breakdown of the dead cells. As a result, the basic cell architecture remains intact initially.
Appearance: Microscopically, cells appear as “ghost” cells, maintaining their shape but lacking nuclei. Microscopically, the tissue appears firm.
Clinical Correlation: Commonly observed in myocardial infarction (heart attack). Key diagnostic indicators include elevated cardiac enzymes like troponins.

2. Liquefaction Necrosis

Etiology: Often results from bacterial or fungal infections and is the typical form of necrosis in the brain due to lack of structural framework.
Pathophysiology: Complete digestion of dead cells by hydrolytic enzymes, often from neutrophils, resulting in a liquid, pus-like consistency.
Appearance: Microscopically, necrotic tissue shows loss of architecture with cell debris in a creamy white liquid.
Clinical Correlation: Common in abscesses and brain infarcts.

3.Caseous Necrosis

Etiology: Typically associated with tuberculosis (TB) infections due to Mycobacterium tuberculosis.
Pathophysiology: Combines elements of both coagulative and liquefactive necrosis. The necrotic area appears as a granular, cheese-like (caseous) material.
Appearance: Microscopically, fragmented cells and amorphous debris are surrounded by a granulomatous inflammatory border.
Clinical Correlation: Commonly seen in lung granulomas in TB and some fungal infections (e.g., Histoplasmosis).

4. Fat Necrosis

Etiology: Commonly follows trauma to fatty tissues (e.g., breast tissue) or results from acute pancreatitis, where lipase enzymes digest adipose tissue.
Pathophysiology: Lipases break down triglycerides into free fatty acids, which combine with calcium to form chalky white deposits (saponification).
Appearance: Microscopically, fat cells lose their structure, and calcium deposits are visible.
Clinical Correlation: Found in pancreatitis (enzymatic fat necrosis) and traumatic injuries to fatty tissues (traumatic fat necrosis).

5.Fibrinoid Necrosis

Etiology: Seen in immune reactions involving blood vessels, such as immune-mediated vasculitis and preeclampsia.
Pathophysiology: Immune complexes combine with fibrin, depositing in vessel walls and resulting in vessel wall damage.
Appearance: Microscopically, vessel walls appear bright pink and amorphous due to deposition of immune complexes and fibrin.
Clinical Correlation: Common in polyarthritis nodosa and other autoimmune vasculitis disorders.

6. Gangrenous Necrosis

Etiology: Primarily due to ischemia, especially in the extremities. Can be classified into:
Dry Gangrene: Coagulative necrosis from chronic ischemia, leading to mummification-like appearance.
Wet Gangrene: Occurs with superimposed bacterial infection, leading to liquefactive necrosis with a foul odor.
Clinical Correlation: Often associated with peripheral vascular disease, especially in diabetes mellitus.

Key Concepts exam

Coagulative Necrosis: Ischemia-driven, architecture preserved.
Liquefactive Necrosis: Complete tissue digestion, common in brain and abscesses.
Caseous Necrosis: Granular, cheese-like, hallmark of TB.
Fat Necrosis: Calcium saponification in adipose tissue (notably pancreas).
Fibrinoid Necrosis: Immune complex deposition in vessels.
Gangrenous Necrosis: Typically affects extremities, differentiated into dry (ischemia) and wet (infection).

Ischemia

Ischemia is a condition where there is a reduced blood flow to tissues, resulting in inadequate oxygen (O₂) and nutrient supply to meet the cellular metabolic demands. It’s a high-yield topic for understanding cellular injury mechanisms, especially because ischemia can lead to both reversible and irreversible injury depending on its severity and duration.

Causes of Ischemia

Vascular Occlusion: Blockage of blood vessels, often due to atherosclerosis or thrombus formation.
Vasospasm: Sudden constriction of blood vessels, reducing blood supply.
Hypotension: Low blood pressure reduces blood flow to organs.
Shock: Systemic hypoperfusion of tissues due to factors like hemorrhage or sepsis.

Pathophysiology of Ischemia

1.Oxygen Deprivation

Cells switch to anaerobic glycolysis to generate ATP, which leads to a build-up of lactic acid and decreased pH (acidosis).
ATP depletion affects cellular processes, leading to impaired Na⁺/K⁺ ATPase activity, causing cellular swelling.

2.Reversible vs. Irreversible Injury in Ischemia

Reversible Injury: If ischemia is brief, the cell may recover upon reestablishing blood flow.
Early changes include cell swelling, chromatin clumping, and mitochondrial swelling.
Irreversible Injury: Prolonged ischemia causes severe cell damage and leads to necrosis.
Loss of mitochondrial function, severe membrane damage, and calcium influx are hallmarks of irreversible injury.

3.Reperfusion Injury

If blood flow is restored after prolonged ischemia, reperfusion can paradoxically lead to further damage due to oxidative stress, inflammation, and calcium overload.

Clinical Correlation: Key Ischemic Conditions

1.Myocardial Ischemia (Heart)

Reduced blood flow to the heart muscle (usually due to coronary artery blockage) leads to angina or myocardial infarction.
Biomarkers: Troponins and CK-MB levels are used to assess myocardial injury.

2.Cerebral Ischemia (Brain)

Leads to transient ischemic attacks (TIAs) or stroke depending on the duration and severity.
Brain tissue is highly sensitive to ischemia and often undergoes liquefactive necrosis.

3.Renal Ischemia

Commonly seen in cases of hypovolemic shock, leading to acute kidney injury (AKI) characterized by acute tubular necrosis.

4.Ischemic Bowel Disease

Reduced blood flow to the intestines (e.g., from embolism or thrombosis) can lead to bowel infarction, causing severe abdominal pain and possible bowel necrosis.

Mnemonic for Ischemic Injury: “I C DRAMA”

I – Ischemia (reduced blood flow)
C – Cellular swelling (Na⁺/K⁺ pump dysfunction)
D – Decreased ATP
R – Reperfusion injury (if blood flow restored)
A – Acidosis (from lactic acid buildup)
M – Mitochondrial damage
A – Apoptosis/Necrosis (cell death if prolonged)

Amyloidosis

Amyloidosis is a disorder characterized by the abnormal deposition of misfolded proteins (amyloid) in various tissues, which impairs normal organ function. Amyloid deposits are composed of beta-pleated sheets, making them resistant to proteolysis.

Key Features of Amyloid

Structure: Beta-pleated sheet configuration.
Staining: Apple-green birefringence under polarized light when stained with Congo red.
Deposits: Can accumulate locally or systemically, affecting organs like the kidneys, heart, liver, and nerves.

Clinical Manifestations by Organ System

Kidneys: Proteinuria leading to nephrotic syndrome, often the most common and severe manifestation.
Heart: Restrictive cardiomyopathy, arrhythmias, congestive heart failure.
Liver and Spleen: Hepatosplenomegaly with possible liver dysfunction.
Nervous System: Peripheral neuropathy, autonomic dysfunction.
Gastrointestinal Tract: Macroglossia (enlarged tongue), malabsorption, GI bleeding.

Diagnosis

Biopsy: Tissue biopsy showing apple-green birefringence with Congo red staining under polarized light.
Blood/Urine Tests: Detection of light chains in primary amyloidosis (AL) through serum and urine protein electrophoresis.
Genetic Testing: For hereditary amyloidosis (TTR mutations).

Management

Primary (AL) Amyloidosis: Chemotherapy (like myeloma treatment) to reduce plasma cell production of light chains.
Secondary (AA) Amyloidosis: Treat underlying inflammatory condition.
Hereditary Amyloidosis: Liver transplant for TTR-related forms.
Supportive Care: Manage symptoms like heart failure, nephrotic syndrome.

Inflammation

Inflammation is the body's protective response to injury or infection, aimed at eliminating harmful stimuli and initiating tissue repair. It involves immune cells, blood vessels, and molecular mediators. There are two primary types of inflammation: acute and chronic.

Acute Inflammation

Purpose: To quickly deliver immune cells and mediators to the site of injury.

Key Features: Rapid onset (minutes to hours), short duration (hours to a few days).

Hallmarks (Cardinal Signs):

Rubor (redness): Due to vasodilation.
Calor (heat): Increased blood flow.
Tumor (swelling): Increased vascular permeability and fluid leakage.
Dolor (pain): Mediated by prostaglandins and bradykinin.
Functio laesa (loss of function): Resulting from tissue damage and swelling.

Key Steps in Acute Inflammation

1.Vasodilation: Increased blood flow to the area.

2.Increased Vascular Permeability: Allows plasma proteins and immune cells to exit the bloodstream and enter the injured tissue.

3.Leukocyte Recruitment and Activation:

Margination: WBCs move towards the blood vessel wall.
Rolling: Selectins (E-selectin, P-selectin) on endothelial cells mediate rolling.
Adhesion: Integrins on leukocytes bind to ICAM/VCAM on endothelial cells.
Transmigration (Diapedesis): Leukocytes squeeze through endothelial gaps.
Chemotaxis: Leukocytes follow chemical signals (e.g., IL-8, C5a) to the site of injury.

4.Phagocytosis: Neutrophils and macrophages engulf pathogens and debris.

Chemical Mediators of Acute Inflammation

Histamine: Released by mast cells; causes vasodilation and increased permeability.
Prostaglandins: Produced by COX enzymes; cause vasodilation, pain, and fever.
Leukotrienes: Increase vascular permeability and act as chemotactic agents.
Cytokines: IL-1, IL-6, TNF-α (fever, chemotaxis, leukocyte activation).
Complement System: C3a, C5a (anaphylatoxins) mediate inflammation and chemotaxis.

Chronic Inflammation

Purpose: Response to persistent infection, autoimmune conditions, or prolonged exposure to toxins.
Key Features: Gradual onset, longer duration (weeks to years).
Cell Types: Dominated by macrophages, lymphocytes, and plasma cells.
Outcomes: May lead to tissue destruction, fibrosis, and formation of granulomas.

Granulomatous Inflammation

Granulomatous inflammation is a specific type of chronic inflammation characterized by the formation of granulomas. Granulomas are organized collections of immune cells, primarily macrophages, that wall off foreign substances or persistent pathogens that the body cannot eliminate. This is a crucial concept in pathology for understanding certain infections, autoimmune diseases, and foreign body reactions.

1.Granuloma Formation

Granulomas are nodular aggregates of epithelioid macrophages (macrophages that have a squamous, epithelial-like appearance) often surrounded by lymphocytes.
The central area of a granuloma may contain multinucleated giant cells, formed by the fusion of macrophages.
Granulomas form when macrophages attempt to isolate the offending agent but are unable to eliminate it, leading to a chronic immune response.

2.Types of Granulomas

Caseating Granulomas: Characterized by central necrosis with a cheese-like appearance.

Commonly associated with infectious diseases, especially tuberculosis (TB) caused by Mycobacterium tuberculosis.
Seen with other infections like Histoplasma and Coccidioides.

Non-Caseating Granulomas: Lack central necrosis.

Common in non-infectious inflammatory conditions such as sarcoidosis and Crohn’s disease.
Also seen in foreign body reactions (e.g., sutures, splinters).

3.Pathogenesis of Granuloma Formation

Triggering Agents: Persistent infectious agents (e.g., TB, fungi) or non-infectious irritants (e.g., sarcoidosis, beryllium exposure).
Immune Response:
Macrophages ingest the agent but fail to destroy it, leading to prolonged antigen presentation.
Helper T-cells (CD4⁺), particularly the Th1 subset, release IFN-γ, which activates macrophages and promotes granuloma formation.
Activated macrophages transform into epithelioid cells and may fuse to form giant cells (e.g., Langhans giant cells in TB).
Fibrosis: Chronic granulomas may become fibrotic over time as part of the healing process.

Causes of Granulomatous Inflammation

Clinical and Histological Features

Clinical Presentation:

Symptoms vary depending on the organ involved and the underlying cause.
For example, pulmonary TB presents with chronic cough, weight loss, night sweats, and hemoptysis.
Sarcoidosis may present with lymphadenopathy, pulmonary infiltrates, and skin lesions.

Histology:

Granulomas appear as collections of epithelioid macrophages, with or without central necrosis.
Caseating Granulomas: Central area of necrosis, surrounded by epithelioid macrophages, lymphocytes, and sometimes giant cells.
Non-Caseating Granulomas: Compact aggregates of macrophages without necrosis.

Special Stains:

Acid-fast stain (Ziehl-Neelsen) for Mycobacterium tuberculosis.
GMS (Grocott methenamine silver) stain or PAS (periodic acid-Schiff) for fungi.

Mnemonic for Granulomatous Diseases: "TB Scares Many Cute Cats"

T – Tuberculosis (Mycobacterium tuberculosis)
B – Bartonella henselae (cat scratch disease)
S – Sarcoidosis
M – Mycobacterium leprae (leprosy)
C – Crohn’s disease
C – Cryptococcosis and other fungal infections

Tumors (Neoplasms)

A tumor or neoplasm is an abnormal mass of tissue that forms when cells grow and divide more than they should or do not die when they should. Tumors can be benign or malignant (cancerous), with important differences in their behavior, growth, and prognosis.

Key Characteristics of Tumors

Pathophysiology of Tumor Development

1.Initiation: Genetic mutations in cells lead to abnormal growth.

Common oncogenes (promote cell growth): RAS, MYC, HER2.
Tumor suppressor genes (inhibit growth): TP53, RB, BRCA1/2.

2.Promotion: Mutated cells proliferate due to additional factors like hormones or chronic inflammation.

3.Progression: Accumulation of more mutations leads to increasing malignancy and potential for metastasis.

Tumor Growth and Spread

1.Local Invasion

Malignant tumors infiltrate and destroy adjacent tissues through degradation of extracellular matrix by matrix metalloproteinases (MMPs).

2.Metastasis Pathways

Lymphatic Spread: Common in carcinomas, especially to regional lymph nodes.
Hematogenous Spread: Common in sarcomas, spread through blood vessels, often to lungs and liver.
Seeding: Tumors spread within body cavities, such as ovarian cancer spreading to the peritoneum.

Grading and Staging of Tumors

1.Grading: Reflects the degree of cellular differentiation.

Low grade: Well-differentiated, cells resemble normal tissue.
High grade: Poorly differentiated (anaplastic), cells look very abnormal.

2.Staging: Indicates the extent of tumor spread (TNM System).

T (Tumor): Size and extent of primary tumor.
N (Node): Involvement of regional lymph nodes.
M (Metastasis): Presence of distant metastasis.

Example: T2N1M0 indicates a moderately sized primary tumor (T2), involvement of regional lymph nodes (N1), and no distant metastasis (M0).

Tumor Markers

Tumor markers are substances produced by cancer cells or by the body in response to cancer. They can aid in diagnosis, prognosis, and monitoring treatment.

Mnemonic for Malignant Tumor Characteristics: "I MEAN BAD"

I – Invasion of surrounding tissues
M – Metastasis potential
E – Encapsulation absent
A – Anaplasia (poor differentiation)
N – Necrosis and hemorrhage in the tumor
B – Blood and lymphatic spread
A – Abnormal mitotic figures
D – Destructive growth

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