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PA 2.1 / 2.2 / 2.3 - Cell Injury: Complete Study Notes

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OVERVIEW FLOWCHART

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PA 2.1 - CAUSES, MECHANISMS, TYPES AND EFFECTS OF CELL INJURY

A. CAUSES OF CELL INJURY

CAUSES OF CELL INJURY
│
├── 1. Hypoxia & Ischemia ─── Most common cause
│       ├── Ischemia (blocked artery)
│       ├── Cardiorespiratory failure
│       ├── Anemia / CO poisoning
│
├── 2. Physical Agents
│       ├── Mechanical trauma
│       ├── Extremes of temperature (burns, frostbite)
│       ├── Radiation
│       └── Electric shock
│
├── 3. Chemical Agents & Drugs
│       ├── Hypertonic glucose/salt
│       ├── O2 (toxic at high conc.)
│       ├── Arsenic, cyanide, mercury
│       ├── Alcohol, cocaine
│       └── Therapeutic drugs (dose-dependent)
│
├── 4. Infectious Agents
│       ├── Viruses, bacteria, fungi
│       ├── Parasites (tapeworms, etc.)
│       └── Mechanisms: toxins, immune response
│
├── 5. Immunologic Reactions
│       ├── Autoimmune disease
│       ├── Allergic reactions
│       └── Chronic immune responses → inflammation → cell injury
│
├── 6. Genetic Abnormalities
│       ├── Extra chromosome (e.g., Down syndrome)
│       ├── Single base substitution (e.g., Sickle cell)
│       ├── Enzyme defects (inborn errors of metabolism)
│       └── DNA damage / misfolded proteins → apoptosis
│
└── 7. Nutritional Imbalances
        ├── Protein-calorie deficiency (PEM)
        ├── Specific vitamin deficiencies
        └── Obesity → DM2, atherosclerosis

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B. MECHANISMS OF CELL INJURY

Key Biochemical Mechanisms (Table)

Integrated Stress Response (ISR)

• Activated by hypoxia, infection, nutrient starvation, misfolded proteins
• Four kinases phosphorylate eIF2α → reduces protein synthesis → adapts cell
• If stress persists → triggers apoptosis

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C. TYPES OF CELL INJURY

CELL INJURY
│
├── REVERSIBLE INJURY ───── Mild / transient stimulus
│       ├── Cell can recover if stimulus removed
│       └── → Returns to normal
│
└── IRREVERSIBLE INJURY ─── Severe / persistent stimulus
        ├── "Point of no return" crossed
        ├── Defined by:
        │    ├── Inability to reverse mitochondrial dysfunction
        │    └── Profound membrane damage
        └── → CELL DEATH
               ├── NECROSIS (pathologic)
               └── APOPTOSIS (physiologic or pathologic)
               [+newer: necroptosis, pyroptosis, ferroptosis]

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D. EFFECTS / CLINICAL SIGNIFICANCE

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PA 2.2 - REVERSIBLE vs IRREVERSIBLE INJURY

Sequential Development of Changes

• In myocardial ischemia: swelling = minutes; light microscope evidence = 4-12 hours

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Comparison Table: Reversible vs Irreversible Injury

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Morphology of Reversible Cell Injury

1. Cellular swelling - due to failure of ATP-dependent Na⁺-K⁺ pump → water influx → organelles swell
2. Fatty change - toxic injury disrupts lipid metabolism → triglyceride-filled vacuoles (mainly in liver)

Other changes visible:

• Plasma membrane blebbing and loss of microvilli
• Mitochondrial swelling (no amorphous densities)
• ER dilation with detachment of ribosomes
• Clumping of nuclear chromatin
• Eosinophilia (↓ cytoplasmic RNA)

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Morphology of Irreversible Injury - NECROSIS

Cellular Changes

• Eosinophilia - loss of RNA + denatured proteins bind eosin
• Vacuolated, moth-eaten cytoplasm - digested organelles
• Myelin figures - whorled phospholipid precipitates (phagocytosed or calcified)

Nuclear Changes (3 Patterns)

NUCLEAR CHANGES IN NECROSIS
│
├── 1. PYKNOSIS ─── Nuclear shrinkage + increased basophilia (chromatin condensation)
│
├── 2. KARYORRHEXIS ─── Pyknotic nucleus fragments into pieces
│
└── 3. KARYOLYSIS ─── Chromatin basophilia FADES due to DNase degradation
                      (Nucleus eventually disappears in 1-2 days)

Patterns of Tissue Necrosis (High-Yield Table)

Apoptosis vs Necrosis (Comparative Table)

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PA 2.3 - INTRACELLULAR ACCUMULATIONS

Overview: 4 Mechanisms of Accumulation

MECHANISMS OF INTRACELLULAR ACCUMULATION
│
├── 1. INADEQUATE REMOVAL of normal substance
│       (defects in production/transport)
│       Example: Fatty liver (steatosis)
│
├── 2. ACCUMULATION due to defect in folding/transport/secretion
│       Example: α1-antitrypsin deficiency (builds up in ER of hepatocytes)
│
├── 3. FAILURE TO DEGRADE - inherited enzyme deficiency
│       Example: Lysosomal storage diseases (Gaucher's, Tay-Sachs)
│
└── 4. DEPOSITION OF ABNORMAL EXOGENOUS SUBSTANCE
        Cell has no enzyme to degrade it
        Example: Carbon (coal dust), silica particles

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A. FAT ACCUMULATION (Steatosis / Fatty Change)

Sites

• Liver (most common - major organ of fat metabolism)
• Heart, skeletal muscle, kidney (less common)

Causes (Mnemonic: DATO AN)

• D - Diabetes mellitus
• A - Alcohol (most common in high-income countries)
• T - Toxins
• O - Obesity / NAFLD
• A - Anoxia
• N - Nutritional deficiency (protein malnutrition)

Mechanism (Liver Fatty Change)

Normal liver fat metabolism:
FFA → Triglycerides → bound to Apoprotein → Lipoprotein → EXPORTED

Fatty change occurs when ANY step is disrupted:
├── ↑ FFA delivery (obesity, DM, starvation)
├── ↓ β-oxidation of FA (hypoxia, toxins like CCl4)
├── ↑ FA esterification to TG (alcohol)
├── ↓ Apoprotein synthesis (CCl4, protein malnutrition)
└── ↓ Lipoprotein secretion (alcohol, CCl4)

Morphology

• Gross: Liver is enlarged, yellow, greasy
• Light microscopy: Clear lipid vacuoles in cytoplasm (triglyceride washed out in processing)
  • Small droplets initially (microvesicular) - nucleus central
  • Large droplets later (macrovesicular) - nucleus pushed to periphery
• Special stain: Oil Red O stains fat red in frozen sections

Cholesterol Accumulation

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B. PROTEIN ACCUMULATION

Types and Examples

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C. CARBOHYDRATE (GLYCOGEN) ACCUMULATION

Causes

1. Diabetes mellitus - abnormal glucose metabolism
   • Sites: renal tubular epithelium, liver, cardiac myocytes, beta cells of islets
2. Glycogen storage diseases (Glycogenoses) - inherited enzyme defects
   • e.g., Pompe (acid maltase deficiency), McArdle (muscle phosphorylase)

Morphology

• Light microscopy: Clear vacuoles in cytoplasm (glycogen dissolves in aqueous fixatives)
• Best identified: Fixed in absolute alcohol (not formalin)
• Special stains:
  • PAS (Periodic Acid-Schiff): Rose-to-violet color
  • Best carmine: Confirms glycogen
  • Diastase digestion: Serial section treated with diastase - glycogen disappears (confirms it IS glycogen, not mucin)

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D. PIGMENT ACCUMULATION

Classification Flowchart

PIGMENTS
│
├── EXOGENOUS (from outside body)
│       ├── Carbon (coal dust) ─────── Most common exogenous pigment
│       │    ├── Inhaled → phagocytosed by alveolar macrophages
│       │    ├── → lymphatics → tracheobronchial lymph nodes (blackened)
│       │    └── Anthracosis (lungs); Coal worker's pneumoconiosis
│       └── Tattoo pigments ─── Indigestible, remain in dermal macrophages lifelong
│
└── ENDOGENOUS (synthesized in body)
        │
        ├── LIPOFUSCIN ("wear-and-tear" pigment)
        │    ├── Composition: polymers of lipids + phospholipids + protein
        │    ├── Origin: lipid peroxidation of polyunsaturated lipids (free radical injury)
        │    ├── Appearance: yellow-brown, finely granular, perinuclear
        │    ├── Significance: telltale sign of free radical damage; NOT injurious itself
        │    └── Seen in: aging liver, heart; cancer cachexia; malnutrition
        │
        ├── MELANIN
        │    ├── Brown-black, endogenous
        │    ├── Formed by: Tyrosinase → tyrosine → DOPA → melanin (in melanocytes)
        │    └── Only endogenous brown-black pigment
        │
        ├── HEMOSIDERIN (iron-containing)
        │    ├── Derived from ferritin aggregates (haemoglobin breakdown)
        │    ├── Golden-yellow to brown granules
        │    ├── Stain: Prussian blue (stains blue)
        │    ├── Local: old hemorrhage site (e.g., bruise turning brown)
        │    └── Systemic: hereditary hemochromatosis, transfusion hemosiderosis
        │
        └── BILIRUBIN
             ├── Normal bile pigment; product of Hb catabolism
             ├── Accumulates in jaundice
             └── Stain: Van Gieson, Hall's bile stain

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SUMMARY TABLE: Intracellular Accumulations (High-Yield for Exams)

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CLINICAL SIGNIFICANCE SUMMARY

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• Robbins, Cotran & Kumar - Pathologic Basis of Disease, 10th Ed. - Chapter 2: Cell Injury, Cell Death, and Adaptations (pp. 47-80)
• Robbins & Kumar - Basic Pathology - Chapter 1: Cell Injury and Death