Cell Injury and Death Overview

Cell Injury and Cell Death

• Cell injury is a response to various stressors that arise from changes in the internal and external environment.
• The cellular response to injury depends on the nature, duration, and severity of the injury, along with the cell's type, extent of injury, and adaptability.
• Cells may adapt to the stress and revert to normal after the stress is removed (cellular adaptations)
• Residual effects of injury may persist
• Injured cells may recover (reversible cell injury), or die (irreversible cell injury).

Cellular Responses to Injury

• Cells may adapt to changes and revert to normal when the stressor is removed (cellular adaptations).
• Residual effects of injury may persist in the cell as evidence of the injury.
• The injured cell may recover (reversible injury) or die (irreversible injury).

Cell Injury: Overview

• A normal cell in homeostasis can undergo adaptation to injury, leading to either reversible or irreversible injury.
• Reversible injury leads to mild, transient conditions.
• Irreversible injury, on the other hand, leads to severe, progressive conditions
• Irreversible injury can result in necrosis or apoptosis.

Nutritional Imbalance

• Nutritional deficiency (starvation, protein-calorie malnutrition [marasmus, kwashiorkor], or mineral deficiency [anemia]) can cause diseases
• Nutritional excess in affluent societies can result in obesity, atherosclerosis, heart disease, and hypertension.

Aging

• Cell aging decreases the ability of cells to replicate and repair, leading to cell death, and ultimately death of the individual.

Psychogenic Diseases

• Psychogenic diseases, such as depression and schizophrenia, do not have specific biochemical or morphological changes caused by mental stress.
• Problems like drug addiction, alcoholism, and smoking result in various organic diseases.

Free Radical Initiation

• Exposure to energy sources like UV light and X-rays can initiate free radicals.
• Conversion of exogenous chemicals/drugs (e.g., carbon tetrachloride) can also lead to free radical formation.
• Oxygen-derived radicals are also a source of free radical formation.

Idiopathic Diseases

• Idiopathic diseases have unknown causes.
• Essential hypertension (90% of cases) is an example of an idiopathic disease.

Types of Cell Injury

I. Reversible Cell Injury

• Cellular changes can regress and disappear when the injurious agent is removed or altered.
• The cell returns to normal function and morphology.
• Example: Fatty change (steatosis)

II. Irreversible Cell Injury

• Occurs when the injury persists or is severe from the start.
• Cells reach a point of no return and progression to death.
• Example: Necrosis and apoptosis.

Fatty Change (Steatosis)

• Accumulation of neutral fat within parenchymal cells.
• Commonly affects the liver, but can also occur in the heart, skeletal muscle, and kidneys.

Fatty Liver

• Liver is the prime site for fat accumulation due to its role in fat metabolism.
• Imbalance in uptake, utilization, and secretion of fat causes fatty liver.
• Fatty change may be mild and reversible or severe and irreversible, and induce death.
• Excess alcohol intake, liver diseases, starvation, malnutrition, diabetes, chronic illnesses, hypoxia, hepatotoxins, and certain drugs can all cause fatty liver.

Etiology of Fatty Liver

• Excessive alcohol consumption is the most common cause.
• Liver diseases, such as hepatitis C, can contribute significantly to fatty liver.
• Starvation and malnutrition can cause fat mobilization.
• Obesity, diabetes, chronic illnesses (e.g., tuberculosis), hypoxia (e.g., anemia), exposure to hepatotoxins (e.g., carbon tetrachloride, chloroform, aflatoxins), and certain drugs (e.g., estrogens, steroids, tetracycline) can also lead to fatty liver development.

Gross Picture: Fatty Liver

• Increased size.
• Smooth surface.
• Rounded border.
• Bulging cut section.
• Pale yellow color.
• Greasy texture.

Microscopic Picture: Fatty Liver

• Numerous lipid vacuoles (microvesicular at the initial stage, enlarging into macrovesicular vacuoles), which displace the nucleus to the cell periphery (signet ring appearance).
• Rupture of cells and merging of fat vacuoles ultimately form fatty cysts.

Effects of Fatty Liver

• Mild fat accumulation is reversible.
• Significant fat accumulation is irreversible and may progress to necrosis and cirrhosis.

Necrosis: Irreversible Cell Injury

• Focal death of cells within a living body due to released hydrolytic enzymes.
• Accompanied by an inflammatory response.
• Causes include hypoxia, various chemical or physical agents, microbial agents, and immunological factors.

Pathogenesis of Necrosis

• Denaturation of proteins: characteristic nuclear changes occur in necrotic cells.
• Cell disintegration by lytic enzymes: autolysis (by the cell's own lysosomal enzymes) and heterolysis (by proteolytic enzymes from surrounding inflammatory cells)
• Morphologically: homogeneous and intensely eosinophilic cytoplasm.

Gross Picture: Necrosis

• Necrotic tissue appears opaque yellow and may be swollen.
• Surrounding tissues are hyperemic due to inflammation.

Microscopic Picture: Necrosis

• Cytoplasm appears homogeneous and eosinophilic.
• Nuclear changes due to protein denaturation include: pyknosis (small, dark nucleus); karyorrhexis (nuclear fragmentation); and karyolysis (faintly dissolved nucleus).

Liver - Hepatocellular Necrosis

• Microscopic descriptions of the features of hepatocellular necrosis include: pyknosis, karyorrhexis, and karyolysis

Architectural Changes in Necrosis

• Necrotic tissue appears rapidly structureless due to cell lysis (autolysis, heterolysis).
• Protein denaturation (coagulation) can precede cell lysis, especially in ischemia.
• Necrotic tissue can retain the architectural outlines of the original tissue (structural ghosts).
• Tissue structure rapidly disintegrates.

Fate of Necrotic Tissue

• Inflammation surrounds the necrotic area due to released chemical mediators.
• Healing involves phagocytosis of necrotic tissue by phagocytes, such as macrophages and lymphocytes.
• Regeneration or fibrosis (tissue in the area) can occur.
• Dystrophic calcification can follow some types of necrosis due to the tissue's altered chemical environment.

Types of Necrosis

• Coagulative necrosis
• Liquefactive necrosis
• Caseous necrosis
• Fat necrosis
• Fibrinoid necrosis

1. Coagulative Necrosis

• Most common type.
• Results from ischemia (reduced blood flow) and less frequently from bacterial or chemical agents.
• Occurs in infarcts of most organs except the central nervous system (CNS).
• Organs commonly affected are the heart, kidney, and spleen
• Protein denaturation precedes cell lysis.
• Cell outlines persist for several days.
• Gradual nuclear degeneration.

Gross Picture: Coagulative Necrosis

• Early stage: Pale, firm, and slightly swollen foci.
• Late stage: Yellowish, softer, and shrunken necrotic area.

Microscopic Picture: Coagulative Necrosis

• Conversion of normal cells into their 'tombstone' forms (structural ghosts), preserving the outlines of cells.
• Swollen cells that appear more eosinophilic.
• Nuclear changes.
• Necrotic tissue becomes structureless later.
• Acute inflammation in the surrounding tissue.

2. Liquefactive Necrosis

• Due to ischemia and bacterial or fungal infections.
• Degradation of tissue by powerful hydrolytic enzymes. Cell lysis exceeds protein denaturation.
• Examples include brain infarcts (due to high lipid content) and abscess cavities (pus).

Gross Picture: Liquefactive Necrosis

• Affected area is soft with a liquefied center containing necrotic debris.
• Cyst wall eventually forms.

Microscopic Picture: Liquefactive Necrosis

• Cystic space contains necrotic cell debris and macrophages.
• Cyst wall composed of proliferating capillaries, inflammatory cells, and glial cell ghosts (brain).
• Proliferating fibroblasts (abscess cavity).

3. Caseous Necrosis

• Found in the center of foci associated with tuberculosis infections.
• Exhibits features of both coagulative and liquefactive necrosis.
• Begins as ischemic coagulative necrosis caused by endarteritis obliterans.
• Hypersensitivity to tuberculoprotein releases cytotoxins causing partial liquefaction of the necrotic cells.

Gross Picture: Caseous Necrosis

• Foci resemble dry cheese, appearing soft, granular, and yellowish.

Microscopic Picture: Caseous Necrosis

• Structureless, eosinophilic necrotic foci with granular debris.
• Characteristic granulomatous inflammation with epithelioid cells, giant cells (e.g., Langhans cells), and peripheral lymphocytes.