Necrosis

Necrosis is the death of cells or tissues in the body because of injury, infection, lack of blood flow or harmful substances like toxins. Unlike apoptosis (programmed cell death), which is a natural and controlled process, necrosis is sudden and uncontrolled.

Causes of Necrosis

Necrosis is the premature death of cells or tissues in the body due to various damaging factors. Here are some of the major causes:

• Physical Injury
• Trauma such as cuts, burns, frostbite, crush injuries or radiation exposure can severely damage tissues, leading to necrosis. For example, severe burns destroy skin cells, preventing regeneration and causing permanent tissue death.

• Infections
• Bacterial, viral, fungal and parasitic infections can trigger necrosis. Some bacteria, such as Clostridium perfringens, produce toxins that destroy tissues, leading to conditions like tissue decay. Severe viral infections may also trigger widespread cell death.

• Ischemia (Lack of Blood Flow)
• When tissues do not receive enough oxygen and nutrients due to blocked blood vessels, they die. Conditions like heart attacks, strokes and tissue decay occur because of prolonged ischemia, leading to necrotic damage.

• Toxins and Chemicals
• Exposure to harmful substances, including poisonous chemicals, venoms, and excessive drug use (e.g., overdosing on certain medications), can directly kill cells. Snake venom, for instance, can rapidly cause necrosis in affected areas.

• Chronic Inflammation and Immune Disorders
• Autoimmune diseases, such as lupus and rheumatoid arthritis, can cause excessive immune responses, leading to tissue damage and necrosis.

• Cancer
• As tumors grow, they may outpace their blood supply, leading to necrosis within the tumor. Some cancer treatments, like chemotherapy, can also induce necrotic cell death.

• Metabolic Disorders
• Conditions like diabetes can impair blood circulation, especially in the extremities, increasing the risk of necrotic tissue formation. Diabetic foot ulcers, for example, result from poor healing and insufficient blood flow.

Types of Necrosis

Necrosis occurs in different forms depending on the cause, the affected tissue and underlying conditions. Each type of necrosis has unique characteristics and plays a significant role in disease progression. Understanding these types helps in diagnosing conditions and determining appropriate treatments to prevent further tissue damage.

1. Coagulative Necrosis

• Coagulative necrosis is the most common type and occurs due to oxygen deprivation (ischemia), often affecting solid organs like the heart, kidneys and spleen. In this type, the proteins inside the cells coagulate, causing the tissue to remain firm. Although the cells die, their structure remains visible for some time before immune cells remove the dead tissue and replace it with scar tissue. A classic example is heart tissue after a heart attack, where the affected area appears pale and firm.

2. Liquefactive Necrosis

• Liquefactive necrosis occurs when tissue is rapidly broken down into a liquid form due to the action of digestive enzymes. It is commonly seen in brain infarctions and bacterial or fungal infections. In the brain, oxygen deprivation leads to the breakdown of neurons, resulting in a soft, liquid mass. In infections, immune cells release enzymes that destroy bacteria but also liquefy the surrounding tissue, leading to pus formation, as seen in abscesses.

3. Caseous Necrosis

• Caseous necrosis is characteristic of tuberculosis infections. It results from the body's immune response to Mycobacterium tuberculosis, creating a soft, cheese-like tissue. Unlike coagulative necrosis, the cell structures are completely destroyed and the affected area appears yellowish-white. This type is often found in the lungs and lymph nodes.

4. Fat Necrosis

• Fat necrosis occurs in fat-rich tissues like the pancreas and breasts, often due to trauma or enzyme release. The breakdown of fat cells releases fatty acids, which combine with calcium to form white, chalky deposits. This process is commonly seen in pancreatitis, where pancreatic enzymes digest fat cells, leading to inflammation.

5. Fibrinoid Necrosis

• Fibrinoid necrosis affects blood vessels, usually in autoimmune diseases such as lupus and vasculitis. It occurs when immune complexes and fibrin proteins are deposited in the vessel walls, making them thick and damaged. Under a microscope, these areas appear bright pink due to the fibrin deposits. This type of necrosis can lead to severe vascular diseases and organ damage.

6. Gangrenous Necrosis

• Gangrenous necrosis affects limbs or intestines due to severe ischemia or infections. It is classified into three types: dry, wet and gas gangrene. Dry gangrene results from reduced blood flow, causing the tissue to become black, dry and shriveled, as seen in diabetic foot ulcers. Wet gangrene occurs when an infection develops in the necrotic tissue, making it swollen, discolored and pus-filled. Gas gangrene is caused by Clostridium bacteria, which produce toxins and gas, leading to severe tissue destruction and life-threatening complications.

Process of Necrosis

The process of necrosis involves several stages, including cell injury, loss of membrane integrity, swelling, organelle breakdown, inflammation and tissue damage.

Stages 1: Cell Injury (Initial Damage)

Necrosis begins when cells experience extreme stress or damage. Common causes of cell injury include:

• Lack of oxygen (hypoxia or ischemia): Occurs when blood supply is blocked, as seen in strokes and heart attacks.

• Infections: Bacteria, viruses and fungi produce toxins that destroy cells.

• Physical trauma: Severe burns, cuts, frostbite and radiation damage cells.

• Chemical toxins: Poisons, drugs and heavy metals disrupt cellular functions.

When a cell is injured, its normal processes stop. Mitochondria (which generate energy in the form of ATP) fail to function properly, leading to energy depletion. Without ATP, the cell cannot maintain its internal balance, making it more vulnerable to damage.

Stage 2: Loss of Membrane Integrity

The plasma membrane acts as a protective barrier, regulating what enters and exits the cell. When necrosis begins, the membrane becomes weak and starts leaking. This happens due to:

• Failure of the sodium-potassium pump, leading to an influx of sodium and water.
• Cell swelling (oncosis) due to water accumulation.
• Calcium overload, which activates harmful enzymes that break down proteins, lipids, and DNA.

The loss of membrane integrity is a key step in necrosis, as it prevents the cell from recovering and leads to further damage.

Stage 3: Swelling and Organelle Breakdown

As water and ions continue to enter, the cell swells and its internal structures (organelles) start breaking down:

• Mitochondria swell and stop producing ATP, causing further energy loss.
• Lysosomes rupture, releasing digestive enzymes that degrade cellular components.
• Endoplasmic reticulum collapses, stopping protein production.

This uncontrolled breakdown of organelles makes the cell completely nonfunctional and accelerates its destruction.

Stage 4: Cell Lysis and Release of Contents

At this stage, the plasma membrane ruptures, spilling the cell's contents into the surrounding tissue. This includes:

• Enzymes that digest nearby healthy cells.
• Proteins and DNA fragments that act as signals for the immune system.
• Damage-associated molecular patterns (DAMPs), which trigger inflammation.

Since necrosis is uncontrolled, the release of these materials causes widespread damage and attracts immune cells to the area.

Stage 5: Inflammatory Response and Tissue Damage

The immune system detects the dead and damaged cells and initiates an inflammatory response. This involves:

• White blood cells (neutrophils and macrophages) migrating to the affected area.
• Cytokines and inflammatory mediators (such as TNF-α and interleukins) being released.
• Reactive oxygen species (ROS) forming, which cause oxidative damage to surrounding tissues.

Inflammation helps remove dead cells, but it can also damage healthy surrounding tissues. If an infection is present, pus may form due to the accumulation of dead cells and immune cells.

Stage 6: Resolution and Tissue Repair

After necrosis, the body tries to remove dead cells and repair the affected tissue. The outcome depends on the extent of the damage:

• Small areas of necrosis may be cleaned up by immune cells, allowing healthy cells to regenerate.
• Large-scale necrosis often leads to scar tissue formation (fibrosis), as new cells cannot replace the lost tissue.
• In some cases, calcification occurs, where dead cells harden due to calcium deposits.

If necrotic tissue is not removed properly, it can lead to complications like chronic inflammation, infections or even gangrene, requiring medical intervention.