About cell death in pathology

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Cell Death in Pathology

(Robbins & Kumar Basic Pathology, 10th ed., Chapter 1)

Overview

Cell death is the end result of severe, irreversible cell injury. There are two principal forms - necrosis and apoptosis - and several other regulated pathways including autophagy, pyroptosis, necroptosis, and ferroptosis. The sequence of events from a healthy cell to death is shown below:

Sequence of reversible cell injury and cell death

Fig 1.2 - Robbins & Kumar Basic Pathology

1. Reversible vs. Irreversible Injury

Before death, cells pass through a stage of reversible injury. Key features:

Cellular swelling (hydropic change / vacuolar degeneration) from failure of energy-dependent Na⁺/K⁺-ATPase
Fatty change (lipid vacuoles) in organs like the liver
Plasma membrane blebbing, ER dilation, mitochondrial swelling, chromatin clumping

When the injury is severe enough to cross the "point of no return," cells die - typically by necrosis if the damage is overwhelming, or apoptosis if driven by specific signals.

An important concept: cellular function is lost well before morphologic evidence of death appears. Myocardial cells become noncontractile after 1-2 minutes of ischemia, yet morphologic features of death take 6-12 hours to appear by light microscopy.

2. Necrosis

Necrosis is the form of cell death associated with uncontrolled cellular digestion and inflammation. It is almost always pathologic.

Mechanisms

Cellular membranes break down
Lysosomal enzymes and leukocyte enzymes digest the cell contents
Cellular contents leak into the extracellular space, triggering an inflammatory response

Morphologic Features (H&E)

Cytoplasmic changes:

Increased eosinophilia (denatured proteins binding eosin; loss of RNA basophilia)
Glassy, homogeneous appearance (loss of glycogen)
Vacuolated, "moth-eaten" cytoplasm when organelles are digested

Nuclear changes (three patterns):

Pattern	Description
Pyknosis	Nuclear shrinkage + increased basophilia; DNA condenses into a dark mass
Karyorrhexis	Fragmentation of the pyknotic nucleus
Karyolysis	Fading of basophilia due to DNase digestion of DNA; nucleus dissolves over 1-2 days

Morphologic Patterns of Tissue Necrosis

Type	Description	Example
Coagulative necrosis	Cell outlines preserved ("ghost cells"); denatured proteins resist enzymatic digestion	Ischemic infarct of heart, kidney
Liquefactive necrosis	Cell dissolved; creamy, liquid mass	Brain infarct; bacterial abscesses
Caseous necrosis	"Cheese-like" friable material; amorphous granular debris enclosed by granulomatous inflammation; no cell outlines	Tuberculosis
Fat necrosis	Outlines of necrotic fat cells with chalky-white calcium soap deposits	Acute pancreatitis (enzymatic); breast trauma
Fibrinoid necrosis	Bright pink, amorphous material in blood vessel walls; deposited immune complexes + plasma proteins	Immune vasculitis, malignant hypertension
Gangrenous necrosis	Coagulative necrosis of a limb + superimposed liquefaction (wet gangrene)	Ischemic limb

Clinical Significance: Serum Markers

Necrosis causes leakage of intracellular proteins into the blood, forming useful diagnostic markers:

Cardiac troponin - myocardial necrosis (MI)
Transaminases (AST/ALT) - hepatocellular necrosis
Alkaline phosphatase - biliary epithelial necrosis

3. Apoptosis

Apoptosis is programmed cell death - an orderly, energy-dependent process in which the cell activates its own destruction without triggering inflammation.

Key Features

Caspase-mediated degradation of nuclear DNA and cytoplasmic proteins
Plasma membrane remains intact throughout
Cell fragments into apoptotic bodies that are rapidly phagocytosed by macrophages
No inflammatory reaction (contents never leak out)

Causes of Apoptosis

Physiologic:

Normal embryonic development (organ sculpting, cavitation)
Turnover of proliferative tissues (intestinal epithelium, lymphocytes)
Hormone-dependent involution (endometrial shedding)
Deletion of self-reactive lymphocytes (prevention of autoimmunity)
Resolution of immune responses (elimination of excess leukocytes)

Pathologic:

DNA damage beyond repair (radiation, toxins) - via BH3-only protein activation
Accumulation of misfolded proteins (ER stress)
Viral infections - virally infected cells killed by cytotoxic T lymphocytes (CTLs)

Mechanisms of Apoptosis

Two distinct pathways converge on caspase activation:

Fig 1.12 - Robbins & Kumar Basic Pathology

A. Mitochondrial (Intrinsic) Pathway

The main pathway in most physiologic and pathologic apoptosis.

Stress signals (growth factor withdrawal, DNA damage, protein misfolding) activate BH3-only proteins
BH3-only proteins shift the balance from anti-apoptotic BCL-2/BCL-XL toward pro-apoptotic BAX/BAK
BAX/BAK dimerize, insert into the mitochondrial outer membrane, and form pores
Cytochrome c and other proteins escape into the cytosol
Cytochrome c + cofactors activate caspase-9
Caspase-9 activates downstream effector caspases (caspase-3, -6, -7) - the executioner caspases

B. Death Receptor (Extrinsic) Pathway

Triggered by signals from the cell surface.

Death receptors (e.g., Fas/CD95, TNF receptor-1) are engaged by their ligands (FasL, TNF)
The death domains of receptor and adaptor proteins cluster to form the DISC (death-inducing signaling complex)
Caspase-8 is recruited and activated
Caspase-8 activates downstream effector caspases
In some cells, caspase-8 cleaves BID (a BH3-only protein), which amplifies the signal through the mitochondrial pathway

End Result

Both pathways activate executioner caspases that cleave:

CAD (caspase-activated DNase) - fragments nuclear DNA into ladder-like ~180 bp pieces
Cytoskeletal proteins - causes cell shrinkage and membrane blebbing
Phosphatidylserine is flipped to the outer leaflet - acts as an "eat me" signal for phagocytes

Morphologic Features of Apoptosis

Cell shrinkage (vs. swelling in necrosis)
Chromatin condensation and nuclear fragmentation (pyknosis, karyorrhexis)
Cytoplasmic blebbing and formation of membrane-bound apoptotic bodies
No inflammation (bodies are rapidly cleared by macrophages)

4. Necrosis vs. Apoptosis - Summary Comparison

Feature	Necrosis	Apoptosis
Cause	Pathologic injury	Physiologic or pathologic
Mechanism	Uncontrolled enzymatic digestion	Caspase-mediated, programmed
Cell size	Swollen	Shrunken
Membrane integrity	Lost	Intact until phagocytosis
Contents	Leak out	Packaged in apoptotic bodies
Inflammation	Yes (always)	No
DNA fragmentation	Random, smear pattern	Internucleosomal, "ladder" pattern
Energy required	No	Yes (ATP-dependent)
Clinical significance	MI, stroke, bacterial infections	Normal development, cancer, immune regulation

5. Autophagy

Autophagy ("self-eating") is a cell survival response to nutrient deprivation. Cytoplasmic components are sequestered in autophagosomes that fuse with lysosomes for digestion and recycling.

Serves as a survival mechanism during starvation (recycling cellular components for energy)
Can also trigger cell death if prolonged or excessive
Plays roles in cancer (both tumor-suppressive and tumor-promoting), neurodegeneration, and immunity

6. Other Regulated Cell Death Pathways

Beyond necrosis and apoptosis, several other pathways have been defined:

Pathway	Key Features
Necroptosis	"Programmed necrosis"; triggered by TNF when caspases are inhibited; involves RIPK1/RIPK3/MLKL; causes inflammation like necrosis
Pyroptosis	Caspase-1 or caspase-11 mediated; triggered by intracellular pathogens via the inflammasome; releases IL-1β and IL-18; highly inflammatory
Ferroptosis	Iron-dependent lipid peroxidation; driven by glutathione peroxidase 4 (GPX4) deficiency; implicated in ischemia-reperfusion injury and neurodegeneration
NETosis	Neutrophil-specific death forming neutrophil extracellular traps (NETs); antimicrobial but also drives tissue damage

7. Mechanisms Underlying Cell Injury Leading to Death

The main biochemical mechanisms that drive cells from reversible injury to death include:

Mitochondrial dysfunction - ATP depletion, mitochondrial permeability transition pore (mPTP) opening
Oxidative stress - excess reactive oxygen species (ROS: O₂⁻, H₂O₂, •OH, ONOO⁻) damaging lipids, proteins, and DNA
Calcium dysregulation - sustained ↑ intracellular Ca²⁺ activates phospholipases, proteases, ATPases, and endonucleases
Membrane damage - lipid peroxidation by ROS, phospholipase activation, loss of selective permeability
ER stress - accumulation of misfolded proteins triggers the unfolded protein response (UPR); if unresolved, triggers apoptosis via BH3-only proteins
DNA damage - activation of p53 and BH3-only proteins leading to apoptosis, or necrosis if massive

Source: Robbins & Kumar Basic Pathology, 10th ed., Chapter 1 - Cell Injury, Cell Death, and Adaptations

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