Cell Death: Necrosis & Apoptosis

Necrosis versus apoptosis

Two ways to die. Necrosis is pathologic death of sheets of cells after ATP depletion: cells and organelles swell, membranes rupture, enzymes leak out, and inflammation follows. Apoptosis is programmed, ATP-DEPENDENT death of single cells: the cell shrinks, its membrane stays intact, and there is NO inflammation.

Membrane rupture spills cell contents and provokes inflammation; apoptosis packages its debris into membrane-bound bodies that phagocytes eat quietly.

Nuclear changes. A dying nucleus undergoes pyknosis (shrinkage and condensation), then karyorrhexis (fragmentation), then karyolysis (fading as DNase digests the DNA): shrink, fragment, fade. Condensation and fragmentation occur in both forms of death, but karyolysis is a necrotic change, because apoptotic cells are usually phagocytosed before the nucleus fades.

Patterns of necrosis

The pattern names the tissue. The same ischemic insult gives firm "ghost" cells in the heart but liquid in the brain, so the morphology points to the organ and cause.

Coagulative and liquefactive. Coagulative infarcts of the heart, kidney and spleen are wedge-shaped, pale and firm. The brain is the exception: it liquefies rather than coagulates. Liquefaction also occurs in bacterial abscesses, where neutrophil hydrolases digest tissue, and in pancreatitis. Red (hemorrhagic) infarcts arise in loose or dual-supply tissue (lung, bowel, testis), and pale infarcts in solid organs (heart, kidney, spleen).

Caseous. This combines coagulative and liquefactive features and forms the friable center of a granuloma ringed by epithelioid macrophages. A caseating granuloma is TB until proven otherwise.

Fat. In acute pancreatitis, lipase releases free fatty acids that bind calcium, producing chalky-white saponification, a form of dystrophic calcification. Saponification consumes calcium and can cause hypocalcemia in severe pancreatitis. Traumatic fat necrosis of the breast is non-enzymatic.

Fibrinoid and gangrenous. Fibrinoid necrosis appears in malignant hypertension, vasculitis (PAN), hyperacute transplant rejection and preeclampsia. Dry gangrene is coagulative necrosis from chronic ischemia (a diabetic or atherosclerotic limb) that leaves tissue mummified. Wet gangrene is superimposed bacterial infection, making it liquefactive, foul and an emergency.

Apoptosis: morphology and settings

Morphology. The cell shrinks and becomes deeply eosinophilic (pink), chromatin condenses, and the cytoplasm buds into membrane-bound apoptotic bodies. Phosphatidylserine flips to the outer membrane as an "eat me" signal, so macrophages clear the bodies without inflammation.

Where it happens. Physiologic apoptosis sculpts embryos (loss of the webs between digits), follows hormone withdrawal (endometrial shedding), deletes self-reactive T cells in the thymus, and removes lymphocytes after an immune response ends. Pathologic apoptosis follows DNA damage from radiation or chemotherapy, viral infection (eosinophilic Councilman bodies in viral hepatitis) and attack by cytotoxic T cells.

Intrinsic and extrinsic pathways

Intrinsic (mitochondrial) pathway. DNA damage, with p53 as a key trigger, or growth-factor withdrawal shifts the balance from anti-apoptotic BCL-2/BCL-xL toward pro-apoptotic BAX/BAK. Cytochrome c leaks from the mitochondria, binds Apaf-1 to form the apoptosome, and activates caspase-9. Remember "IntrINsic = INside the mitochondria."

Extrinsic (death-receptor) pathway. Fas (CD95) binding FasL, or TNF-α binding TNFR1, recruits the adaptor FADD and activates caspase-8. Cytotoxic T cells use FasL to kill targets (they can also inject granzyme through perforin pores), and Fas-FasL signaling helps delete self-reactive cells during thymic negative selection.

Caspases. Caspases are cysteine-aspartate proteases. The initiators are caspase-8 (extrinsic) and caspase-9 (intrinsic); both pathways converge on executioner caspases 3, 6 and 7, which cleave the cytoskeleton and activate endonucleases that cut DNA between nucleosomes, producing a "ladder" on gel electrophoresis.

In follicular lymphoma, t(14;18) places BCL-2 under the IgH promoter. Excess BCL-2 blocks cytochrome c release, so B cells that should die accumulate. The BCL-2 inhibitor venetoclax exploits this pathway in CLL.