Invariably pathologic (culmination of irreversible cell injury)
Numerous macrophage receptors are involved in the binding and engulfment of apoptotic cells, facilitating efficient clearance.
Metastatic calcification is associated with hypercalcemia and can occur in normal tissues, often resulting from conditions like primary parathyroid tumors or vitamin D-related disorders.
Dystrophic calcification can occur in aged or damaged heart valves and is a common cause of aortic stenosis in the elderly.
Frequent
Excessive intake or defective transport or catabolism.
Dystrophic calcification occurs when calcium deposits in injured or dead tissue despite normal calcium metabolism.
1) Abnormal metabolism (e.g., fatty change in the liver), 2) Mutations affecting protein folding and transport, 3) Enzyme deficiencies leading to lysosomal storage diseases, 4) Inability to degrade phagocytosed particles.
Dystrophic calcification is initiated by the extracellular deposition of crystalline calcium phosphate in membrane-bound vesicles, which may come from injured cells, or the intracellular deposition of calcium in the mitochondria of dying cells.
Major causes include increased secretion of parathyroid hormone, bone destruction due to accelerated turnover, vitamin D-related disorders, and renal failure resulting in phosphate retention.
On gross examination, calcium salts appear as fine white granules or clumps, often felt as gritty deposits.
Russell bodies are accumulations of newly synthesized immunoglobulins found in the RER of plasma cells, appearing as rounded eosinophilic structures.
The death receptor pathway is initiated when Fas ligand binds to Fas receptors, resulting in the recruitment and activation of adaptor proteins that activate caspase-8, which then activates downstream caspases leading to apoptosis.
Necrotic cells may persist for a time or be digested by enzymes. They can be replaced by myelin figures, which may be phagocytosed or degraded into fatty acids that bind calcium salts, leading to calcification.
The two distinct pathways of apoptosis are the mitochondrial (intrinsic) pathway and the death receptor pathway.
The mitochondrial (intrinsic) pathway is responsible for apoptosis in most physiological and pathological situations.
Dying cells secrete soluble factors that recruit phagocytes to aid in their clearance.
Enzymatic digestion; may leak out of cell
The plasma membrane flips to the outer leaflet, which is recognized by tissue macrophages, leading to phagocytosis of the apoptotic cells.
Apoptotic cells rapidly shrink, form cytoplasmic buds, and fragment into apoptotic bodies composed of membrane-bound pieces of cytosol and organelles.
Fatty change, or steatosis, is the accumulation of triglycerides within parenchymal cells, most often seen in the liver, but can also occur in the heart, skeletal muscle, kidney, and other organs.
In cases like nephrotic syndrome, excessive protein leakage results in larger amounts being reabsorbed, leading to the formation of vesicles with protein, visible as pink, hyaline cytoplasmic droplets.
Fat necrosis in acute pancreatitis is caused by the release of activated pancreatic lipases that liquefy fat cell membranes and split triglyceride esters, resulting in chalky white areas known as fat saponification.
It is characterized by preserved outlines of necrotic cells with loss of nuclei and an inflammatory infiltrate, commonly seen in infarcts of solid organs except the brain.
Bcl-2 and Bcl-xL maintain mitochondrial membrane integrity by inhibiting pro-apoptotic proteins like Bax and Bak, thus preventing apoptosis.
Gangrenous necrosis usually refers to the condition of a limb that has lost its blood supply and has undergone coagulative necrosis across multiple tissue layers.
Necrosis can occur in severe pathologic conditions such as marked ischemia, infections, and certain inflammatory reactions.
Nuclear changes include pyknosis (nuclear shrinkage and increased basophilia), karyorrhexis (fragmentation), and karyolysis (fading basophilia due to DNA digestion).
Enlarged (swelling)
The nuclei show various stages of chromatin condensation and aggregation, ultimately leading to karyorrhexis and DNA fragmentation into nucleosome-sized pieces.
The clearance is so efficient that dead cells disappear without leaving a trace, and inflammation is virtually absent.
Histological examination reveals shadowy outlines of necrotic fat cells surrounded by basophilic calcium deposits and an inflammatory reaction.
Dystrophic calcification is common in areas of caseous necrosis, such as in tuberculosis, where affected lymph nodes may become radiopaque.
Apoptosis is a pathway of cell death where cells activate enzymes to degrade their own DNA and proteins, resulting in intact plasma membranes and minimal inflammatory response. This contrasts with necrosis, which often leads to cell lysis and inflammation.
Cells activate a precise set of molecular pathways that culminate in death (apoptosis).
Deposition of calcium at sites of cell injury and necrosis.
Intracellular accumulations refer to abnormal amounts of substances accumulating in the cytoplasm, within organelles (typically lysosomes), or in the nucleus. These substances may be synthesized by the affected cells or produced elsewhere.
The mitochondrial (intrinsic) pathway is activated by stress signals like growth factor withdrawal and DNA damage, while the death receptor (extrinsic) pathway is activated by ligand-receptor interactions on the cell surface, particularly involving TNF receptors. Both pathways culminate in the activation of caspases.
BH3-only proteins sense a lack of survival signals or DNA damage, activating effector molecules that increase mitochondrial permeability, leading to the release of cytochrome c into the cytosol and subsequent caspase activation.
In the brain, liquefactive necrosis results in dissolution of the tissue, transforming it into a liquid that is removed by phagocytes.
Pigments can be exogenous (like carbon) or endogenous (like lipofuscin, melanin). They accumulate through inhalation, aging, or certain metabolic processes.
Unlike necrosis, which is always a pathologic process, apoptosis can occur in healthy tissues as a means of maintaining cell numbers during development.
Cellular function may be lost long before cell death occurs, and morphological changes lag behind loss of function and viability.
The loss of growth factor signaling during embryogenesis is presumed to trigger apoptotic mechanisms.
Pyknosis → karyorrhexis → karyolysis
Caseous necrosis is characterized by a large area of caseous necrosis containing yellow-white (cheesy) debris, often surrounded by macrophages and inflammatory cells, forming a granuloma.
Because apoptotic fragments are quickly extruded and phagocytosed without eliciting an inflammatory response.
Fibrinoid necrosis is a special form of necrosis that usually occurs in immune reactions where antigen-antibody complexes are deposited in blood vessel walls, producing a bright pink appearance on H&E preparations.
Not thought to be regulated by specific signals or biochemical mechanisms; happens accidentally due to severe injury.
Reabsorbed proteins in kidney tubules and immunoglobulins in plasma cells.
Carbon, lipofuscin (breakdown product of lipid peroxidation), or iron (usually resulting from overload, as in hemosiderosis).
The accumulation of misfolded proteins triggers apoptotic death, often seen in the context of ER stress.
Decreased hormone levels lead to reduced survival signals, resulting in apoptosis in hormone-dependent tissues.
Pathologic calcification is an abnormal deposition of calcium salts, along with smaller amounts of iron, magnesium, and other minerals, occurring in various disease states.
Intact; altered structure, especially orientation of lipids
The main pathways are inadequate removal and degradation, excessive production of an endogenous substance, or deposition of an abnormal exogenous material.
Necrosis
Excessive glycogen deposits can occur due to abnormal glucose metabolism, especially in poorly controlled diabetes mellitus and glycogen storage diseases.
Lipofuscin, or 'wear-and-tear pigment', accumulates with aging or atrophy and indicates past free radical injury, but it is not harmful to cells.
Hemosiderin is a golden yellow to brown pigment derived from hemoglobin that accumulates in tissues during local or systemic excess of iron.
Apoptosis is regulated by biochemical pathways that control the balance of death- and survival-inducing signals, leading to the activation of enzymes called caspases.
The end result of apoptotic cell death is the clearance of apoptotic bodies by phagocytes.
DNA damage activates pro-apoptotic proteins through BH3-only sensors, leading to apoptosis.
Coagulative necrosis is a form of necrosis where the tissue architecture is preserved for several days after cell death, resulting in a firm texture due to denaturation of proteins and enzymes.
When cells are severely disturbed, such as loss of oxygen and nutrient supply or exposure to toxins.
Cellular cholesterol metabolism is tightly regulated to ensure normal generation of cell membranes without significant intracellular accumulation.
In macrophages and smooth muscle cells of vessel walls in atherosclerosis, as a result of defective catabolism and excessive intake.
Defects in lysosomal enzymes that break down glycogen, leading to glycogen storage diseases.
Deposition of calcium in normal tissues caused by hypercalcemia, usually a consequence of parathyroid hormone excess.
Necrosis is a form of cell death where cellular membranes fall apart, cellular enzymes leak out, and ultimately digest the cell. It elicits a local host reaction known as inflammation.
Liquefactive necrosis occurs when focal bacterial or occasional fungal infections stimulate rapid accumulation of inflammatory cells, leading to tissue being digested into a viscous liquid.
Activated BH3 proteins shift the balance towards pro-apoptotic proteins Bax and Bak, leading to mitochondrial membrane permeabilization and the release of cytochrome c, which activates caspase-9 and initiates apoptosis.
Apoptosis is a process that eliminates cells with intrinsic abnormalities and promotes clearance of cell fragments without eliciting an inflammatory reaction. It can occur in both pathologic and healthy tissues.
Necrotic cells show increased eosinophilia, a glassy homogeneous appearance, vacuolation, and defined nuclear changes like pyknosis, karyorrhexis, and karyolysis.
Viral proteins can activate the mitochondrial pathway, which leads to the apoptosis of infected cells.
Causes include toxins, protein malnutrition, diabetes mellitus, obesity, anoxia, and alcohol abuse, with diabetes associated with obesity being the most common in industrialized nations.
The biochemical mechanisms of necrosis include failure of ATP generation due to reduced oxygen or mitochondrial damage, damage to cellular membranes, irreversible injury to lipids, proteins, and nucleic acids, and effects of reactive oxygen species.
Morphologically visible protein accumulations are less common than lipid accumulations.
Apoptotic cells produce 'eat-me' signals, such as the exposure of phosphatidylserine on their outer membrane, which entices phagocytes to clear them.
The interstitial tissues of the vasculature, kidneys, lungs, and gastric mucosa.
Inflammation during necrosis is triggered by substances released from dead cells that serve to eliminate debris and initiate the repair process.
Accumulation of free triglycerides in cells, resulting from excessive intake or defective transport, often due to defects in synthesis of transport proteins; it is a manifestation of reversible cell injury.
Caseous necrosis is characterized by a cheeselike appearance, often associated with tuberculous infections, where the necrotic focus appears granular and pink under microscopic examination.
Coagulative necrosis maintains tissue architecture for days, while liquefactive necrosis results in complete digestion of tissue into a liquid state.
Apoptosis eliminates cells that are damaged beyond repair, such as those with severe DNA damage, misfolded proteins, or those infected by certain viruses.
Apoptosis eliminates excess leukocytes after immune responses and purges lymphocytes that recognize self-antigens to prevent autoimmune diseases.
Tissue-specific necrosis can be detected by measuring the levels of unique intracellular proteins that leak into circulation following cell death, such as creatine kinase in cardiac muscle and alkaline phosphatase in hepatic bile duct epithelium.
Apoptotic bodies are fragments of apoptotic cells that become highly 'edible' and are rapidly consumed by phagocytes, leading to efficient clearance without significant leakage of cellular contents.
Melanin is synthesized by melanocytes and acts as a protective screen against harmful UV radiation, accumulating in the skin and dermal macrophages.
Extensive calcifications in the lungs may produce respiratory deficits and massive deposits in the kidneys (nephrocalcinosis) can lead to renal damage.
Caspases are cysteine proteases that cleave proteins after aspartic acid residues and are essential in the process of apoptosis.
Phagocytic cells may become overloaded with lipids in several processes, with atherosclerosis being the most important.
Caspases are proteolytic enzymes that, once activated, cleave various cellular substrates leading to the degradation of proteins and nuclear components, resulting in the characteristic fragmentation of apoptotic cells.
Mitochondrial membrane permeabilization allows the escape of cytochrome c into the cytosol, activating caspases and leading to cell death through apoptosis.
During normal development, some cells die and are replaced by new ones, ensuring that unwanted cells are eliminated without causing inflammation.
Both the mitochondrial and death receptor pathways are involved in the elimination of self-reactive lymphocytes.
