Aspects of pathology include aetiology (cause), pathogenesis (mechanism of development), molecular and morphologic changes and clinical manifestations (functional aspects). Normal cells are able to handle physioloic demands, maintaining a steady state by homeostasis. Stress (severe phsyiology or pathology eg increased demand/stimulation by hormones/peptides, reduced nutrients, reduced stimulation, chronic irritation) may cause reversible functional and structure adaptation (hypertrophy, hyperplasia, atrophy, metaplasia). More severe stress or injurious stimuli (ischaemia, infection, toxins) cause cellular injury, which may be reversible (mild, transient) or irreversible (severe, progressive). Irreversible injury leads to cell death via necrosis or apoptosis. Metabolic alterations or chronic injury may cause intracellular accumulations (proteins, lipids, carbohydrates, calcium). Aging is from cumulative low-grade injury.
Reversible cellular changes, including:
- Hypertrophy – Increase in the size of cells (and thus functional capacity) without cell division from increased functional demand, esp cells than cannot divide (skeletal and cardiac muscle, nerve cells). Increased synthesis of structural components, accelearated metabolism with incresed RNA and oranelles for protein synthesis. May be physiologic or pathologic. Induced by mechanical sensors, growth factors (TGF-β, IGF-1, fibroblast growth factor), vasoactive agents (α-adrenergic agonists, endothelin-1, angiotensin II). Hypertrophy may be associated with switch of contractile proteins eg muscle from α isoform of myosin to β isoform (slower, more economical). Hypertrophy may be of a certain organelle.
- Hyperplasia – Increased number of cells from increased functional demand, usually increasing the mass of organ/tissue. Frequently occurs with hypertrophy. Physiologic hyperplasia may be hormonal (increased capacity when needed, eg breast), or compensatory (after tissue damage/resection, eg liver). Pathologic hyperplasia usually from excessive hormones or growth factors, eg endometrial hyperplasia, BPH. Some viruses eg papillomavirus may produce growth factors. Cells may proliferate from mature existing cells or sstems cells if proliferative capacity is compromised (eg intrahepatic stem cells in hepatitis). Increases risk of cancer.
- Atrophy – Reduction in the size and number of cells, reducing overall size of the organ/tissue. Reduction in size from catabolism of structural proteins via autophagy (lysosomal system), reducing celullar metabolism and protein synthesis. Reduction in number of cells by cell death eg apoptosis. Involution is physiologic atrophy involving apoptosis (reducing number of cells). May be physiologic (eg embryonal structures, postpartum uterus) or pathologic. Pathologic atrophy from disuse (reduced function/workload, reversible if there is no apoptosis), denervation, ischaemia (eg senile atorphy of brain, heart), inadequate nutrition (eg cachexia = muscle wasting), loss of endocrine stimulation (eg breast, endometrium, vaginal epithelium after menopause) or pressure (eg enlarging benign tumour, ?from ischaemic changes).
- Metaplasia – Reversible change to another cell type that is able to withstand the stress better. Most commonly columnar to squamous epithelium in smoking (bronchial tree), calculi (salivary glands, pancreas, bile ducts, bladder), vitamin A deficiency; but this also causes loss of mucous secretion and ciliary action. The influences causing metaplasia may initiate malignant transformation of the metaplastic epithelium. Barret oesophagus is metaplasia from squamous to columnar epithelium. Connective tissue metaplasia is formation of mesenchymal tissue (cartilage, bone, adipose) in eg muscle in myositis ossificans. From reprogramming of stems cells in normal tissue, or undifferentiated mesenchymal cells in normal connective tissue. Initiated by cytokines, growth factors, extracellular matrix components.
Causes of cell injury:
- Oxygen deprivation (hypoxia) – From reduced blood flow (ischaemia), inadequate blood oxygenation, reduced blood oxygen carrying capacity (eg anaemia, CO) or severe blood loss. Ischaemia tends to cause more rapid and severe injury than hypoxia alone due to impaired delivery and removal of anaerobic glycolysis substrates and metabolites. Mild/chronic -> atrophy; severe/prolonged -> cell injury and death.
- Ischaemia-reperfusion injury – Additional damage to reversibly injured cells from free radicals (incomplete reduction of oxygen), inflammation or activation of the complement system.
- Physical agents – Mechanical trauma, temperature extremes, sudden change in pressure, radiation, electric shock.
- Chemical/toxic agents – Hypertonic glucose/salt, poisons (arsenic, cyanide inhibits phosphorylation of ATP, mercury increases membrane permeability), pollutants (insecticides, herbicides), industrial/occupational (CO, asbestos), drugs (therapeutic and recreational incl alcohol). Chemicals may cause direct injury or indirect injury (most, via toxic metabolites, free radical formation).
- Infection – Diverse mechanisms of injury.
- Immunologic reaction – Including endogenous self-antigens, reaction to external agents.
- Genetic derangement – Deficiency of functional proteins, susceptibility to injury by another cause.
- Nutritional imbalance – Protein/calorie deficiency, vitamin deficiency/excess, excess cholesterol.
Mechanisms of cell injury:
- Depletion of adenosine triphosphate (ATP) – Required for plasma membrane sodium pump (increasing cell solute and hence swelling), anaerobic glycolysis (acummulating lactic acid and inorganic phosphates reducing pH), influx of calcium (failed Ca pump), reduced protein synthesis, unfolding of proteins, ultimately irreversible damage to mitochondrial and lysosomal membranes (necrosis).
- Mitochondrial damage – Earliest sign of sublethal injury. From calcium, reactive oxygen species, oxygen deprivation. Reduces ATP (mitochondrial permeability causing loss of membrane potential), leakage of pro-apoptotic proteins.
- Influx of calcium – From ischaemia or toxins. Reduces ATP, activates celullar enzymes (phospholipase, protease, endonuclease, ATPase), induces apoptosis.
- Reactive oxygen species (ROS, free radicals) – From normal metabolism, radiation, inflammation, metabolism of chemicals/drugs, transition metals, nitric oxide. ROS damage lipids, proteins, DNA.
- Membrane damage – From ROS, reduced phospholipid synthesis, phospholipid breakdown, cytoskeletal abnormal. Causes mitochondrial damage, plasma membrane damage (loss of osmotic balance and cellular contents, lysosomal membrane damage (enzyme release). Hydropic degeneration (swelling) of organelles.
- Protein and DNA damage – From drugs, radiation, ROS, inherited mutations. Induces apoptosis.
Necrosis – Severe damage to membranes -> lysosomal enzymes enter cytoplasm, digesting the cell -> leakage of cellular contents. If necrotic cells/debris are not promptly destroyed and resorbed there is attraction of calicum and other minerals causing dystrophic calcificaiton. This is always pathologic.
- Coagulative necrosis (most common) – Architecture of tissue is preserved for days. Injury (usually ischaemia, all organs except brain) denatures structural proteins and enzymes, hence blocking proteolysis. Necrotic cells are eventually removed by phagocytosis. Infarct is localised region of coagulative necrosis.
- Liquefactive necrosis – Digestion of cells creating liquid viscous mass. From focal infection stimulating leukocytes and enzyme liberation. Frequently creamy yellow (pus) due to dead leukocytes. Also occurs in hypoxic deaths of CNS (unknown reason).
- Gangrenous necrosis – Usually coagulative necrosis involving multiple tissue planes of an ischaemic limb. Superimposed bacterial infection causes more liquefactive necrosis = wet gangrene.
- Casseous necrosis – Collection of fragmented/lysed cells and amorphous granular debris (cheesy yellow-white) within an inflammatory border. Characteristic of granuloma in eg TB.
- Gummatous necrosis – In syphilis
- Fat necrosis – Focal regions of fat destruction from released activated pancreatic lipases. The released fatty acids combine with calcium to produce chalky-white fat saponification.
- Fibrinoid necrosis – Usually immune reactions of blood vessels with immune complex deposition in arterial walls causing leak of these complexes along with fibrin. Seen in hypertension and vasculitis.
Apoptosis – Physiologic in embryogenesis, hormone withdrawal (mentrual cycle, postlaction, postmenopausal, castration – prostate), cell loss in proliferating populations (eg immature lymphocytes, germinal centres, intestinal crypts, homeostasis), elimination of potentially harmful lymphocytes (to prevent auto-immunity), after serving cellular useful purpose (end of inflammatory or immune response). Pathologic apoptosis occurs after DNA damage, accumulation of misfolded proteins, certain infections (esp viruses), obstruction (pancreas, parotid, kidney). There is nuclear dissolution (chromatin condensation), cellular fragmentation (cytoplasmic blebs and apoptotic bodies) without complete loss of membrane integrity, activation of caspases -> rapid removal of the cellular debris (membrane alterations to promote phagocytosis). Does not incite an inflammatory reaction (cf necrosis), but may coexict with necrosis.
Nutrient deprivation induces portions of the cytosol (autophagic vacuoles) to fuse with lysosomes (autophagolysosome), with degradation products used as nutrients.
Accumulations of normal cellular constituents or abnormal substances (exogenous or product of abnormal synthesis/metabolism). Within the cytoplasm (usually phagolysosomes) or nucleus. From abnormal metabolism to remove a normal substance (eg hepatic steatosis, protein droplets in renal tubules), defect in protein folding/transport (eg α1-antitrypsin), lack of enzyme to metabolize (eg lysosomal storage disease), accumulation of exogenous materials (lacks enzymatic or transport ability). Accumulation is reversible.
- Triglycerides (steatosis, fatty change) – In liver (primary fat metabolism), heart, muscle, kidney. From toxins, protein malnutrition, DM, obesity, anoxia. In the liver there is excess accumulation of triglycerides or defective metabolism and export of lipids (alcohol in NASH). In the heart from prolonged moderate hypoxia (causing bands or involved yellow and uninvolved darker red-brown myocardium = tigered effect) or profound hypoxia or myocarditis (uniformly affected myocytes). Fatty change is a manifestation of sublethal impairment of metabolism, common in the liver. More severe fatty change may impair cellular function.
- Cholesterol and cholesterol esters – In atherosclerosis, xanthomas (subepithelial connective tissue of skin and tendons in hyperlipidemia), cholesterolosis (in lamina propria of gallbladder of unknown aetiology), Niemann-Pick disease. Foam cells are macrophages filled with lipid vacuoles.
- Proteins – Reabsorption droplets in proximal renal tubules (in proteinuria), active synthesis in proteins (eg plasma cells producing immunoglobulins), defective intracellular transport and secretion (α1-antitrypsin), accumulation of cytoskeletal proteins (alcoholic hyaline, Alzheimer disease), aggregation of abnormal/misfolded proteins (proteinopathies/protein-aggregation diseases eg amyloidosis).
- Glycogen – In glucose or glycogen metabolic disease eg DM (renal tubular epithelial cells, liver cells, heart muscle, β islet cells of Langerhans), glycogen storage diseases (glycogenoses).
- Pigments – Exogenous eg carbon (anthracosis in lungs and LN), tatooing; or endogenous (lipofuscin, melanin, haemosiderin).
Abnormal deposition of calcium with iron, magnesium and other mineral salts.
- Dystrophic calcification – In areas of necrosis, despite normal serum calcium. Common in atheromas, damaged heart valves. Fine white granules/clumps with gritty texture. Calcium ion binds to phosopholipid in membrane -> phosphate binds -> deposition of calcium phosphate near the membrane -> micocrystal formation which may further propagate.
- Metastatic calcification – Hypercalcemia with deposition in normal tissues, also accentuates dystrophic calcification. From increaesd PTH (hyperparathyroidism), destruction of bone tissue (bone tumours, accelerated turnover eg Paget disease, immobilisation), vitamin D-related disorders (intoxication, sarcoidosis, idiopathic hypercalcaemia of infancy), or renal failure (retention of phosphate causing secondary hyperparathyroidism). Deposition in interstitium of gastric mucosa, kidneys, lungs, systemic arteries, pulmonaryveins.
Progressive decline in cellular function and viability from genetic abnormal and accumulation of damage from exogenous influences. Changes include:
- Reduced cellular replication ?incomplete replication of chromosome ends (telomere shortening, repeated sequences of TTAGGG).
- Accumulated metabolic and genetic damage from ROS
Regeneration results in complete restitution with proliferation of cells and tissues, in tissues with the capacity (haematopoietic system, epithelia of skin and GIT) as long as the stem cells in the tissue are not destryed. Repair restors some original structures but can leave structural derangements, consisting of a combination of regeneration and scar formation. Fiborsis refers to extensive deposition of collagen by fibroblasts (stimulated by growth factors and cytokines). Tissues of the body include:
- Continuously dividing (labile) tissues – Surface epithelia including stratified squamous (skin, oral cavity, vagina, cervix, excretory ducts), columnar (GIT, uterus) and transitional (urinary tract); bone marrow and haematopoietic tissues). Derived from adult stem cells.
- Quiescent/stable tissues – Normal low level of replication, but have the ability to rapidly divide. Include parenchymal liver, kidneys, pancreas, mesenchymal cells (fibroblasts, smooth muscle), vascular endothelium, lymphocytes, leukocytes.
- Nondividing/permanent tissues – Cannot undergo mitosis. Include neurons, skeletal and cardiac muscle. Skeletal muscle may regenerate through idfferentiation of satellite cells in the endomysial sheaths. Repair of neural tissue is by proliferation of glial cells; of cardiac muscle by scarring.
Liver regeneration can occur at a rate of doubling liver remnant after a month posterior 60% resection, by growth of enlargement of lobes (compensatory growth/hyperplasia).Almost all hepatocytes replicated during regeneration, replicating once or twice before returning to a quiescent perioud. Intrahepatic sttem/progenator cells do not play a part.