Pathology Test Block 1

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Nucleus

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Contains all the genetic information, required to produce and maintain viability of an organism.

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Chromosomes

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In dividing cells, the DNA is condensed and recognized as chromosomes.

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Chromatin

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In the resting or non-dividing cell, the DNA is finely dispersed throughout the nucleus as chromatin.

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RNA

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The nucleus contains RNA. It is essential for the translation of the genetic information into functional protein products.

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Cytoplasm

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Contains a cytoskeleton consisting of microfilaments, intermediate filaments (which are cell type specific), and microtubules which maintain cell structure and allow for cell mobility.

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Cytosol

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Amorphous ground substance of the cytoplasm. Consists of water and soluble nutrients, carbohydrates, lipids, and proteins.

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Mitochondria

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"power plants" of the cell and supply the energy needed to fuel all of the other activities of the cell. Normally this energy is produced as ATP resulting from oxidative phosphorylation.

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Ribosomes

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Consist of aggregates of ribosomal RNA (rRNA). They are essential in translating the genetic code of the nuclear DNA into proteins.

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Endoplasmic reticulum

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This organelle consists of a complex of internal cellular membranes that bridge the cytoplasm from the nucleus to the plasma membrane.

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Rough ER

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The endoplasmic reticulum associated with ribosomes. It is responsible for manufacturing protein either for intracellular use or for export from the cell.

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Smooth ER

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Functions to metabolize drugs, hormones, etc. and to synthesize steroid hormones.

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Golgi apparatus

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Responsible for producing the building blocks of cellular membranes and "packaging" protein or protein complexes assembled on the ER. The packaged proteins may be used within the cell, incorporated into the cell membrane, or exported from the cell for use elsewhere.

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Lysosomes

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These organelles are derived from the golgi apparatus and consist of powerful digestive enzymes. These enzymes are isolated from the surrounding cytoplasm by a lysosomal membrane, but the lysosomes can fuse with other cytoplasmic structures to digest, degrade, recycle, or expel from the cell unwanted or no longer needed materials.

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Plasma membrane

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seperates the cell cytoplasm from the interstitial fluid and extracellular matrix. Comprised of proteins lipids, and carbohydrates arranged as a complex polar bilipid membrane. It is the cell's communication port with the external environment. The plasma membrane is an active, metabolic, living structure which is essential for cell viability and which requires a significant amount of energy to maintain in functional order.

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Ectoderm and Endoderm

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Give rise to epithelial cells which cover the external and internal surfaces of the body, including the inner lining of the vessels, ducts, and small spaces. Epithelial cells lie ona basement membrane.

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Mesoderm

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Gives rise to mesenchymal cells which form the blood and connective tissue which contribute to the structural framework of organs (fibrous tissue) or lend structural support to the body as a whole (bones, cartilage, muscle).

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Parenchymal tissue

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Refers to the essential functionsal elements of an organ and generally is compromised of epithelial cells

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Stromal tissue

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Makes up the architecture or structural framework of an organ and is generally comprised of mesenchymal cells.

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Atrophy

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Decrease in the size (or in some instances the number) of individual cells that had previously been of normal size.

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Pathologic atrophy

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Results froma variety of conditions that restrict either oxygenation, nutrition, or stimulation (neural or endocrine) of the cell. Cellular organelles are decreased in number due to either increased catabolism or decreased synthesis of cell constituents.

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Hypertrohpy

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An increase in the size of individual cells in response to an increased functional demand. Generally, this involves an increase in structural components of those cells that are not commonly considered capable of mitotic division.This refers predominantly to cardiac and skeletal muscle cells when they are required to work against increased resistance.

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Atrophic tissue

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Smaller than normal

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Hypertrophic tissue

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larger and heavier than normal

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Hyperplasia

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An increase in the number of cells usually in repsonse to increased hormonal or growth factor stimulation.

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Hyperplastic tissue

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increased in volume

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Aplasia and Hypoplasia

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Refer to failure of development or underdevelopment, respectively, of an organ or tissue and are therefore developmental disorders rather than adaptive responses.

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Metaplasia

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A substitution of one mature cell type for another mature cell type. In most cases, metaplasia is a process in which a new harsher environment induces a change to a more protective tissue type. On the negative side however, the normal function of the original tissue is lost and in some cases, persistence od the adverse environment may ultimately induce dysplastic or neoplastic transformation of the metaplastic tissue.

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Dysplasia

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An atypical or abnormal (but still potentially reversible) growth of cells that is usually induced by chronic irritation or stimulation. Dysplasia is generally regarded as a potential precursor to malignant neoplasia which is a permanent abnormal growth of cells that is uncoordinated with the growth of normal cells.

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Cell injury

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Depending on the mechanism of injury, cell injury produces structural and functional changes to the cell.

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Cellular swelling

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The first morphologic change to occur after injuries that interfere with plasma membrane permeability and therefore the regulation of intracellular volume and ionic concentrations. Due to increased water, the cell appears enlarged with a pale cytoplasm but a normally positioned nucleus.

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Hydropic change (vacuolar degeneration)

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An exaggerated state of cellular swelling where segments of swollen distended endoplasmic reticulum appear in the cytoplasm as clear vacuoles that may displace the nucleus to the periphery of the cell. In addition, compression of the surrounding microvasculature by the swollen cells and the consequent decrease in blood flow may contribute to further cell injury.

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Swollen tisue

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enlarged in volume and increased in weight

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Fatty change (steatosis)

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Refers to an absolute increase in lipis (triglycerides, cholesterol, etc.) within parenchymal cells. Most often seen in the liver but may also involve the heart and kidney. With any interruption of normal cellular lipid uptake, synthesis, metabolism, or excretion, clear lipid vacuoles appear in the cytoplasm. As the vacuoles coalesce or enlarge, they displace the nucleus to the periphery of the cell.

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To distinguish fat vacuoles from water vacuoles:

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Their lipid nature can be confirmed with special stains for fat (Sudan black, Oil red O)

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Intracellular accumulation of lipids may simply represent non-specific injury to the cell, but it also occurs in specific disease states such as:

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Atherosclerosis, lipid storage diseases, alcoholic liver disease, obesity, and diabetes mellitus.

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Fatty ingrowth

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A usually asymptomatic process in which adipose cells accumulate within stromal connective tissue that lies between parenchymal cells. It is most frequently seen in the pancreas and heart.

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Glycogen infiltration

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Involves an increase in intracellular glycogen due to abnormal glucose or glycogen metabolism as in the inherited glycogen storage diseases or in hyperglycemic states such as diabetes. Morphologically, glycogen is also seen as clear vacuoles in the cytoplasm (hepatocytes tend to accumulate glycogen in a perinuclear indentation that gives the appearance of nuclear vacuoles) and can be distinguished from water and lipids by the use of special stains (Periodic acid-schiff or PAS)

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Hyaline degeneration

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Accumulations of protein in the cell appear as homogeneous, glassy, pink-staining hyaline. The term "hyaline" only refers to the histologic appearance of the protein and not its specific chemical compostition. Hyaline may be deposited intracellularly or extracellularly

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Accumulation of pigments in the cell

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Endogenous or exogenous pigments may accumulate within cells because of increased synthesis, impaired excretion, phagocytosis, etc. The presence of intracellular pigment may or may not in itself be injurious, but excessive accumulation of exogenous pigments (carbon, iron, lead, silver) may reflect environmental contamination. Excessive accumulation of endogenous pigments may reflect an underlying disease or metabolic disorder.

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Common endogenous pigments include:

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1) Lipofuscin (lipochrome)
2) Melanin
3) Iron
4) Bilirubin

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Lipofuscin (Lipochrome)

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This finely granular yellow-brown, "wear and tear" pigment indicates chronic free radical injury (lipid peroxidation) of cell membranes. It frequently becomes apparent with the aging of a cell and tends to be present as residual bodies in perinuclear lysosomes. Although it does not appear to interfere with cell function, when extensive it may impart a brown discoloration to the tissue("brown atrophy" of the heart and liver)

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Melanin

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This is a brown-black pigment that is produced by melancytes and in specific areas of the brain (neuromelanin). Certain disorders may be related to either generalized or localized underproduction or overproduction of melanin.

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Iron

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Iron may be stored in various forms such as ferritin or hemosiderin.

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Hemosiderin

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(Iron) Is a granular gold-brown pigment derived from the breakdown of hemoglobin.

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Hemosiderin-laden cell

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(usually macrophages) are frequently found around areas of hemorrhage or chronic vascular congestion. May also be found in the reticuloendothelial system and a variety of parenchymal cells such as heart, liver, pancreas, skin, etc.when present in excessive amounts (hemosiderosis), usually as the result of hemolysis of red blood cells.

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Hemochromatosis

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A common inherited (autosomal recessive) genetic defect in normal iron metabolism produces a severe metabolic disorder (hemochromatosis) that results in massive deposition of iron in tissues throughout the body leading to extensive damage.

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Prussian Blue

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A histologic stain that identifies the presence of iron in pigment.

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Bilirubin

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This is a green-brown pigment that is also a breakdown product of hemoglobin (porphyrin rings) but, unlike hemosiderin, does not contain iron. It is the major pigment of bile, and can accumulate in fluid and tissue whenever there is a disturance in bilirubin uptake, conjugation, or excretion by hepatocytes or when there is obstruction to normal biliary flow

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Cell death

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Although the line between reversibly and irreversibly injured cells may at times be quite indistinct, when an altered steady state induces sufficient biochemical disturbances to cause permanent, irreparable damage to the cell, cell death ensues.

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Histologic indicators of cell death:

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1) cytoplasmic changes
2) nuclear changes

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Cytoplasmic changes

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Eosinophilia (redness) and homogenization of the cytoplasm is due to loss of cytoplasmic RNA and to the disaggregation of polysomes and denaturation of cytoplasmic proteins.

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Nuclear changes

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The nucleus responds by chromatin condensation (pyknosis), fragmentation (karyorrhexis), or dissolution (karyolysis). Although it is irreparable damage to the cell membrane that actually spells death for the cell, these nuclear changes are the definitive morphologic evidence of irreversible injury and cell death.

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Apoptosis

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Refers to a distinctive form of cell death which involved individual cells or small clusters of cells. It is an energy-dependant, active process under strict regulatory control. Unlike necrosis, the cell does not elicit and inflammatory response.

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Necrosis

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A form of cell death initiated by overwhelming exogenous injury to the cell. Necrosis is ultimately associated with inflammation and subsequent tissue repair.

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Coagulative necrosis

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This is the most common pattern of necrosis and is due to inadequate oxygenation of the cells. Generally the result ofa reduction of blood flow (ischemia) to the cells, but other factors that leas to hypoxemia (anemia, abnormal hemoglobin function) may also produce this pattern of necrosis.

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Results of coagulative necrosis

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Nuclear material is usually lost, and denaturation of structural proteins allows preservation of faded, "ghost-like" cellular outlines and the underlying tissue architecture while denaturation of the endogenous degradative enzymes prevents cellular digestion. Eventually, the dead cells are removed by the action of exogenous proteolytic enzymes and phagocytic "scavengers", and the tissue is replaced either by regeneration of new cells or, more likely, scar.

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Dry Gangrene

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Refers to ischemic coagulative necrosis of the skin and subcutaneous tissues of the extremeties. Gangrenous necrosis of the toes and feet is a common complication of the peripheral vascualr disease associated with uncontrolled diabetes mellitus. The affected tissue desiccates and assumes a dark green-black coloration. Demarcation from adjacent viable skin is usually distinct.

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Wet Gangrene

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Results from tissue hypoxia secondary to ischemia or venous congestion of tissue which secondarily becomes infected (often by anaerobic bacteria) resulting in putrefaction of the necrotic tissue. The tissue is moist, dark, and malodorous.

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Gangrenous necrosis of internal viscera (bowel, appendix, gallbladder)

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(Wet gangrene) is a serious event which can rapidly lead to death unless there is surgical intervention.

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Gas Gangrene

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A variant caused by clostridium bacteria which ferment carbohydrates to produce carbon dioxide. The tissue appears much like wet gangrene but is also crepitant to palpation.

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Liquefactive necrosis

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This pattern results when proteolytic digestion of dead cells (either by endogenous or exogenous catalytic enzymes) is not delayed by enzyme denaturation. This is characteristic of tissues injured by bacterial infections which attract large numbers of neutrophils (creating an abscess) and ischemic destruction of brain tissue.

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Caseous necrosis

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A form of necrosis in which the preservation of the underlying tissue outlines is lost and replaced by grandular, amorphous, acellular substance which on gross examination resembles blue cheese.It is encountered principally in infectious diseases involving mycobacteria and fungi. When present, it frequently is seen in association with a specialized form of chronic inflammation known as granulomatous inflammation.

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Enzymatic fat necrosis

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Produced by lipolytic activity of pancreatic enzymes on fat cells. It is usually seen during the course of pancreatitis when pancreatic lipases are released into abdominal fatty tissues and convert triglycerides to free fatty acids which complex with calcium to form calcium soaps. Grossly this produces white chalky deposits in fatty tissue.

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Traumatic fat necrosis

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Produced by traumatic rupture of fat cells with subsequent phagocytosis of the lipid material by macrophages. Seen most frequently in female breast tissue, traumatic fat necrosis produces a granulomatous "foreign body" inflammationand histologically does not have the enzymatically "digested" appearance seen with enzymatic fat necrosis.

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Fibrinoid necrosis

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Characterized by a smudgy, amorphous, eosinophillic material usually deposited in or around the walls of small blood vessels. Although not apparent on gross examination, the histologic appearance resembles fibrin deposits- hence the term fibrinoid. This is often associated with immunologically related disease.

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Dystrophic calcification

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The more common form of calcification. Refers to the deposition of calcium salts, often in necrotic tissue, in the face of normal serum calcium levels. Within dying cells, calcium accumulates in the irreparably damaged mitochondria but extracellular calcium deposits also develop utilizing membrane bound vesicles as a nidus for propagation.

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Calcium appearance in dystrophic calcification.

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Histologically, calcium may appear as small concentrically laminated spheres (psammoma bodies) or as variably sized amorphous basophilic deposits.

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Metastatic calcification

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Refers to the deposition of calcium in normal tissue of patients with high serum calcium levels. The histologic appearance is similar to dystrphic calcification but the distribution is generally more widespread.

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The "health" of a cell is dependent upon:

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Production of energy
Synthesis of essential proteins
Maintenance of structural integrity
Ability to replicate

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Hypoxemia

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Poor oxygen saturation of the blood

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Ischemia

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Insufficient vascular supply

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Hypoxia

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Oxygen deficiency

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Oxygen deficiency of the cell

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Interferes with the cellular production of energy and the ability to maintain a normal intracellular chemical composition.Influx of calcium, sodium, and water causes cellular swelling and protein production is disrupted. Up to this point, these changes are potentially reversible but if oxygen deprivation continues, the cell becomes irreveribly injured because of damage to the cell membrane.This membrane damage leads to further permeability changes that perpetuates and exacerbates membrane destruction. The porous cell membrane also allows cytoplasmic enzymes to leak into the extracellular space and circulation. Ultimately, the lysosomal membranes become porous and release degradative enzymes into the cytoplasm resulting in cellular digestion.

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What cells are more prone to hypoxia/anoxia?

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In general, the cells that have high metabolic activity (i.e. neurons) are most sensitive to the effects of hypoxia/anoxia while those with low metabolic activity (connective tissue) are more resistant.

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Free Radicals

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Free radicals are extremely unstable and reactive molecules which are able to provoke inappropriate disulfide bonding of proteins, peroxidation of lipids and damage to DNA.

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Free Radical Formation

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Partial reduction of oxygen to create superoxides (O2), hydroxyl ioons (OH), and hydrogen peroxide (H2O2) is an important, but not the only, source of free radicals within the cell. Free radicals can also be created by ionizing radiation, metabolism of drugs, or as byproducts of normal metabolism. They are inactivated by spontaneous decay, by naturally occurring antioxidants, or by interaction with specific enzymes. In reacting with other substances (especially in peroxidation of membrane lipids), however, additional free radicals may be formed which can initiate a chain of autocatalytic events leading to irreversible cell membrane damage. The impact of free radicals in cell injury is dependent on the balance between the rate of formation and the rate of inactivation.

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Physical Injury: Mechanical trauma

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This results when sufficient outside force is applied to body tissues to disrupt their structure or function. The type of injury sustained is determined by the amount of force, the rate at which it is applied, the surface area of the tissues involved, and the type of tissue.

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Mechanical injury produces wounds such as:

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abrasions (loss of superfical cells as the result of friction or crushing), contusions (disruption of blood vessels by blunt force), lacerations (the tearing of tissue resulting from excessive stretching), incisions (cuts produced by a sharp instrument), avulsions (tearing away of body parts), and puncture wounds (piercing or penetration of tissue caused by a sharp object or instrument).

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Physical Injury: Temperature extremes

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Cell injury and/or cell death results if tissue is maintained at a temperature greater that 15 degrees C below or more than 5 degrees C above normal body temperature. The severity of injury is related to the duration of the exposure. Freezing of tissue interferes with ionic concentrations due to crystallization of intracellular water, denatures proteins, and physically disrupts cell membranes leading to cell death (frostbite). Excessive heat applied to cells causes nuclear swelling with disruption of nuclear membranes and coagulation of intracellular proteins

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Physical Injury: Ionizing Radiation

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The dosage, mode of delivery, and the oxygenation of the tissues all influence the effect of radiation. High levels of ionizing radiation causes cellular injury by transfer of radiant energy which may, through radiolysis of intracellular water, induce the formation of free radicals (esp. hydroxyl ions) and cause acute death of the cell. Even low levels of radiation may cause disruption of molecular bonding within the DNA that can result in single or double-stranded breaks. This may lead to mutations, inhibit cell division, or alter the ability to divide or to maintain normal homeostasis by interfering with the regulation and/or structure of the protein products of the genes. In general, cells with a low natural turnover rate are most radioresistant while those with a high natural turnover are most radiosensitive.

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Physical Injury: Electricity

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Electricity can cause cell injury or death either due to interruption of neural transmissions of the cardiac conduction/respiratory control systems or by the generation of heat.

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Physical Injury: Atmospheric Pressure

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The degree of injury depends on the magnitude, direction, rate, and duration of pressure change. In general, increased pressure is tolerated better than decreased pressure.

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Chemical/Drug Injury

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This can cause tissue damage by a wide variety of pathways. Chemicals and drugs can be inhaled, ingested, or absorbed through the skin and can stimulate, suppress, or disrupt critical biochemical pathways, alter membrane permeability, or destroy essential molecular components and cell organelles. Although some chemicals cause direct damage to cells, the toxicity of many other chemicals may be related to the induction of intracellular free radicals or toxic metabolic intermediate compounds. The severity of injury is generally dose-dependent. Age, genetic constitution, underlying disease, nutritional status, and other factors all influence the susceptibility to specific injuries by drugs or environmental chemicals.

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The effects of chemicals and drugs depend in part on their:

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Eventual distribution within the body, their metabolism, and their mode of excretion.

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Biologic Injury

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The wide spectrum of infectious organisms (viruses, bacteria, fungi, parasites, etc.) can induce cell enjury through direct cytopathic or cytotoxic effects or indirectly through inflammatory.immunologic host defense mechanisms.

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Nutritional Injury

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Nutritional imbalances (either deficiencies or excesses) may interfere with the ability to maintain cell structure and function.

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Inflammatory/Immunologic Injury

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Although these host defense mechanisms are crucial to the well-being of the body as a whole, either excessive or inadequate expression of these mechanisms may result in cell injury or death.

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Genetic Injury

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Genetic damage may interfere with the ability to maintain normal cell homeostasis by altering the regulation and /or structure of the protein products of the genes or by disrupting the normal replication and differentiation of the cells.

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Increased osmotic pressure of the interstitial fluid

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An increase in total body sodium due to excessive salt intake, increased absorption or decreased excretion of sodium by the kidneys, or reduced renal blood perfusion can lead to generalized edema.

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Decreased oncotic pressure of the plasma protein

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A decrease in serum albumin may also produce a generalized edema. This may be due to a failure of albumin synthesis (liver disease, malnutrition) or excessive albumin loss (glomerulopathy, enteropathy), etc.

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Increased hydrostatic pressure of the intravascular fluid

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This leads to localized edema and usually involves increased hydrostatic pressure on the venous (rather than arterial) side of the vascular bed resulting from interference with or obstruction to venous blood flow.

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Obstruction of lymphatic drainage (Lymphedema)

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This also produces a localized edema and is usually the result of lymphatic obstruction by cancer, scarring (post-inflammatory, post-radiation, etc.), parasitic disease (filaria), or lymphadenectomy.

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Increased capillary permeability

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The inner surface of all vessels are lined by endothelial cell which, among other functions, control the permeability ("leakiness") of the vessel. Injury to the endothelial cells as a result of inflammation, immunologic reactions, or other tissue injury will produce a localized edema.

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A type of edema fluid: Transudate

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This is a protein-poor (<3 gm/dL) fluid which has a specific gravity <1.012. It develops from imbalances in the normal hemodynamic forces and is frequently seen with congestive heart failure, liver disease, renal disease, and GI disorders.

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A type of edema fluid: Exudate

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This is a protein-rich (>3 gm/dL) fluid which has a specific gravity >1.020. It is generally the result of endothelial damage and alteration of vascular permeability and is seen with inflammatory/immunologic disorders, etc.

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The clinical significance of edema depends on:

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severity, location, rapidity of development, and underlying cause.

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Vascular Congestion

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This refers to decreased blood flow in veins, venules, and capillaries usually due to impaired venous drainage.It results in a bluish discoloration of tissue (cyanosis) due to accumulation of reduced (oxygen depleted) hemoglobin. Since impaired venous drainage also leads to increased intravascular hydrostatic pressure, edema is a common accompaniment of congestion.

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Chronic Vascular Congestion

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Chronic congestion may lead to sufficient impairment of tissue oxygenation that there is tissue necrosis and subsequent fibrosis. The effects of chronic congestion are most often seen in the liver, lungs, and spleen.

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Vascular Hyperemia

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This refers to increased blood flow through dilated ateries, arterioles, and capillary beds. Clinically, this results in increased warmth and redness (erythema) in affected tissue.Hyperemia is an active, reflexive mechanism designed to allow greater blood flow to areas of inflammation, to tissues needing more oxygen, or as a mechanism of heat dissipation. When associated with inflammation, hyperemia is followed by localized edema resulting from increased vascular permeability.

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Heart Failure

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A clinical condition manifested by numerous signs and symptoms that arise when the heart is no longer able to maintain normal cardiac output. The signs and symptoms of heart failure are generally due to hypoxic and congestive effects on organs and tissues other than the heart itself.

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Left-sided heart failure

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This occurs when the left ventricle is unable to maintain adequate cardiac output. As a result, the hydrostatic pressure within the left side of the heart increases and is transmitted "backward" into the pulmonary venous circulation. Although a decreased cardiac output may cause neurologic symptoms (restlessness, irritablity) due to cerebral hypoxia, the clinical manefestations of the left heart failure are primarily pulmonary in origin and induce easy fatigability, shortness of breath (SOB), or dyspnea on exertion (DOE), paroxysmal nocturnal dyspnea (PND), orthopnea, and cough.

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Edema in a left-sided heart failure

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Transudative fluid leaves the pulmonary capillaries producing an edematous thickening of the alveolar walls. When the capacity of the interstitial lymphatics to drain the excess fluid is surpasses, the transduate subsequently seeps into the alveolar sacs producing pulmonary edema. This may be ausculated as pulmonary rales. As the edema intensifies, pleural effusions may develop. On a chronic basis, there may be small capillary hemorrhages and dispedesis of red cells in the alveolar spaces. These red cells are phagocytized by alveolar macrophages, the hemoglobin is broken down to hemosiderin (a brown pigment), and the hemosiderin-laden macrophages ("heart failure" cells) characteristic of chronic pulmonary congestion are thereby formed.Over time, there is also irreversible fibrous thickening of the alveolar walls contributing to the grossly appreciated "brown induration" of the lungs.

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Right-sided heart failure

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This occurs when the right side of the heart is unable to maintain adequate ventricular output to the lungs. It is usually due to the inability to overcome an increase in pulmonary arterial pressures (pulmonary hypertension). Although this is most frequently the result of pre-existing left heart failure, it may also be due to other causes. The increased hydrostatic pressure in the right side of the heart is transmitted "backward" into the systemic venous return and clinically results in: engorgement and distention of neck veins, passive congestion of the liver, portal hypertension, dependent pitting edema, increased body weight.

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Right-sided heart failure: engorgement and distention of the neck veins

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This may lead to cerebral congestion and hypoxia resulting in irritability, restlessness, and stupor.

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Right-sided heart failure: Passive congestion of the liver

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Acute congestion is reflected by engorgement of hepatic central veins and sinusoids. Chronic congestion of the central veins and sinusoids results in hypoxia and atrophy of centrilobular hepatocytes and fatty change of peripheral periportal hepatocytes. This imparts a mottled red-brown and yellow-tan gross appearance known as "nutmeg liver". Long standing chronic congestion may induce a fibrosis known as cardiac sclerosis.

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Right-sided heart failure: Portal hypertension

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This may result in ascites (accumulation of fluid within the peritoneal cavity due to increased hydrostatic pressure within the portal venous system) and congestive splenomegaly (chronic congestion of the splenic sinusoids leads to fibrous thickening of the sinusoidal walls and an enlarged, firm spleen).

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Ascites

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Accumulation of fluid within the peritoneal cavity due to increased hydrostatic pressure within the portal venous system.

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Congestive Splenomegaly

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Chronic congestion of the splenic sinusoids leads to fibrous thickening of the sinusoidal walls and an enlarged, firm spleen.

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Right-sided heart failure: Dependent pitting edema

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This is an interstitial edema of subcutaneous tissue that is most pronounced in the dependent portions of the body.

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Right-sided heart failure: Increased body weight

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In addition to other factors, congestive hypoxia of the kidneys promotes retention of sodium and water which adds to the interstitial fluid accumulation.

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Liver disease (cirrhosis, hepatocellular damage)

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Hepatic injury may result in decreased syntheses of plasma protein, increased hydrostatic pressure and pooling of blood in the venous circulation, hepatic lymphatic obstuction, etc.

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Renal disease (glomerulopathy, tubular dysfunction)

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This may result in loss of plasma protein, increased sodium retention, etc.

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GI disease (starvation, malabsorption, enteropathy)

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This may result in plasma protein deficiences, etc.

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Inflammatory/Immunologic disorders (infections, hypersensitivities)

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These can result in vascular endothelial damage or increased vascular permeability creating localized exudates.

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Edema

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This refers to the accumulation of excess fluid in cells or tissues.

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Intracellular edema

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Generally a reflection of cellular injury and altered cell membrane permeability.

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Interstitial edema

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The extracellular, extravascular fluid compartment. Reflects either a disturbance in the normal hemodynamic forces that control fluid transfer between the vascular and extravascular space, or it indicated injury to the vessels that result in increased vascular permeability. Interstitial edema may be confined to a localized area or it may be a diffuse process involving all tissues of the body (anasarca).

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Pathogenesis

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Look in notes!

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Hemorrhage

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This refers to active bleeding into extravascular tissues or spaces resulting from disruption of the integrity of vascular walls.

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Petechiae (pinpoint)

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Hemorrhages into skin, mucous membranes, or serosal surfaces.

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Purpura

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Hemorrhages less than 1.0 cm into the skin, mucous membranes, or serosal surfaces.

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Ecchymoses

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Hemorrhages greater than 1.0 cm into the skin, mucous membranes, or serosal surfaces.

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Hematomas

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Extravascular blood clots

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Hemothorax, hemopericardium, hemoperitoneum....

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Blood in body cavities are referenced to the location.

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Epistaxis

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Blood from the nose

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Hemoptysis

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Coughing of blood from the lungs.

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Hematemesis

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Vomiting of blood

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Melena

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Dark "tarry" blood in the stool.

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Hematochezia

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Bright red blood in the stool.

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Hemorrhage amount

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A small volume of blood loss may be insignificant; a large volume of blood loss may be fatal.

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Hemorrhage location

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A large hemorrhage into soft tissue may be insignificant; a small hemorrhage in the brainstem may be fatal.

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Hemorrhage rate of loss

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Chronic blood loss allows compensatory mechanisms to develop and is tolerated better than acute blood loss.

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Hemostasis

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This refers to the body's intrinsic ability to slow down or stop hemorrhage. This is accomplished by forming an intravascular blood coagulum (thrombus) as the result of a complex interaction between the vascular wall, the blood platelets, and the circulating coagulation and anticoagulation factors. Normal hemostasis involves a delicate balance between factors that promote blood coagulation and thrombus stabilization and factors that inhibit blood coagulation and promote thrombus dissolution.

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Blood clot

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Refers to the formation of an extravascular blood coagulum or a postmortem intravascular coagulum formed only from the plasma coagulation factors.

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Vasoconstriction

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A type of hemostasis that occurs immediately. The walls of arteries, arterioles, and large veins contain a smooth muscle layer which, on injury, contracts thereby decreasing the diameter of the vessel lumen and reducing blood flow.This mechanism helps stop bleeding from minor trauma.

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Platelet Plugs

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A type of hemostatis that occurs in minutes. When the endothelium of a vessel is injured, the platelets adhere to the area of injury and pile up to block the leakage. This helps control bleeding from venules, capillaries, and arterioles.

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Platelets

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Platelets are small cytoplasmic fragments of larger cells called megakaryocytes (which are found in bone marrow). They contain granules carrying specific chemical mediators that aid in thrombus formation and are released into circulation peripheral blood (150,000-350,000/mL).

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Coagulation

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A type of hemostasis that occurs within several minutes. This involves interaction between the platelets, calcium, and various protein coagulation factors which are primarily synthesized in the liver and are normally present in circulating blood in an inactive state. Coagulation is initiated by "activation" of one of the inactive factors which, in turn, activates the next factor which activates the next factor, etc. in a "waterfall" fashion. Coagulation can be initiated through two seperate pathways both of which then converge on a common pathway with the end result being the formation of fibrin.

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Fibrin

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An insoluble fiber-like protein which creates a network of interlacing fibers that traps platelets and blood cells to form a fibrin plug.

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Intrinsic pathway of coagulation

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This pathway is activated by contact of factor XII (Hageman factor) with the subendothelial matrix of the damaged vessel wall. The time is takes for blood to coagulate by this mechanism is measured in the laboratory by the partial thromboplastin time (PTT).

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Extrinsic pathway of coagulation

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This pathway is activated by chemicals that are released from injured tissue (tissue thromboplastin) and from platelets. The time it takes for blood to coagulate by this mechanism is measured in the laboratory by the Prothrombin time (PT).

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Common pathway of coagulation

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Both the intrinsic and extrinsic pathways converge on inactive factor X to produce activated factor X (prothrombin activator or thromboplastin) which converts prothrombin to thrombin. Thrombin, an enzyme, catalyzes the conversion of fibrinogen into fibrin.

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Prothrombin

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A coagulation protein formed by the liver.

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Thrombolysis (Fibrinolysis)

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This is a process that opposes and counteracts coagulation and prevents coagulation of blood in areas where it is not needed. It invloves a circulating inactive protein, plasminogen (produced in the liver) which, in the presence of excess thrombin, becomes activated to plasmin. Plasmin degrades fibrin into smaller protein fragments (which can be measured in the blood) and thereby prevents coagulation from occuring.

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Coagulation factor abnormalities

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In these disorders, bleeding is often severe with hematomas and ecchymoses developing afer minor trauma.

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Congenital bleeding disorders

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These are usually characterized by single factor deficiencies. (Hemophilia A, Hemophilia B, Von Willebrand disease)

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Aquired bleeding disorders

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These are usually characterized by multiple factor deficiencies and clotting abnormalities. (Vitamin K deficiency, sever liver disease)

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Hemophilia A (Factor VIII deficiency)

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This is a sex-linked inherited abnormality. Patients have difficulty controlling bleeding after minor trauma. Bleeding into joint spaces (hemarthrosis) will, with time, lead to crippling athropathy. Patients will have a normal platelet count, normal PT, and increased PTT.

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Hemophilia B (Christmas disease, Factor IX deficiency)

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This has the same inheritance pattern and similar symptoms as Hemophilia A but is about 20% as common.

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Von Willebrand disease

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This is an autosomal dominant inherited disease affecting a coagulation factor produced by the endothelial cells (von willebrand factor) that normally promotes platelet aggregation at sites of endothelial injury. It is characterized by easy bruisability and bleeding but with little or no bleeding joints.

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Vitamin K deficiency

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Synthesis of factors II, VII, IX, and X in the liver are dependent on the presence of vitamin K (a fat soluble vitamin ingested in the diet and synthesized by intestinal flora). Deficiencies may occur in cases of malnutrition, malabsorption, biliary obstruction, or drug therapy.

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Severe liver disease

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This can impair the hepatic synthesis of factors II, V, VII, IX, X, and fibrinogen.

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Platelet abnormality: Thrombocytopenia

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This refers to a decrease in the number of platelets and is generally characterized by petechial bleeding from small vessels into the skin, GI tract, mucous membranes, urinary tract, and brain. This abnormality may result from decreased platelet production, increased platelet utilization, or increased platelet destruction.

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Platelet abnormality: Functional disorders

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Various diseases result from abnormalities in platelet function rather than abnormalities in platelet numbers. These may be inherited or acquired. For instance, aspirin interferes with the funtion of platelets.

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Vessel Abnormalities (increased vascular fragility)

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These disorders are generally manifested by petechial hemorrhages into the skin or mucous membranes and usually are not severe, life threatening situations. As with the other components of coagulation, these disorders may be inherited or acquired.

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Predisposing factors (Virchow's triad) of thrombosis

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1) alteration of vascular endothelium
2) alteration of blood flow
3) alteration of blood components

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1st predisposing factor of thrombosis in Virchow's triad: alterationof vascular endothelium

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Structural or functional changes to the endothelium may initiate thrombus formation.

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2nd predisposing factor of thrombosis in Virchow's triad: alteration of blood flow

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Stasis or turbulence will disrupt the normal laminar flow of blood and bring platelets in direct contact with the endothelium, allow increased concentration of activated coagulation factors, inhibit ingress of coagulation inhibitors, promote endothelial damage, and allow propagation of pre-existing thrombi.

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3rd predisposing factor of thrombosis in Virchow's triad: alterations of blood componenets

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The presence of coagulants or deficiencies of natural anticoagulants may lead to hypercoagulability and inappropriate thrombosis.

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Arterial thrombi

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These form in areas of atheroslcerotic damage to the vessel or wall or, in the heart, over areas of previous myocardial infarction. As arterial thrombi develop (particularly those in the heart and large arteris where there is high blood flow), they tend to develop alternating layers (lines of Zahn) of fibrin and aggregated platelets which grossly gives the thrombus a grey laminated appearance (white thrombus).

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Cardiac and aortic thrombi

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Tend to be firmly attached to the underlying vessel wall (mural thrombi) and are generally not occlusive.

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Thombi in small arteries (coronary, cerebral, femoral)

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These may be occlusive.

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Lines of Zahn

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Alternating layers of fibrin and aggregating platelets in arterial thrombi.

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Venous thrombi

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These usually form in areas of blood stasis; are typically found in deep leg veins, superficial leg veins, and less commonly in periprostatic, periovarian, and periuterine pelvic venous plexuses; and are frequently occlusive. Since they develop in arease of stasis, there is less tendency to develop lines of Zahn and a greater tendency for red blood cells to become trapped in the developing thrombus to grossly create a dark red-blue appearance (red thrombus).

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Capillary thrombi

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There are usually due to local endothelial damage. They generally consist of platelets and fibrin and are not grossly visible.

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Clinical significance of thrombosis

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The clinical manifestations of thrombosis vary greatly depending on the size, number, location, rapidity of development, and availability of collateral circulation.

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Infarction

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This refers to the process of tissue necrosis secondary to an abrupt reduction in tissue oxygenation. Except for the brain, anoxia results in coagulation necrosis. Infarcts are usually the result of sudden interference with the arterial blood supply to the tissue but, in some instances, they may be due to obstruction of venous drainage or to conditions that decrease the oxygen carrying capacity of the blood. Slowly developing cascular occlusions are less prone to cause infarction since collateral circulation may develop around the obstruction.

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What are most sensitive to the effects of hypoxia/anoxia?

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Tissues that are highly specialized and/or are more metabolically active.

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Clinical significance of infarction

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The effects of the infarct depends on the location and size. A small infarct of the myocardium may be clinically insignificant while a small infarct of the brainstem may be fatal. On the other hand, a large infarct of the cerebral cortex may result only in neurologic deficits while a large infarct of the myocardium may cause sudden death.

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Pale infarct

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In those tissues that have a single blood supply without significant anastomoses (kidney, spleen, heart), occlusion of an artery will result in coagulation necrosis of the tissues supplied by that artery. Since blood perfusion of the tissue is interrupted, the tissue becomes pale.

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Red (hemorrhagic) infarct

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Tissues that have a single blood supply with rich anastomoses (small bowel) or dual blood supply (lung, liver) are somewhat protected against abrupt hypoxia due to the alternate blood source. If necrosis does occur, however, that alternate blood source may bleed into the necrotic tissue creating a red infarct.

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Infarcts that result from venous obstruction

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Tend to be hemorrhagic.

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Infarcts due to arterial occlusion

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Tend to be wedge-shaped with the apex located close to the point of obstruction. Initially they are somewhat ill-defined but become progressively demarcated with time.

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Infarcted tissue will eventually be replaced by:

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Scar tissue

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Disseminated Intravascular Coagulation (DIC)

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This is an acquired disorder complicating a wide variety of disease states particularly obstetric emergencies, malignancies, sepsis, and major trauma. It is a coagulation abnormality involving coagulation factors and platelets.

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Primary mechanism of Disseminated intravascular coagulation (DIC)

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The primary mechanism is activation (by the release of thromboplastic substances into the circulation and/or widespread injury to endothelial cells) of intrinsic and/or extrinsix coagulation pathways in the microcirculation. Numerous fibrin thrombi are formed consuming platelets, fibrinogen, and coagulaations factors and secondarily activating the fibrinolytic system. The microthrombi may lead to microinfarcts of the affected tissue, acute tubular necrosis of the kidneys, and hemolytic anemia while the consumption of clotting factors and activation of the fibrinolytic system may lead to a hemorrhagic diatheses.

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Acute Disseminated Intravascular Coagulation (DIC)

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Patients with acute DIC are more prone to hemorrhagic problems.

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Chronic Disseminated Intravascular Coagulation (DIC)

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Chronic DIC tends to have more problems with thromboses.

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A frequent complication of Disseminated Intravascular Coagulation (DIC)

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Shock is a frequent complication and treatment must be based on the individual patient.

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Laboratory values for Disseminated Intravascular Coagulation (DIC)

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Decreased platelets, an increased bleeding time, increased prothrombin time (PT), increased partial thromboplastin time (aPTT), decreased fibrinogen, and increased fibrin split products (FSP).

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Embolization

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This refers to the process in which an intravascular free-floating mass (embolus) is carried with the blood flow through the vascular system to a point distant to its site of origin or entry. When emboli impact and occlude vessels, infarction of tissue distal to the point of impact will occur. Thromboemboli, like thrombi, may undergo lysis or organization.

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Emboli

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The vast majority of emboli are fragments of preexisting thrombus (thromboembolus) but other material such as air, fat, plaque, etc can act as an emboli if they gain access to the circulation. Emboli will impact and occlude vessels when the diameter of the vessel becomes smaller than the diameter of the embolus.

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Systemic (arterial) Emboli

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80-85% of arterial emboli arise from mural thrombi in the left ventricle or left atrial appendage of the heart but valve vegetation, aortic mural thrombi, etc may also embolize. Depending on the size of the embolus and its site of impaction, it may or may not cause infarction. Major sites of impactioin include lower extremities, brain, kidney, and spleen.

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Pulmonary (venous) Emboli

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These are the third most common cause of sudden death (after myocardial infarct and stroke). More than 95% arise from thrombi in the deep leg veins (popliteal, femoral, iliac), travel through enlarging venous channels, through the right heart, and into the pulmonary arteries. The clinical significance depends on the size and number of the emboli as well as the general cardiovascular status of the patient.

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Fat emboli

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These most frequently occur after long-bone trauma when marrow fat is exposed to the venous circulation. Fat emboli larger than 20 micrometers are filtered in the lung while smaller aggregates may pass through the lung and lodge in brain and/or kidneys. They may give rise, 1-3 days after the trauma, to a potentially lethal clinical syndrome of progressive respiratory distress, CNS impairment (restlessness, confusion, incontinence, and coma) and possible renal dysfunction that is related to the mechanical and chemical effects of fat in the circulation.

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Air Emboli

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These may originate from abortion procedures, traumatic pneumothorax, Caisson disease, etc. While small air bubbles may block the microvasculature, larger amouts (100 cc) may cause "air lock" in the right heart.

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Shock

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The inadequate perfusion and resultant hypoxia of all body tissues.

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Hypovolemic shock

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Acute loss of blood or fluid from circulation may be due to hemorrhage, burns, vomiting, diarrhea, "third-spacing" (shifting of intravascular fluid to extravascular sites)

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Third-spacing

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Shifting of intravascular fluid to extravascular sites

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Cardiogenic shock

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The inability of the heart to maintain adequate output may be due to myocardial infarcts, cardiac tamponade, pulmonary embolic, etc.

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Vascular Shock

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These forms of shock share a common denominator of pooling blood in the peripheral vasculature leading to a central "hypovolemia" and hypoperfusion of vital organs.

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Neurogenic vascular shock

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The inability to maintain peripheral vascular tone with subsequent peripheral pooling of blood may be due to CNS injury or drugs.

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Septic (endotoxic) vascular shock

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Severe gram-negative bacterial infections may profuce endotoxins that cause peripheral vascular pooling. The ensuing shock may also be complicated by direct toxic damage to the vessels and by disseminated intravascular coagulation.

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Anaphylactic vascular shock

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Hypersensitivity reactions may lead to widespread vasodilation (causing peripheral vascular pooling) and increased capillary permeability with fluid loss from the vasculature. Both can lead to hypovolemia and hypoperfusion of vital organs.

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Shock: tissue effects

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Depending on the severity and the duration of tissue hypoxia, there may be necrosis of neurons in the brain, renal tubular epithelial cells (acute tubular necrosis), centrilobular hepatocytes of the liver, and mucosal epithelium of the GI tract (ischemia enteritits).

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Shock: cardiac output

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Except for early septic shock, the other forms of shock result in increased cardiac output which is reflected by a compensatory tachycardia.

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Shock: blood volume

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Whether an actual reduction in blood volume or a "relative" reduction in blood volume from peripheral pooling, this leads to hypotension and a weak, thready pulse. Decreased effective blood volume also stimulates the kidneys to retain sodium and water. This (in addition to acute tubular necrosis) produces Oliguria.

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Shock: blood flow

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In hypovolemic and cardiogenic shock, peripheral vasoconstriction leads to cool, clammy skin. In septic shock, the peripheral vasodilation and increased vascular permeability leads to warm, moist skin. Increased levels of reduced hemoglobin in the peripheral tissues may cause cyanosis.

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Shock: acid/base

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Lactic acidosis develops as a result of the tissue hypoxia and this leads to restlessness, mental obtundation, and a compensatory hyperventilation.

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2 major internal defense mechanisms of the body against potentially injurious agents:

Back 200

1) inflammatory response
2) immunologic response
Leukocytes are involved in these defenses and are initially derived from the bone marrow and then circulate through the peripheral bloodstream and lymphatic system or are "fixed" at certain sites throughout the body.

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Hematopoetic activity

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It orginates in the embryonic yolk sac and in the fetus resides primarily in the liver. By the time of birth, the chief blood producing organ is the bone marrow. In infancy, nearly all the bone marrow is used to make blood, but with age the active bone marrow becomes confined to the vertebral bodies, ribs, sternum, pelvic bones, and epiphyses of the femur and humerus.

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Regulation of the inflammatory/immunologic response

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This is accomplished by a myriad of chemical mediators derived from the leukocytes themselves (cytokines), the blood plasma (components of the complement, kinin, coagulation, fibrinolytic systems), and the injured tissue. The cytokines may consist of preformed cellular products or products synthesized during the inflammatory/immunologic response. These cells also closely react with components of intracellular matrix. The inflammatory response of tissue injury is the first in a series of carefully orchestrated, chemically mediated reations designed to ultimately lead to repair of the damaged tissue. Although this response to injury is classically broke down into acute inflammation, chronic inflammation, and repair, there is significant overlap between the three stages and with the immunologic response.

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Polymorphonuclear leukocytes (granulocytes)

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These are white blood cells containing an irregular lobulated nucleus and large cytoplasmic granules.

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Neutrophils (a polymorphonuclear leukocyte)

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These cells compromise 50-65% of the circulating white blood cells and have a life span of 3-4 days in the blood and 1-2 days in the extravascular tissue. They can phagocytize and destroy bacteria and other minute particulate matter, elaborate chemotactic factors, and produce digestive enzymes to degrade and "mop up" necrotic cellular debris. When activated, neutrophils can also undergo an oxidative burst to produce superoxide free radicals.

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Eosinophils (polymorphonuclear leukocytes)

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These compromise 1-5% of circulating white blood cells and have large eosinophilic cytoplasmic granules. Among other chemical mediators, they can produce major basic protein (MBP) which is toxic to parasites but also epithelial cells. Eosinophils play a prominent role in parasitic diseases, allergic disorders (Type 1 hypersensitivity reactions), and asthma.

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Basophils (polymorphonuclear leukocytes)

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These compromise approximately 1% of circulating white blood cells and have large blue staining cytoplasmic granules which contain MBP and lysophospholipase in addition to serotonin, heparin, and histamine. They carry surface receptors for IgE immunoglobulins and, like neutrophils and monocytes, with the proper stimulus can produce and secrete platelet activating factor (PAF).

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Platelet activating factor (PAF)

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Causes vasodilation, increased permeability of venules, and synthesis of arachidonic acid metabolites.

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Mast cells

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The tissue-bound equivalent of circulating basophils. They secrete mediators (such as histamine) that are important in early inflammatory response. Mast cells are located primarily around small blood vessels and serous membranes.

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Lymphocytes (mononuclear leukocytes)

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These are small cell (slightly larger than red blood cells) consisting primarily of a round hyperchromatic nucleus with very little cytoplasm. They comprise 30-40% of circulating white blood cells and are key mediators of the immune response. They can synthesize chemical mediators (lymphokines) that are involved in lymphocyte recruitment and proliferation as well as other aspects of host defense.

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Monocytes (mononuclear leukocytes)

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4-8% of circulating white blood cells. These are the major source of tissue macrophages. When these cells leave the circulation and enter tissue, the are termed histiocytes when they are in the resting state and macrophages when reacting to a stimulus. These cells act to phagocytize large particulate matter and are also capable of pinocytosis of soluble material. They can be "activated" and "deactivated" according to their microenvironment. They secrete numerous monokines that are important in both the inflammatory and immune host defenses.

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Monocytes are activated by:

Back 211

Gamma interferon

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Monocytes are deactivated by:

Back 212

transforming growth factor B

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Monokines include:

Back 213

acid hydrolases, neutral proteases, chemotactic factors, arachidonic acid metabolites, free radicals, and growth promoting factors.

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Platelets

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These are derived from bone marrow megakaryocytes and enclose electron dense granules that contain vasoactive amines and Ca++; alpha granules that contain platelet derived growth factor and coagulation proteins; and lysosomes that contain acid hydrolases. They are also a source of serotonin.

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Acute inflammation

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This is a defensive action by the host that affords an immediate response to tissue injury.

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Acute inflammatory response

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Consists of a well-orchestrated series of chemically mediated vascular, neurologic, and cellular events which rapidly mobilizes host defenses to mitigate the severity of the injury and prepare the tissue for repair

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Defects of acute inflammation

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A variety of diseases characterized by recurrent infection are the result of defects at various point in this complex process and, like other self-protective mechanisms, premature activation or exuberance of the inflammatory response can itself result in significant tissue damage.

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Local manifestations of acute inflammation include:

Back 218

heat, redness, swelling, pain, and loss of function.

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Vasoconstriction

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In order to retard blood loss and promote coagulation after tissue injury, often there is an immediate but transient, constriction of arterioles. This may be an adrenergic neurogenic response that stimulates smooth muscle contraction.

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Vasodilation

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Soon after, in the area of injury, arterioles rapidly dilate and the precapillary sphincters of nonfunctioning capillary beds are relaxed thereby allowing an increased volume and rate of blood flow (hyperemia) through the tissue. Mediated by histamine, this phenomenon results in the clinically appreciated heat and redness of inflammation.

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Permeability changes

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As hyperemia develops, the vessels become increasingly permeable allowing the escape of fluid and proteins into the interstitium of the tissues which acts as a dilutional agent against toxins or antigens and results in clinically apprecaited swelling.

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Immediate-transient response

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An increase in permeability of venules begins 1-10 minutes after onset of mild injry and lasts 15-30 minutes. This increase in permeability appears to be mediated primarily by serotonin and histamine, although other chemical mediators such as bradykinin may be involved.

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Serotonin is released by:

Back 223

platelets

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Histamine is released by:

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mast cells

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Venular endothelial cells in immediate-transient response

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Venular endothelial cells which normally are continuous and held together by tight junctions have a high concentration of histamine receptors. When stimulated, they contract creating intracellular gaps that allow fluid leakage into interstitial tissue. This response can be modified by anti-histamines. this immediate, but transient response may be followed hourse later by a second prolonged increase in permeability felt to be due to additional cytokine mediated structural effects on the endothelial cells in the area of injury.

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Immediate-sustained response

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This is the response seen with most clinically significant tissue injury and invloves an immediate increase in the permeability of venules, capillaries, and/or arterioles, apparently mediated by direct physical damage to the endothelial cells and vessel walls. On occasion, the increased vasculara permeability may be delayed for many hours presumably the result of delay in endothelial injury or leukocyte activation and usually involves only the capillaries and venules.

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Hemoconcentration and stasis

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As fluid escapes into the surrounding tissues, the concentration of cellular elements remaining inside the vessel walls increases. The normal laminar flow of blood is disrupted and the red blood cells tend to clump together in the center of the vessel while the white blood cells fall to the outer margins and begin to line the endothelial surface, a process called margination.

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Adhesion

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As the blood flow slows down because of the loss of fluid from the vessels, the marginating white blood cells begin to loosely "stick: to and roll along and adhere to the endothelial surface, a process called pavementing. This is accomplished through the expression of a variety of adhesion molecules on the surface of the leukocytes and venular endothelial cells.

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Major families of adhesion molecules are:

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selectins, integrins, immunoglobulin superfamily, and mucin-like glycoproteins. The expression of these molecules is modulated by a variety of factors including cytokines and chemoattractants.

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Emigration (transmigration)

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This is the process by which the leukocytes escape from blood vessels (primarily venules) by squeezing between widened endothelial cell junctions, through the basement membrane, and into the perivascular interstitial tissue. Soon after injury, large numbers of neutrophils escape from the venules to be later followed by monocytes and then lymphocytes. This temporal sequencing may be due to variable expression and selectivity of adhesion molecules as well and the influence of various chemical mediators on specific leukocytes.

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Chemotaxis

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This is an unidirectional migration of cells toward an attractant, usually a chemical substance, along a concentration gradient. Once released from the vasculature, leukocytes migrate toward injury sites as specific surface membrane receptors recognize various chemotactic agents (chemokines). Neutrophils have surface receptors for bacterial products, C5a, arachidonic acid metabolites, and kallikrein while chemotactic products that attract monocyte/macrophages include various lymphokines, platelet-derived growth factor, and C5a. Binding of these receptors ultimately leads to an increase in intracellular Ca++ which activates contractile elements of the cytoskeleton. As the chemotactic gradient increases, Ca++ influx persists and membrane phospholipids are converted to arachidonic acid metabolites. There is also degranulation of storage vesicles and formation of free radicals within the leukocytes.

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Aggregation

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The type of cells that aggregate at a site of injury depends somewhat on the causative agent of that injury and may reflect a sequential release of cell-specific chemotactic factors. In general, with acute inflammation, neutrophils arrive at the site of injury first. Later, the slow moving macrophages and lymphocytes arrive. In viral and rickettsial infections lymphocytes are the predominant inflammatory cell, and in allergic hypersensitivity reactions and parasitic infections, eosinophils may predominate.

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Phagocytosis

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This is a clearing mechanism for particulate material form a site of injury characteristic of neutrophils and monocytes (macrophages) and involves 3 stages.

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Stage 1 of phagocytosis: recognition and attachment

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This may require serum derived opsonins, including complement fragments and specific subtypes of IgG, to coat the surface of the "inductee". These opsonins are recognized and bound by receptors on the leukocyte membrane.

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Stage 2 of phagocytosis: engulfment

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This occurs by pseudopodial extensions of the cell cytoplasm which completely enclose the foreign particle. Fusion of this phagosome with one or more cytoplasmic lysosomes forms a phagolysosome which is a necessary prelude to intracellular killing and degradtion. Attachment of lysosomes to an incompletely ingulfed phagosome may lead to discharge of degradative enzymes into the extracellular tissue inadvertently causing further tissue damage.

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Stage 3 of phagocytosis: killing and/or degradation

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Strong antimicrobial activity is provided by oxygen-dependent and oxygen-independent mechanisms. The production of hydrogen peroxide, reactive oxygen metabolites, and nitrous oxide are bactericidal. The H2O2-myeloperoxidase-halide system of neutrophils in which the azurophilic granules containing myelperoxidase are emptied into phagolysosomes and react with H2O2 and Cl- to form HOCl is lethal to susceptible organisms. Acid hydrolases contribute to the ultimate degradation of bacteria and other particales within the phagolysosome.

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Chronic granulomatous disease of childhood

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An inherited disorder in which the mechanism of killing/degradation of phagocytosis is impaired.

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Lysosomal enzymes, free radicals, and arachidonic acid metabolites may all be released into the extracellular space during phagocytosis causing:

Back 238

Although this can intensify or perpetuate the inflammatory response, it may also cause considerable tissue injury through endothelial damage, inactivation of antiproteases, and activation of antioxidants.

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Serous inflammation

Back 239

This is often the result of mild injury and consists of the extravasation of an exudate derived from serum or the mesothelial cells lining the body cavities. Example: cutaneous blisters

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Catarrhal inflammation

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This is associated with a profuse excretion of watery or mucoid fluid from a mucous membrane. Example: runny nose

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Fibrinous inflammation

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This results in a fibrin-rich exudate which forms shaggy fibrin strands that may ultimately produce adhesions. Example "bread and butter" pericarditis

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Serosanguinous or hemorrhagic inflammation

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This occurs with highly virulent or fulminating infections where extensive vascular damage occurs resulting in the extravasion of red blood cells. Example: meningococcal septicemia

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Suppurative (purulent) inflammation

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This indicates the presence of pus which consists of tissue breakdown products, neutrophils, and in most cases microorganisms. Example: furuncles, carbuncles

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Abscess

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This is a localized collection of pus associated with liquefaction necrosis of tissues

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Empyema

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This is a localized collection of pus in a natural anatomic cavity (usually pleural cavity).

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Ulcerative inflammation

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This refers to a localized sloughing of inflammatory and necrotic debris from cutaneous or mucosal surfaces. Example: decubitus ulcer, peptic ulcer

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Gangerous inflammation

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This implies enzymatic and bacterial decomposition (putrefaction) of necrotic tissue. Example: gangrene associated with diabetic vascular disease

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Membranous or pseudomembranous inflammation

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This refers to the formation of "membranes" composes of matted fibrin, mucus, and inflammatory cells on focally necrotic epithelial surfaces. Example: pseudomembrane of diphtheria or clostridia infections

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Systemic manifestations of acute inflammation

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These may include fever, shaking chills, weakness, and muscle aching.

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Laboratory findings of acute inflammation

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Any inflammation of clinical significance is usually reflected by an increase in the total number of leukocytes circulating in the peripheral blood which is called leukocytosis. (normal= 6,000-8,000/ml. in blood)

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Leukocytosis

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May be accompanied by increased percentage of immature neutrophils in the peripheral blood ("left shift").

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Leukemoid reactions

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Extreme elevations of the white blood cell count are referred to as leukomoid reactions and may approach the leukocyte counts encountered in some leukemias.

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Chronic inflammation

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This may arise following an acute inflammatory reaction in which the inciting agent is not destroyed or with repetitive bouts of acute inflammation. Chronic inflammation may begin as a low grade, smoldering response to persistent infection by organisms with low virulence (tuberculosis), prolonged exposure to nondegradable but toxic substances (silicosis), or autoimmune reactions (rheumatoid arthritis) without ever showing the classical signs of acute inflammation. In any event, the host response is more an immunologic response than an acute inflammatory response. In some instances, acute and chronic inflammation may coexist for long periods of time.

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Chronic nonspecific inflammation

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Characterized by a proliferative (fibroblastic) response rather than the exudative response seen in acute inflammation. The inflammatory cells are primarily mononuclear (macrophages, lymphocytes, and plasma cells) rather than polymorphonuclear cells seen in acute. Chemotactic mediators (lymphokines) attract and then immobilize additional mononuclear cells at the site of injury. They are interspersed among the proliferating fibroblasts and capillaries that are preparing for tissue repair. Chronic inflammation is often associated with subsequent scarring and structural and/or functional impairment of the involved tissue.

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Granulomatous inflammation

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A specific pattern of chronic inflammation which may occur in response to a variety of agents (esp, mycobacteria, foreign bodies, fungi) which are indigestible or have low antigenicity. They may also be seen in "immunologic" disorders.

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Granulomas

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The pathologic hallmark of granulomatous chronic inflammation and consist of small, nodular (1-2 mm) collections of modified macrophages known as epithelioid cells. These are almost invariably surrounded by a rim of fibroblasts and mononuclear cells, principally lymphocytes. There may or may not be central ceseous necrosis. Giant cells (formed by a syncytium or fusion of epithelioid cells) are often, but not always, found within the granuloma.

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Immunologic response

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May be evoked by any molecule (antigen) which the body perceives as "foreign".

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Antigen

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Most antigens are protein molecules. The ability of an antigen to evoke an immune response is determined by its size, shape, solubility, and chemical structure.

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HLA antigens

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"self" antigens that all cells (except red blood cells) of an individual have expressed on their cell membrane. No two people (except identical twins) have identical HLA antigens on their cells. During embryonic life, lymphocytes that are capable of reacting to an individual's "self" antigens are destroyed, and the immune system is therefore "programmed" to recognize "self".

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T-lymphocytes (T-cells)

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These compromise the majority (75%) of circulating lymphocytes in the peripheral blood. They are programmed by the thymus gland, through the process of gene rearrangement, each T-lymphocyte acquires a unique DNA sequence for its surface T-cell antigen receptor. After released from the thymus, they circulate in the blood and also populate the paracortical regions of lymph nodes and the white cell sheaths around the splenic arterioles. Based on differences in cell surface proteinss, functionally distinct subpopulations of T-cells have been identified.

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B-lymphocytes

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These compromise about 15% of circulating lymphocytes and represent lymphocyes that have been "prgrammed" in the bone marrow. They make up the germinal centers of lymph nodes and also reside in the splenic white pulp. When faced with an antigenic challenge, these cells, with the help of T-cells, mature into plasma cells capable of producing antibodies (immunoglobulins) directed against that specific antigen, or they become B-memory cells.

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T and B-lymphocytes

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They circulate throughout the vascular and lymphatic systems or take up residence in peripheral lymphoid organs and tissues. These peripheral organs and tissues function to identify and process "non-self" antigens so that an immune response can be mounted against them.

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Lymph nodes monitor:

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the lymphatic system

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Spleen monitors:

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the blood

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Mucosal associated lymphoid tissue (MALT) monitors:

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Substances traversing the various mucous membranes

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Specialized cells (Langerhan's cells) monitor:

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Substances traversing the skin.

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T-cytotoxic cells (CD8+)

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These will directly attack cells that contain antigen perceived as foreign. They are particularly effective against viruses and fungi, and are largely resposible for transplant rejection.

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T-helper cells (CD4+)

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These augment antibody production by stimulating B-cell proliferation and differentiation into plasma cells.

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T-suppressor cells (CD8+)

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These may dampen antibody production against a specific antigen by inhibiting B-cell proliferation or by restraining T-helper cell acctivity.

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T-memory cells

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These confer life-long memory of specific antigens so that with re-exposure to that antigen, the time delay needed for processing of the antigen is averted.

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Plasma cells

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Are tissue-based and do not circulate in the peripheral blood. They are formed from B-cells with the help of T-cells.

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Natural killer (NK) cells

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These compromise about 10% of ciculating lymphocytes and have a "mixed bag" of membrane markers. Their function is not dependent on antigen stimulation. They are directly cytotoxic and act by binding to foreign cells and lysing the cell membrane through the action of various secreted lymphokines. They are important in transplant rejection, destruction of virally-infected cells, and tumor surveillance.

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Cell-mediated immune response

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This is the process in which an antigen, having been processed by macrophage and presented to a T-lymphocyte, evokes the production of "activated" T-lymphocytes (cytotoxic T-cells) which will directly attack and bind to that specific antigen.

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Humoral immune response

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This is the process in which an antigen evokes the production of circulating antibodies to that antigen.

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Basic structure of an immunoglobulin (antibody):

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4 polypeptide chains; 2 heavy chains and 2 light chains held together by disulfide bonds. At the carboxyl end of the protein chain, both the light chains and heavy chains have a region of constant amino acid structure that directs their biologic activity and subclassifies the light chains as either kappa or lamda chains and the heavy chains as either IgM, IgG, IgA, IgE, or IgD. Toward the amino end of the protein chain, each light chain and heavy chain also has a region of variable amino acid sequencing that allows antigens specificity.

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Fc portion of the immunoglobulin

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Predominantly the region of constant amino acid sequence. Will bind to Fc receptors on phagoctytic cells. It can also initaite the complement cascade resulting in acute inflammatory reaction.

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Fab portion of the immunoglobulin

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Predominantly the region of variable amino acid sequencing. Bind to the antigen.

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IgM

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This is the class of immunoglobulins first formed in response to an antigenic challenge and is comprised of 5 basic immunoglobulin structural units held together by a short polypeptide chain (J chain). It is effective in agglutinating antigen, activating compliment, and lysing cell walls.

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IgG

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Although the smallest immunoglobulin in terms of molecular weight, IgG comprises over 85% of the circulating antibodies and is the only immunoglobulin which can cross the placenta from mother to fetus. Receptors for the Fc prtion are found on macrophages, neutrophils, lymphocytes, and eosinophils. Although several subtypes of IgG with slightly different biologic functions exist, a mjor function is to serve as opsonins to enhance phagocytosis.

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IgA

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This is present in the blood but is also secreted onto mucosal surfaces (esp. respiratory and GI) as a dimeric structure known as secretoty IgA which helps protect against mucosal invasion by microorganisms.

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IgE

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This mediates allergic reactions and does not circulate in the blood. It is found primarily in tissue bound to mast cells in and around respiratory and intestinal mucosa.

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IgD

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The function is largely unknown. It is found on the surgace membranes of B-lymphocytes and may play a role in the development and maturation of the humoral immune system.

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Antibody response

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The initital B-cell response to an antigenic challenge results in the production of IgM antibodies which first appear after a lag time of several days, reach a peak at about 2 weeks, and then decline. The more antigen-specific IgG antibodies appear around day 10, reach a higher peak, and remain at a high level for a longer period of time. The T-cells may also interact to regulate the B-cell response. T-helper cells can supress the B-cell response. T-cells also enable the activated B-cells, during their maturation into plasma cells, to switch from the initial IgM antibody production to IgG antibody production.

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Immunologic memory

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The long-lived T and B-memory cells which are also produced after the first exposure to an antigen enable the immune response, upon subsequent exposure to that antigen to react more rapidly and to produce greater quantities of antibody (primarily IgG) and/or activated T-cells then occurs with the initial response (the anamnestic response).

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Thymic aplasia (DiGeorge syndrome)

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This results from embryologic failure of the thymus and parathyroid glands to develop. These persons are unable to develop a T-lymphocyte immune response and therefore lack cellular immunity. In addition, because of the lack of T-helper cells, antibody production may be impaired as well. These persons are especially vulnerable to viral and fungal infections.

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Infantile agammaglobulinemia (bruton agammaglobulinemia)

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This is a sex-linked recessive disease in which there is failure of B-cell maturation and therefore failure of the humoral response system. These persons have very small quantities of immunoglobulin in their serum and are vulnerable to severe bacterial infections.

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Alymphocytic agammaglobulinemia (swiss type agammaglobulinemia, severe combined immunodeficiency disease)

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This is an autosomal recessive inherited disease in which there is a defect in the lymphocyte stem cell population. There is a marked decrease in the number of both T and B-lymphocytes as well as thymic hypoplsia and poorly developed lymphoid tissues. Therefore, there is neither a humoral nor a cellular immune mechanism. Unless bone marrow transplantation is successful, these persons usually die early in childhood from recurrent severe infections.

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Acquired immunodeficiency syndrome (AIDS)

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This is a result of lymphocyte (primarily helper T-celll) destruction by the human immunodeficiency virus. Monocytes and their derivatives may also be affected. This interferes with both humoral and cellular immunity, and these patients are therefore susceptible to a wide variety of infections. They also have an increased incidence of lymphoid malignancies.

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Hypersensitivity reactions

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Immune responses injurious to the host. They can be divided into 4 categories depending on the mechanism of tissue damage involved.

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Type 1 hypersensitivity reaction (anaphylaxis/atopy)

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Humoral immune response. This occurs most commonly in tissues exposed to external antigens (skin, respiratory tract, GI tract). In this reaction, there are no symptoms on first exposure to the antigen, but B-cells produce IgE antibody to the antigen. The IgE antibodies are then bound to the Fc surface membrane receptors of mast cells and basophils. On second exposure, the antigen reacts with the bound IgE and there is immediate release of histamine and chemotactic chemicals from the mast cell granules initiating the typical allergic response. There is also a delayed or late-phase response produced by the release of leukotrienes. Allergic asthma, utricaria (hives), food allergies, hayfever, and life-threatening anaphylaxias are a few of the disorders mediated by this mechanism.

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Type II hypersensitivity reaction (cytotoxic/cytolytic hypersensitivity)

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Humoral immune response. In this reaction, circulating antibodies (primarily IgG and IgM) attack antigens that are bound to, or are a component of, another cell's membrane or a component of extracellular tissue. Antigen-antibody interaction promotes destruction of the target cell by phagocytosis or lysis of the cell membrane. Autoimmune hemolytic anemias, hemolytic disease of the newborn, blood transfusion reactions, and certain drug reactions are mediated by this mechanism. Antibodies may also attach to target cells receptors and block their activity as seen in myasthenia gravis.

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Type III hypersensitivity reaction (immune complex disease)

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Humoral immune response. Antigen normally reacts with antibody to form an antigen-antibody (immune) complex which is rapidly cleared from the circulation and tissue spaces by phagocytic cells. Under certain conditions, these complexes may not be eliminated and become deposited in tissue. The antigen-antibody complexes may be localized or, in the case of circulating antigen-antibody complexes be deposited in numerous areas of the body. The complement cascade is activated by reaction of C1 with an antigen-antibody complex. The byproducts of the cascade act variously to promote vascular permeability, phagocytosis, chemotaxis of inflammatory cells, and lysis of cell membranes. Post-infectious glomeruloephritis, systemic lupus erythematosus (SLE), immune vasculitis and other "autoimmune" diseases are mediated by this mechanism.

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Type IV hypersensitivity reaction (delayed hypersensitivity, cell-mediated hypersensitivity)

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Cell-mediated immune response. In this reaction, after processing by macrophages, antigen reacts not with circulating antibodies, but with specifically activated T-lymphocytes. Macrophages transform into 'epithlioid' cells and the resultant release of cytokines (especially interferon gamma) enhaces the inflammatory response to the antigen (delayed hypersensitivity) often resulting in granulomatous inflammation complete with giant cells. Alternatively, there may be direct T-lymphocyte mediated target cell destruction without granuloma formation. TB skin tests, certain aspects of graft rejection, sarcoidosis, and other "autoimmune" diseases are mediated by type IV hypersensitivity.

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Transplant/graft rejection

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Rejection involves both humoral and cell-mediated mechanisms.

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Hyperacute transplant/graft rejection

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Occurs within minutes and is mediated by preformed antibody reacting to graft endothelial cells. This leads to extensive fibrinoid necrosis of small vessels, thrombosis, and acute inflammation.

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Acute transplant/graft rejection

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Does not begin until days or weeks have passed and can be mediated by humoral and.or cell-mediated mechansisms. Sensitized lymphocytes react to foreign graft proteins (especially class I HLA antigens) and release lymphokines chemotactic for macrophages and neutrophils. T-cells targer the foreign cells and help augment B-cell antibody production.

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Chronic transplant/graft rejection

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Occurs after months or years and is the result of slow humoral mediated damage to the vasculature.

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Autoimmune disease

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These diseases appear to result from an immune response mounted against the body's own tissue antigens. They range from tissue specific diseases to systemic diseases. Most of these diseases have demonstrable circulating autoantibodies and/or sensitized T-cells which may be directed against almost any circulating or tissue antigen which is recognized as "foreign". These may be specific cell surface antigens, immunoglobulins, DNA, etc. Inherited genetic susceptiblity plays a role in the development of autoimmune disease in some individuals while certain microbial infections may play a role in other cases,