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418 Cards in this Set
- Front
- Back
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increase in size of an organ or tissue due to an increase in the size of cells
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hypertrophy
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cause of hypertrophy
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increased workload
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increase sin size of an organ or tissue caused by an increase in the number of cells
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hyperplasia
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example of hyperplasia
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glandular proliferation during pregnancy
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failure of cell production
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aplasia
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absence of an organ due to aplasia
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agenesis
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decrease in cell production that is less extreme than aplasia
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hypoplasia
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decrease in the size of an organ or tissue from a decrease in the mass of preexisting cells
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atrophy
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causes of atrophy
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disuse
nutrition/oxygen deprivation diminished endocrine stimulation denervation aging |
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intracytoplasmic vacuoles containing debris from degraded organelles
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autophagic granules
sign of atrophy |
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replacement of one differentiated tissue by another
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metaplasia
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replacement of epithelium with squamous cells, often in areas with chronic irritation
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squamous metaplasia
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formation of new bone at sites of tissue injury
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osseous metaplasia
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proliferation of hematopoietic tissue at sites other than bone marrow such as liver or spleen
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myeloid metaplasia
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causes of hypoxic cell injury
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ischemia: obstruction of blood flow
anemia: reduced number of O2 carrying RBCs CO poisoning: chemical alteration of Hemoglobin resulting in reduce O2 carrying capacity decreased perfusion of tissues by O2 carrying blood poor oxygenation of blood (pulmonary disease) |
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signs of early stage hypoxic cell injury aka decreased ATP availability
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failure of cell membrane pump (NaKATPase pump) causing
cellular swelling (hydropic change), swelling of ER, swelling of mitochondria, disaggregation of ribosomes- failure of protein synthesis stimulation of phosphofructokinase activity: increased glycolysis, accumulation of lactate, decreased intracellular pH |
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signs of late stage hypoxic cell injury
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plasma, lysosome,and organelle membrane damage (loss of phospholipids)
formation of myelin figures cell blebs- disordered cytoskeleton |
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cell death
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irreversible damage to cell membranes leading to massive Ca influx and extensive calcification of mitochondria
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enzymes used in the diagnosis of MI
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aspartate aminotransferase (AST or SGOT)
Lactate dehydrogenase Creatine kinase troponins myoglobin |
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necrotic cells release _______ into circulation due to loss of cell membrane integrity
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intracellular enzymes and other proteins
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enzymes released due to liver damage
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alanine aminotransferase (ALT)
alkaline phosphatase gamma-glutamyltransferase (GGT) |
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cell tolerance to hypoxia:
neuron cardiac/liver cells muscle |
neuron: 3-5 minutes
heart/liver: 1-2 hours skeletal muscle: many hours |
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molecules with single unpaired electrons in the outer orbital
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free radicals
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examples of free radicals
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superoxide, hydroxyl radical
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how are free radicals generated?
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metabolism
oxygen toxicity ionizing radiation UV light drugs and chemicals: use P450 system reperfusion after ischemic injury |
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mechanisms that degrade free radicals
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intracellular enzymes like glutathione peroxidase, catalase, superoxide dismutase
spontaneous decay exogenous and endogenous antioxidants (vit. A, C, E, cysteine, glutathione, selenium, ceruloplasmin, transferin) |
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sum of degradative and inflammatory reactions occurring after tissue death caused by injury within a living organism
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necrosis
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degradative reactions in cells caused by intracellular enzymes indigenous to cell
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autolysis
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cellular degradation by enzymes derived from sources extrinsic to cell
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heterolysis
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degradative reaction in cells by intracellular enzymes AFTER DEATH of entire organism
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postmortem autolysis (not necrosis)
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type of necrosis caused by a sudden cutoff of blood supply to an organ supplied by end arteries with limited collateral circulation.
esp. heart and kidney |
coagulative necrosis
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tissue changes in coagulative necrosis
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-preservation of tissue architecture
-increased cytoplasmic eosinophilia (protein denaturation, loss of cytoplasmic RNA) -nuclear changes: |
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morphological hallmark of irreversible cell injury
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nuclear changes
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chromatin clumping and shrinking with increased basophilia
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pyknosis
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fragmentation of chromatin
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karyorrhexis
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fading of chromatin material
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karyolysis
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necrosis caused by ischemic injury to central nervous system including suppurative infection
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liquefactive necrosis
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necrosis caused by vascular occlusion and most often affects lower extremities
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gangrenous necrosis
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when gangrenous necrosis is complicated by infective heterolysis and consequent liquefactive necrosis
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wet gangrene
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necrosis that occurs as part of granulomatous inflammation
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caseous necrosis
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infection characterized by the formation of pus (liquefied tissue debris and neutrophils)
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suppurative infection
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leading cause of caseous necrosis
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TB
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necrosis with cheese like consistency
histologically: amorphic eosinophilic apearance |
caseous necrosis
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when gangrenous necrosis occurs without liquefaction
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dry gangrene
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deposition of fibrin like proteinaceous material in arterial walls
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fibrinoid necrosis
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necrosis caused by severe injury to tissue with high fat content
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traumatic fat necrosis
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complication of acute hemorrhagic pancreatitis, causes a release of proteolytic and lipolytic pancreatic enzymes that digest the parenchyma, fatty acids are released forming calcium salts (saponification)
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enzymatic fat necrosis
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programmed cell death
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apoptosis
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extrinsic pathway of apoptotic initiation of apoptosis
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death receptors are members of TNF receptor family that contain a cytoplasmic domain involved in protein interactions
mediated by FAS receptor activating procaspase |
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intrinsic or mitochondrial pathway of apoptosis
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increased mitochondrial permeability and release of pro-apoptotic molecules into cytoplasm (no role for death receptors)
Growth factors and other signals stimulate production of anti-apototic members of BCL-2 family of proteins |
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apoptosis by direct activation of caspases by granzyme B (T-cell protease that activates the caspase cascade)
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cytotoxic T-cell activation
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anti-apoptotic signals
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GF, BCL-2, BCL-x family of proteins
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the final phase of apoptosis is mediated by a proteolytic cascade of which enzymes?
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caspase
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caspase
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c: cysteine protease
aspase: ability to cleave aspartic acid residues proteolytic cascade of apoptosis |
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importance of caspases
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prompt clearance of apoptotic cells before they undergo secondary necrosis and release cellular contents resulting in inflammation
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tumor suppressor gene, accumulates when DNA is damaged and arrests cell cycle in G1 phase to allow time for repair.
If no repair occurs, triggers apoptosis |
p53
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apoptosis due to growth factor deprivation
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growth factor deprivation: (hormone sensitive cells, lymphocytes not stimulated by antigens/cytokines, neurons deprived of growth factors)
triggered by intrinsic (mitochondrial) pathway too many pro-apoptotic members related to anti-apoptotic Bcl family |
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DNA damage mediated apoptosis
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DNA damage (genotoxic stress)
p53 acculumates when DNA is damaged and arrests cell cycle in G1 phase if DNA repair fails, p53 triggers apoptosis |
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apoptosis induced by tumor necrosis factor family of receptors
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cell surface receptor FAS induces apoptosis when it is engaged by Fas ligand which is produced by cells of immune system
important in recognizing self antigens |
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Cytotoxic T-lymphocyte mediated apoptosis
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kill target cell by directly inducing the effector phase of apoptosis
CTLs secrete perforin (transmembrane pore forming molecule) which allows entry of CTL granule granzyme B GRANZYME B CLEAVES ASPARTATE residues and ACTIVATES cellular CASPASES |
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dysregulated apoptosis
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defective apoptosis and increased cell survival
increased apoptosis and excessive cell death |
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subcellular responses to injury
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lysosomal catabolism: heterophagy (endocytosis, phagocytosis, pinocytosis); autophagy (autophagic vacuole, autophagolysome)
induction of smooth ER mitochondrial alterations (change in membrane permeability) cytoskelal abnormalities |
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examples of induction or hypertrophy of smooth ER
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drug tolerance
detoxification |
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examples of cytoskeletal abnormalities
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thin filaments (movement)
microtubules intermediate filaments (maintain cell shape) |
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intracellular accumulations
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normal cellular constituents: water, lipids, proteins, carbs
abnormal substance (exogenous: mineral, infectious agent products or endogenous: abnormal synthesis or metabolism) pigment |
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reasons for abnormal intracellular accumulations
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1. endogenous substance is produced at a normal rate but rate of metabolism is inadequate to remove it.
2. accumulates due to genetic or acquired defects in metabolism, transport, packaging, or secretion. 3. exogenous substance accumulates because cell is unable to degrade it or transport it to other sites |
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cholesterol deposit examples
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atherosclerosis
xanthomas Niemann pick disease |
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lipid accumulation
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fatty liver- most often due to alcohol abuse
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protein accumulation examples
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amyloidosis
due to defects in protein folding |
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hyaline accumulation
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collagenous fibrous tissue in old scars may appear hyalinous
in HTN and DM the walls of arterioles esp. in kidney become hyalinized |
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glycogen accumulation
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in DM: found in kidney tubules
glycogen storage disease |
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pigment accumulation
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exogenous pigments: tatoos, coal dust
endogenous: lipofusin, melanin, hemosiderin/rust |
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dystrophic calcification
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necrosis and damaged tissues
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metastatic calcification causes
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increase PTH
destruction of bone vitamin D related disorders renal failure |
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structural and biochemical changes with aging
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decreased repair
decreased synthesis less efficient organelles |
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what is replicative senescence?
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cells become arrested after a fixed number of cell divisions
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prolonged life span due to _____ receptor in response to __________
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IGF-1
decreased caloric intake |
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general pathology
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reactions of cells and tissues to abnormal stimuli that underly all diseases
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special pathology
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specific responses of specialized organs and tissues to more or less well defined stimuli
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4 aspects of disease that form the core of pathology
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etiology
pathogenesis morphologic changes clinical manifestations |
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etiology
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cause:
intrinsic or genetic acquired: environment |
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pathogenesis
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sequence of events from initial stimulus to expression
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morphologic changes
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structural alteration in cells or tissues that are either characteristic of the disease or diagnostic
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father of modern pathology
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Rudolf Virchow
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pathologic hyperplasia
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excessive hormonal stimulation or growth factors acting on target cells
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cause of hyperplasia
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increased production of growth factors and hormones and transcription factors
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increase in size of cells
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hypertrophy
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increase in number of cells
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hyperplasia
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shrinkage in size of cell by loss of cell substance
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atrophy
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causes of pathologic atrophy
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decreased workload (disuse)
loss of innervation (denervation) diminished blood supply (ischemia) |
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what is replicative senescence?
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cells become arrested after a fixed number of cell divisions
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prolonged life span due to _____ receptor in response to __________
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IGF-1
decreased caloric intake |
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general pathology
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reactions of cells and tissues to abnormal stimuli that underly all diseases
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special pathology
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specific responses of specialized organs and tissues to more or less well defined stimuli
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4 aspects of disease that form the core of pathology
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etiology
pathogenesis morphologic changes clinical manifestations |
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etiology
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cause:
intrinsic or genetic acquired: environment |
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pathogenesis
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sequence of events from initial stimulus to expression
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morphologic changes
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structural alteration in cells or tissues that are either characteristic of the disease or diagnostic
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father of modern pathology
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Rudolf Virchow
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pathologic hyperplasia
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excessive hormonal stimulation or growth factors acting on target cells
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cause of hyperplasia
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increased production of growth factors and hormones and transcription factors
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increase in size of cells
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hypertrophy
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increase in number of cells
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hyperplasia
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shrinkage in size of cell by loss of cell substance
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atrophy
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causes of pathologic atrophy
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decreased workload (disuse)
loss of innervation (denervation) diminished blood supply (ischemia) inadequate nutrition (marasamus, cachexia) loss of endocrine stimulation aging (senile) pressure |
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example of physiologic atrophy
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during development
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mechanism of atrophy
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increased protein degradation
acid hydrolases from lysosomes released to degrade endocytosed proteins ubiquitin proteasome pathway hormones (glucocorticoids, thyroid hormones) stimulate proteasome mediated protein degradation (insulin opposes) cytokines like TNF increase proteolysis |
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histological change in atrophy
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increased number of autophagic vacuoles
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reversible change from one cell type to another
reaction due to chronic irritation |
metaplasia
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most common example of metaplasia
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change in respiratory tract from columnar to squamous epithelium
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Barrett esophagus
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change from squamous to columnar cells due to gastric acid reflux
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3 ways free radicals can damage cells
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1. lipid peroxidation of membranes (oxygen damages double bonds in polyunsaturated membrane lipids)
2. DNA fragmentation (react with thymine in nuclear and mitochondrial DNA) 3. protein cross linking (promote sulfhydryl mediated protein cross-linking resuling in increased degradation) |
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mitochondrial dysfunction
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increase cytosolic Ca associated with ATP depletion results in increased CA uptake into mitochondria activating phospholipase and leading to phospholipid breakdown
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reversible cell injury
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plasma membrane alterations
mitochondrial changes dilation of ER nuclear alterations |
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morphological changes following cell death in a living tissue
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necrosis
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What happens in acetaminophen poisoning
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acetaminophen is detoxified into a highly toxic metabolite by cytochrome p-450
the metabolites are detoxified by interaction with GSH When GSH is depleted the toxic metabolites accumulate and destroy nucleophilic macromolecules causing massive liver cell necrosis 3-5 days after ingestion treatment: N-acetylcysteine activated charcoal |
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loss of membrane integrity, enzymatic digestion of cells, and frequently a host reaction
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necrosis
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cell plasma membrane remains intact but structure is altered so it becomes a target for phagocytosis
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apoptosis
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morphological features of apoptosis
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cell shrinkage
chromatin condensation cytoplasmic blebs phagocytosis |
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human genome
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approximately 20,000-25,000 human genes
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study of chromosomes
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karyotyping
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karyotype staining
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use Giemsa staining- G banding
metaphase spread arranged long to short |
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karyotype notation
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total number of chromosome, sex chromosome complement, description of abnormalities in ascending numerical order
p: petit arm q: long arm banded regions are numbered from the centromere outward |
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major categories of genetic disorders
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1. chromosome abnormalities (ex. trisomy)
2. single-gene disorders (ex. cystic fibrosis, marfan, sickle cell anemia, huntingtons) (inheritied in recognizable patterns) 3. multifactorial disorders (combo of mutations and environment) 4. mitochondrial disorders (really multifactorial) (mutations in the nonchromosomal DNA of mitochondria) |
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most common of the chromosomal disorders and major cause of metal retardation
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Trisomy 21- Down syndrome
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increased risk of trisomy 21:
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advanced maternal age (meiotic nondisjunction of chromosome 21)
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clinical features of Down syndrome
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flat facial profile
oblique palpebral fissures epicanthic folds congenital heart disease leukemia risk abnormal immune response reduced life span (now median age of death- 47) mental retardation intestinal stenosis gap between 1st and 2nd toe umbilical hernia abundant neck skin |
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XXY
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Klinefelter syndrome: male hypogonadism with 2 or more X chromosomes and 1 or more Y chromosomes
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most common cause of hypogonadism in the male
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Klinefelter's syndrome
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signs of Klinefelter syndrome
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eunuchoid body habitus
abnormally long legs small atrophic testes lack secondary male sex characteristics gynecomastia IQ slightly lower rarely diagnosed before puberty elevated FSH levels low testosterone high estradiol |
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monosomy of X chromosome
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Turner syndrome
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most common sex chromosome abnormality in females:
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Turner syndrome
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Signs of Turner syndrome
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hypogonadism in females
edema of dorsum of hand and foot swelling of nape of neck- distened lymphatic channels- cystic hygroma -bilateral neck webbing and persistent looseness of skin on back of neck -Congenital heart disease -preductal coarctation of aorta and bicuspid aortic valve -failure to develop normal secondary sex characteristics at puberty -normal mental status -shortness of stature -most important cause of primary amenorrhea -hypothyroidism -glucose intolerance -insulin resistance -obesity -treatment: GH- worsens insulin resistance -broad chest -wide spaced nipples -pigmented nevi -streak ovaries -cubitus valgus |
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determinant of genetic sex
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Y chromosome
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sex based on histologic characteristics of gonads
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gonadal sex
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gender depending on presence of mullerian or wolffian ducts
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ductal sex
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sex based on appearance of external genitalia
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phenotypic or genital sex
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disagreement between criteria for determining sex
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sexual ambiguity
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true hermaphrodite
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presence of both ovarian and testicular tissue
very rare may have ovaries on one side and testes on other or ovotestes- mix of tissue |
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pseudohermaphrodite
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disagreement between phenotypic and gonadal sex
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female pseudohermaphroditism
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XX
development of ovaries and internal genitalia is normal external genitalia- ambiguous or virilized- exposure to androgenic steroids during gestation Congenital adrenal hyperplasia |
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male pseudohermaphroditism
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possess a Y chromosome
Gonads are testes genital duct or external genitalia are incompletely differentiated- ambiguous or female ext. genitalia defective virilization of male embryo due to genetically determined defects in androgen synthesis or action |
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molecular basis of disorder
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enzyme defects
defects in receptors or transport systems alteration in nonenzyme proteins adverse reactions to drugs |
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enzyme defect diseases
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phenylketonuria
tay-sachs SCID Lesch-Nyhan syndrome alpha-1 antitrypsin deficiency |
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phenylketonuria
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inability to convert phenylalanine to tyrosine
most often in caucasians (scandinavian) severe mental retardation by 6 months treated with diet 90% of children born to such women are mentally compromised with congenital defects |
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Tay-Sachs disease
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gangliosidosis
sphingolipidoses- group of lysosomal storage diseases Ashkenazi jews mental deteriorization at 6 months of age cherry red spot on macula muscle flaccity, blindness, pathetic vegetative state |
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severe combined immunodeficiency
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defects in both cell mediated and humoral immune responses
infants with thrush, rash, failure to thrive defects in T cell with secondary effects on humor immunity X linked recessive (more common in boys) or caused by an autosomal recessive deficiency of adenosine deaminase- toxic to T cells |
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Lesch-Nyhan syndrome
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x-linked
lack of hypoxanthine guanine phosphoribosyl transferase (HGPRT) in males with an increase in uric acid HGPRT- used in salvage pathway of purine synthesis resulting in an increase in de novo synthesis hyperuricemia, neurologic deficits, mental retardation, self-mutilation, gouty arthritis |
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alpha-1 antitrypsin deficiency
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failure to inactivate neutrophil elastase in lungs-> destruction of elastin in walls of lung alveoli
pulmonary emphysema |
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single gene disorder
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familial hypercholesterolemia
vitamin D resistance Cystic Fibrosis Sickle Cell anemia Thalassemias |
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familial hypercholesterolemia
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mutation in the gene encoding the receptor for LDL which is involved in the transport and metabolism of cholesterol
loss of feedback control premature atherosclerosis increased risk of MI tendinous xanthomas |
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most frequent mendelian disorder
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familial hypercholesterolemia
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genetic inheritance of familial hypercholesterolemia
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heterozygotes: 50% of normal LDL receptors
homozygotes: virtually no normal LDL receptors (MI before age 20) both have decreased clearance and increases synthesis of LDL also have impaired IDL transport to liver (same receptors)- IDL becomes more LDL |
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vitamin D resistance
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single gene disorder
decreased synthesis of 1,25OH2D- advanced renal disease, inherited deficiency in renal alpha-1-hydroxylase (Vit. D dependant rickets type 1) end organ resistance to 1,25OH2D- inherited absence or defective receptor for acute metabolite of vit. D (vit D dependant rickets type 2) |
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cystic fibrosis
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-defective Cl ion transport in exocrine glands, sweat glands, lungs, pancreas
-most lethal genetic disease that affects caucasians -autosomal recessive (heterozygotes asymptomatic) -abnormally viscous mucous secretions -many different possible mutations, grouped into 6 classes based on effects on CFTR protein -sweat test: measure ionic component to determine severity |
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Thalassemia
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-single gene/transport system
-due to decreased synthesis of either the alpha or beta globin chain of HbA (a2B2) -B thalassemia: decreased B synthesis, a-thalassemia- decreased A synthesis -free chains aggregate into insoluble inclusions and hemolysis in the spleen -b-thalassemis is most common in mediterannean or africa and southeast asia -anemia manifests 6-9 months after birth (HbF changes to HbA) |
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peripheral blood smear abnormalities in thalassemia
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anisocytosis: variation in size
poikilocytosis: variation in shape microcytosis: small size hypochromia: poor hemoglobinization |
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severity of a-thalassemia
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-depends on number of a-globin genes affected (4 possible)
-silent carrier: 1 a-globin chain deleted -a-thalassemia trait: deletion of 2 a-globin -hemoglobin H disease: deletion of 3 a-globin genes -hydrops fetalis- deletion of all 4 a-globin genes |
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sickle cell anemia
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-single gene, transport system
-produce defective hemoglobin -normal adult hemoglobin a2B2, small amounts of HbA2 (a2delta2) and fetal (a2gamma2) -abnormality in B-globin gene -POINT MUTATION CAUSING SUBSTITUTION OF VALINE FOR GLUTAMIC ACID RESIDUE IN BETA CHAIN |
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prevalence of sickle cell anemia
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-8% of black americans are heterozygous
-in homozygotes: almost all hemoglobin is HbS -in heterozygotes: 40% of hemoglobin is HbS- sickle cell trait |
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what is the benefit of sickle cell trait
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protection against falciparum malaria
where malaria is endemic in Africa: 30% are heterozygotes |
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single gene disorders that have alterations in non-enzyme proteins
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osteogenesis imperfecta
ehlers-danlos syndrome marfan syndrome duchenne muscular dystrophy spherocytosis neurofibromatosis |
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Osteogenesis imperfecta
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-deficiency of TYPE 1 COLLAGEN
-brittle bone disease -joints, eyes, ears, skin, teeth affected -autosomal dominant inheritance -less severe: make normal collagen, just in decreased amounts -more severe or lethal: make abnormal chains that cannot form triple helix configuration |
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signs of OI
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-blue sclerae
-increased number of fractures -hearing loss (bones conduction) -dental imperfections -deficiency of dentin |
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type 1 form of OI
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mutations aquired not inherited
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type 2 form of OI
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-fatal in utero
-multiple fractures before birth |
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Ehlers-Danlos syndrome
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DEFECT IN SYNTHESIS OR STRUCTURE OF FIBRILLAR COLLAGEN
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inheritance of ehlers-danlos syndrome
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-variable inheritance: autosomal dominant or autosomal recessive
-6 types |
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signs of Ehlers-Danlos syndrome
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-skin and joint hypermobility
-dislocations -skin, arterial, uterine rupture -congenital scoliosis -ocular fragility -bruising -cutis laxa |
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Marfan syndrome
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defect in extracellular glycoprotein FIBRILLIN-1
fibrillin- major component of microfibrils in ECM, scaffolding for elastic fibers disorder of connective tissue especially: skeleton, eyes, cardiovascular system diagnosis based on major involvement of 2 of the 4 major organ systems |
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inheritance of Marfan syndrome
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autosomal dominant (70-85%)
remainder caused by new mutations |
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Duchenne muscular dystrophy
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-X linked
-most common and severe form of muscular dystrophy -becomes evident at age 5 -wheelchair bound at age 10 |
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spherocytosis
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intrinsic defect in red cell membrane making cell spheroid, less deformable, and vulnerable to splenic squestration and destruction
red cells must undergo extreme deformation to leave the cords of billroth and enter sinusoids of the spleen- spherocytes trapped, lactic acid accumulates, pH falls, glycolysis limited, macrophages phagocytose spherocytes |
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inheritance of spherocytosis
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autosomal dominant (75%)
remainder autosomal recessive inheritance- more severe |
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treatment of spherocytosis
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splenectomy
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neurofibromatosis Type 1
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-autosomal dominant
-most common type -neurofibromas -gliomas of optic nerve -pigmented nodule of iris (Lisch nodule) -cutaneous hyperpigmented macules (cafe au lait spots) -highly variable effects -may have no symptoms -or spinal deformities, disfiguring lesions, compression of vital structures including spinal cord |
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neurofibromatosis type 2
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-autosomal dominant
-range of tumors esp. bilateral 9 nerve schwannomas and multiple meningiomas -ependymomas of SC -non-neoplastic lesions: schwannosis, meningioangiomatosis, glial hamartia -non-sense mutations cause a more severe phenotype than missense |
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glial hamartia
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microscopic nodular collections of glial cells at abnormal locations, often in superficial and deep layers of cerebral cortex
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multifactorial disease
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congenital malformations
adult diseases mitochondrial diseases |
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congenital malformations
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-cleft lip
-club foot -congenital heart defects -pyloric stenosis -neural tube defect |
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multifactorial diseases
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coronary heart disease
HTN Alzheimers cancer diabetes gout bipolar affective disorder schizophrenia alcoholism |
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type of disorder that result from the combined actions of environmental influences and mutant genes
dosage like effect- range of severity |
multifactorial disease
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5 features that characterize multifactorial inheritance
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1. risk is conditioned by number of mutant genes inherited
2. the rate of recurrence of the disorder (2-7%) is the same for all first degree relatives 3. the likelihood that both twins will be affected is less than 100% but much greater than non-identical twins 4. risk of recurrence of phenotypic abnormality in subsequent pregnancies depends on outcome of previous pregnancies (if 1 child affected- 7% chance next affected, after 2 affected, risk rises to 9%) 5. expression of trait may be continous or discontinuous (might have to cross a threshold before apparent) |
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transmission of certain single gene disorders does not follow mendelian principles
|
nonclassical inheritance
|
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examples of disorders with nonclassical inheritance
|
fragile X syndrome
|
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Fragile X syndrome
|
-non-classical inheritance
-2nd most common cause of mental retardation after down syndrome -much more common in males -constriction in long arm of x chromsome -long face, large mandible -large everted ears -large testicles (macro-orchidism) -hyperextensible joints -high arched palate -mitral valve prolapse -can mimic CT disorder |
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pharmacology interested in genetic factors related to drug sensitivity and adverse reactions
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pharmacogenetics
|
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3 requirements to be an autoimmune reaction
|
1. presence of autoimmune reaction
2. evidence that reaction is not due to tissue damage 3. absence of other well-defined cause of disease |
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immunologic tolerance
|
state in which the individual is incapable of developing an immune response to a specific antigen
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self tolerance
|
lack of responsiveness to individual's own antigens
2 types central and peripheral tolerance |
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central tolerance
|
deletion of self reactive T and B lymphocyte clones during maturation in (thymus (t cells) and bone marrow (b cells)
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peripheral tolerance
|
back up mechanisms to kill self reactive T cells:
-anergy -supression by regulatory T cells -clonal deletion by activation induced cell death |
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potential causes of autoimmunity
|
1. inheritance of susceptible genes
2. environmental triggers, particularly infections, which promote the activation of self-reactive lymphocytes |
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organ specific autoimmunity examples
|
type 1 DM
MS |
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systemic autoimmune disease
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SLE: antibodies against DNA, platelets, red cells, protein-phospholipid complexes
|
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systemic lupus erythematosus
|
-antinuclear antibodies (ANAs)
-antibodies against cell surface antigens of blood cells -antibodies against cytoplasmic components -injury to skin, joints, kidney, and serosal membranes -usually in women -more severe in african-american women -usually arises in 20-30s |
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lupus ANAs against 4 targets
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1. DNA
2. Histones 3. nonhistone proteins bound to RNA 4. to nucleolar antigens |
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Technique to detect ANAs
|
immunofluorescence
-most common test -sensitive test- but not specific to lupus -DIAGNOSTIC TEST FOR LUPUS: ANTIBODIES TO DOUBLE STRANDED DNA- SMITH ANTIGEN |
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4 patterns of nuclear fluorescence that suggest the type of antibody in the patient's serum
|
1. homogenous or diffuse nuclear staining
2. rim or peripheral staining patterns 3. speckled pattern 4. nucleolar pattern |
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risk factors for developing lupus
|
-genetic makeup regulates the formation of autoantibodies (HLA)
-but expression of the disease is influenced by non-genetic factors -some have inherited deficiencies of early complement components (might favor tissue deposits) -drugs like hydralazine, procainamide, d-penicillamine can induce a SLE response -exposure to UV light exacerbates disease -sex hormones -immunologic factors: T and B cells activated against self |
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main manifestations of lupus
|
hematologic
arthritis skin fever fatigue weight loss renal |
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most common causes of death in lupus
|
renal failure
intercurrent infections coronary artery disease |
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Chronic Discoid Lupus Erythematosus
|
-skin manifestations that mimic SLE
-skin plaques with edema, erythma, scaliness, FOLLICULAR PLUGGING, skin atrophy, surrounded by elevated erythematous border -check for antibodies to double stranded DNA |
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subacute cutaneous lupus erythematosus
|
-widespread rash, superficial, non-scarring rash
-mild systemic symptoms |
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drug induced lupus erythematosus
|
-SLE like syndrome due to:
hydralazine procainamide isoniazid d-penicillamine develop ANAs, but many don't have clinical symptoms |
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Sjogren syndrome
|
-dry eyes (keratoconjunctivitis sicca)
-dry mouth (xerostomia) immunologically mediated destruction of lacrimal and salivary glands most often occurs in women: 50-60 y.o. isolated form: sicca syndrome secondary form: with another autoimmune disease (60%) |
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disorders associated with secondary sjogren syndrome
|
RA (most commmon)
SLE polymyositis scleroderma vasculitis mixed CT disease thyroiditis |
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Tests to diagnose Sjogren syndrome
|
antibodies against SS-A (Ro)
antibodies against SS-B (La) SS-A early onset, longer duration of disease, extraglandular manifestations BIOPSY OF LIP- MICROSCOPIC EXOCRINE GLANDS |
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Mikulicz syndrome
|
lacrimal and salivary gland enlargement
can be caused by sarcoidosis, leukemia, lymphoma, tumors |
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lymph node abnormalities in sjogren syndrome
|
enlargement with pleomorphic infiltrate of cells with frequent mitoses
increased risk of non-hodgkin lympohomas (b cell type) in salivary glands and lymph nodes increased risk of lymphoid malignacies |
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scleroderma
|
-abnormal accumulation of fibrous tissue in skin and multiple organs (GI, kidneys, heart, muscles, lungs)
-aka systemic sclerosis -occurs more often in women age 50-60 |
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2 types of scleroderma
|
diffuse: widespread skin involvement at onset progressing to early visceral involvement
limited: skin involvement is confined to fingers, forearms, face |
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CREST syndrome of scleroderma
|
C: calcinosis
R: raynaud phenomenon E: esophageal dysmotility S: sclerodactyly T: telangiectasia antibodies to centromeres |
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causes of scleroderma
|
combination of abnormal immune response and vascular damage leading to accumulation of growth factors that act on fibroblasts and stimulate collagen production
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vascular changes with scleroderma
|
:microvascular disease
:intimal proliferation :capillary dilation with leaking and destruction :nailfold capillary loops (early in couse) |
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distinctive features of scleroderma
|
-raynaud phenomenon
-dysphagia -distal esophagus dilation and atony -abdominal pain, intestinal obstruction, malabsorption syndrome, weight loss, anemia -respiratory difficulties due to pulmonary fibrosis -R sided cardiac dysfunction -myocardial fibrosis-> arrhythmias or cardiac failure -mild proteinuria -most ominous manifestation: malignant HTN - fatal renal failure -more severe in blacks |
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inflammatory myopathies
|
-injury and inflammation of mainly skeletal muscles
3 disorders: 1. dermatomyositis 2. polymyositis 3. inclusion body myositis |
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mixed connective tissue disease
|
coexistence of features of SLE, polymyositis, RA, systemic sclerosis, high titers of antibodies to RNP particle containing U1 RNP
little renal disease extremely good response to corticosteroids possibly just a heterogeneous mixture of subsets of SLE, systemic sclerosis, and polymyositis |
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polyarteritis nodosa and other vasculitides
|
-necrotizing inflammation of blood vessel walls
|
|
|
immunodeficiencies
primary: secondary |
primary: genetically determined
secondary: due to environment, infection, age, malnutrition, iatrogenic |
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x-linked agammaglobulinemia of bruton
|
-failure of B cell precursors to mature
-light chains are not produced -more susceptible to bacteria -more common in males -usually manifests in infancy or childhood |
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signs of immunodeficency in x-linked agammaglobulinemia of bruton
|
recurrent bacterial infections
-acute and chronic pharyngitis -sinusitis (need abx) -otitis media -bronchitis -pneumonia commonly caused by H. influenzae, S. pneumoniae, s. aureus persistant infection by giardia lamblia (normally resisted by secreted IgA) most viral, fungal, protozoal infections are handled by T cell mediated immunity arthritis may be due to mycoplasma infection |
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X linked agammaglobulinemia of bruton
|
-B cells absent or decreased in circulation
-depressed levels of all classes of immunoglobulins -underdeveloped germinal centers of lymph nodes, peyers patches, appendix, tonsils -plasma cells absent -normal T cell mediated reactions -treatment: replacement therapy of immunoglobulins |
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common variable immunodeficiency
|
-hypogammaglobulinemia
-usually affects all antibody classes -usually normal or near normal numbers of B cells in blood and lymphoid tissues -T cells cannot differentiate into plasma cells -affects both sexes equally -onset later in childhood or adolescence |
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|
common variable immunodeficiency
vs. x linked agammaglobulineamia |
common variable immunodeficiency:
normal numbers of B cells in blood and lymphoid tissue B cells cannot differentiate into plasma cells affects both sexes equally enlargement of B cell areas feedback inhibition is stopped due to lack of IgG risk of lymphoid malignancy high frequency of autoimmune disease X-linked agammaglobulinemia: mostly in males germinal centers of lymph nodes, peyer's patches, appendix, tonsils underdeveloped plasma cells absent T cell reactions are normal B cells absent or decreased |
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|
isolated IgA deficiency
|
mucosal defenses are weakened
more susceptible to infections in respiratory, GI, UG tracts recurrent sinopulmonary infections and diarrhea do not give IgA unless they have not antibodies to IgA- can cause severe or fatal anaphylactic reactions |
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hyper IgM syndrome
|
functionally abnormal T cells fail to induce B cells make antibodies that undergo isotype switching
recurrent pyogenic infections due to low IgG antibodies IgM antibodies react with blood giving rise to autoimmune hemolytic anemia, thrombocytopenia, and neutropenia |
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|
Di george syndrome
|
failure of development of the 3rd and 4th pharnygeal pouches (become thymus, parathyroids, thyroid)
-variable loss of T cell mediated immunity -tetany (lack of parathyroids) -congenital defects of heart and great vessels -abnormal appearance of mouth, ears, face -absence of cell mediated immunity (low T lymphcytes) -normal number of plasma cells -poor defense against fungal and viral infections -T cell zones of lymphoid organs are depleted (paracortical areas of lymph nodes, periarteriolar sheaths of spleen) -T cell function improves with age, by 5 years no noticeable deficit -if thymus is completely absent- transplant |
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|
severe combined immunodeficiency
|
defects in both humoral and cell-mediated immune response
thrush, diaper rash, failure to thrive Tx: bone marrow transplant 2 most common forms: -ADA deficiency-remnants of Hassall's corpuscles present -X linked SCID: thymus contains lobules of undifferentiated epithelial cells resembling fetal thymus -Both have hypoplastic lymphoid tissue, marked depletion of T cell areas and sometimes both T and B cell zone depletion |
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immunodeficiency with Thrombocytopenia and Eczema (Wiskott-Aldrich Syndrome)
|
X linked recessive
thrombocytopenia, eczema, vulnerable to recurrent infection normal thymus progressive secondary depletion of T lymphocytes in peripheral blood and T cell zones of lymph nodes patients do not make antibodies to polysaccharide antigens WASP- protein family that link membrane receptors like antigen receptors to cytoskeletal elements, maintain cytoskeleton integrity, signal transduction |
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|
amyloidosis
|
amyloid: pathologic proteinaceous substance deposited between tissues and organs
cross-B-pleated sheet conformation made of mostly fibril proteins accumulation causes pressure atrophy |
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|
3 most common forms of amyloid proteins
|
1. AL (amyloid light chain)- derived from plasma cells and contains immunoglobulin light chains
2. AA (amyloid associated)- made by liver 3. A beta: found in cerebral lesion of alzheimer diease |
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|
how are amyloidosis classified
|
based on constituent chemical fibrils
primary amyloidosis: systemic or generalized pattern associated with IMMUNOCYTE DYSCRASIA secondary amyloidosis: when a complication of underlying CHRONIC INFLAMMATORY or tissue destructive pattern |
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|
primary amyloidosis
|
systemic or generalized pattern of amyloidosis associated with immunocyte dyscrasia
usually plasma cell dyscrasia, multiple myeloma, plasma-cell tumor, osteolytic lesions |
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|
reactive systemic amyloidosis
|
amyloidosis secondary to an associated inflammatory condition
protracted breakdown of cells due to inflammatory conditions associated with: -RA -ankylosing spndylitis -inflammatory bowel disease (chrohn and ulcerative collitis) heroine users who inject subcutaneously have a high occurence rate of generalized AA amyloidosis chronic skin infections associated with skin popping of narcotic |
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hemodialysis associated amyloidosis
|
amyloid deposits of B2-microglobulin due to long term hemodialysis
may deposit in joints, synovium, or tendon sheaths |
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|
heredofamily amyloidosis
familial Mediterranean fever |
autosomal recessive
fever with inflammation of serosal surfaces (including peritoneum, pleura, synovial membrane) mainly in armenian, sephardic jewish, and arabic origins associated with widespread involvement of AA proteins indistinguishable from reactive systemic amyloidosis |
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|
localized amyloidosis
|
-limited to a single organ or tissue
-nodular deposits most often in lung, larynx, skin, urinary bladder, tongue, eye -frequently infiltrates of lymphocytes and plasma cells are present in periphery of amyloid masses |
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endocrine amyloid
|
amyloid deposits in endocrine tumors
ex. medullary carcinoma of thyroid gland, islet tumors of pancreas, pheochromocytomas |
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amyloid of aging
|
systemic amloidosis in elderly
senile cardiac amyloidosis can cause restrictive cardiomyopathy and arrhythmias (in both homo and heterozygotes) amyloid composed of TTR (transthyretin) molecule 4% of black population in US have mutant allele |
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|
pathogenesis of amyloidosis
|
-abnormal protein foldings deposited in tissue
1. normal proteins that have a tendency to fold improperly, associate and form fibrils, do so when produced in increased amounts 2. mutant proteins: structurally unstable and prone to misfoldings and subsequent aggregation normally misfolded proteins are degraded intracellularly in proteasomes or by macrophages if quality control mechanisms fail- misfolded proteins accumulate |
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|
clinical manifestations of amyloidosis
|
weakness
weight loss light-headedness syncope non-specific until organ more affected |
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|
normal fluid homeostasis
|
1. maintenance of vessel wall integrity
2. maintenance of intravascular pressure and osmolarity 3. maintenance of blood as a liquid until injury necessitates clot formation |
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|
shock
|
temperature <96.8 or >101.3
resp >20 HR >90 WBC >12000 or <4000 (immunocompromised) >10% band forms <90 mmHg MAP <65mmHg with fluid resuscitation |
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|
3 most important causes of pathology in western society that are disturbances in normal blood flow
|
MI
PE CVA |
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|
thrombosis
|
clotting at inappropriate sites
|
|
|
embolism
|
migration of clots
|
|
|
obstruction of blood flow to tissue causing cell death
|
infarction
|
|
|
inability to clot after vascular injury leads to
|
hemorrhage
|
|
|
edema
|
increased fluid in interstitial tissue spaces: hydrothorax, hydropericardium, hydroperitoneum
|
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|
anasarca
|
severe generalized edema with profound subcutaneous tissue swelling
|
|
|
Edema due to increased hydrostatic pressure
|
impaired venous return
-CHF -constrictive pericarditis -ascites (liver cirrhosis) -venous obstruction or compression -thrombosis -external pressure -lower extremity inactivity with dependency Arteriolar dilation -heat -neurohumoral dysregulation |
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Edema due to reduced plasma osmotic pressure (hypoproteinemia)
|
protein losing glomerulopathies
liver cirrhosis (ascites) malnutrition protein-losing gastroenteropathy |
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Edema due to lymphatic obstruction
|
inflammatory
neoplastic post surgical post irradiation |
|
|
causes of edema due to sodium retention
|
excessive salt intake with renal insufficiency
increased tubular reabsorption of sodium renal hypoperfusion increased renin-angiotensin-aldosterone secretion |
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|
edema due to inflammation
|
acute or chronic inflammation
angiogenesis |
|
|
dependent edema
|
edema due to gravity
prominent feature of congestive heart failure R ventricle failure |
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|
non-dependent edema
|
edema due to nephrotic syndrome
affects all parts of the body equally periorbital edema characteristic finding in severe renal disease (edema often in loose CT area like eyelids first) pitting edema |
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|
hyperemia
|
INCREASED INFLOW leads to engorgement with oxygenated blood resulting in ERYTHEMA
|
|
|
congestion
|
DIMINISHED OUTFLOW leads to capillary beds swollen with deoxygenated blood resulting in CYANOSIS
|
|
|
hemorrhage
|
extravasation of blood due to vessel rupture
capillaries- bleed in chronic congestion artery/vein rupture: trauma, atherosclerosis, inflammatory or neoplastic erosion of vessel wall |
|
|
hematoma
|
accumulation of blood within a tissue
|
|
|
petechiae
|
minute 1-2mm hemorrhages into skin, mucous membranes, or serosal surfaces
associated with increased intravascular pressure, low platelet counts (thrombocytopenia), defective platelet function (as in uremia), or clotting factor deficits |
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|
purpura
|
slightly larger than 3 mm hemorrhages
associated with increased intravascular pressure, low platelet counts (thrombocytopenia), defective platelet function (as in uremia), or clotting factor deficits or trauma, vasculitis, or increased vascular fragility (amyloiditis) |
|
|
ecchymoses
|
1-2cm subcutaneous hematomas
usually after trauma |
|
|
causes of subcutaneous hematomas
|
associated with
increased intravascular pressure, low platelet counts (thrombocytopenia), defective platelet function (as in uremia), or clotting factor deficits or trauma, vasculitis, or increased vascular fragility (amyloiditis) |
|
|
color change in hematomas
|
1. erythrocytes are degraded and phagocytosed by macrophage
2. hemoglobin (red-blue) is then converted to bilirubin (blue-green) 3. converted to hemosiderin (gold-brown) |
|
|
large accumulations of blood in a body cavity
|
hemothorax, hemopericardium, hemoperitoneum, hemoarthrosis
|
|
|
Risk with extensive hemorrhage
|
jaundice from massive breakdown of Red cells and release of bilirubin
|
|
|
2 functions of hemostasis
|
1. maintain blood in a fluid, clot-free state
2. ready to induce a rapid and localized hemostatic plug at site of vascular injury |
|
|
thrombosis
|
formation of a blood clot in uninjured vasculature or thrombotic injury of a vessel after minor injury
pathological opposite of hemostasis |
|
|
3 components that regulate hemostasis and thrombosis
|
1. vascular wall
2. platelets 3. coagulation cascade |
|
|
intrinsic pathway of clotting cascade
|
factor 12- hageman factor
kallikrein factor 11 factor 9 factor 8- thrombin |
|
|
extrinsic pathway of clotting
|
factor 7 activates
tissue factor (thromboplastin) |
|
|
intrinsic and extrinsic pathways of clotting meet at
|
factor 10
|
|
|
common pathway
|
factor 10
factor 5 Factor 2 (prothrombin is activated to 2a thrombin) thrombin cleaves fibrinogen to fibrin |
|
|
virchow triad
|
3 risk factors for thrombus formation
1. endothelial injury (most important) 2. blood hypercoagulability 3. stasis or turbulent blood flow |
|
|
endothelial injury
|
does not require physical disruption
dysfunctional endothelium may release too many procoagulant factors or too few anticoagulant effectors may occur due to hemodynamic stresses of 1. HTN, 2. turbulent flow over scarred valves, 3. bacterial endotoxins 4. hypercholesterolemia 5. homocystinuria, 6. cigarette smoke |
|
|
factors that favor thrombus formation
|
exposure of membrane bound tissue factor-> extrinsic coagulation sequence
|
|
|
factors that inhibit thrombosis
|
antithrombin 3- inactivates thrombin and factors 10 and 9
tissue factor pathway inhibitor: inactivates tissue factors 7, 10 PGI2, NO, adenosine diphosphate inhibit platelet aggregation t-PA stimulates fibrinolytic cascate |
|
|
turbulence
|
contributes to thrombosis
form countercurrents, pockets of stasis instead of normal laminar flow with platelets flowing centrally |
|
|
how does stasis and turbulence alter blood flow?
|
1. bring platelets in contact wtih endothelium
2. prevent dilution of activated clotting factors with fresh blood most common cause of thrombosis 3. retard the inflow of clotting factor inhibitors 4. promote endothelial cell activation |
|
|
hypercoagulability: definition and causes
|
definition:
any alteration of the coagulation pathway that predisposes to thrombosis causes: primary-genetic secondary- acquired |
|
|
Secondary (acquired) hypercoaguability states due to:
|
cardiomyopathy
nephrotic syndrome hyperestrogenic state OC use sickle cell anemia smoking |
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|
thrombosis
|
area of attachment to underlying vessel or heart wall
|
|
|
arterial thrombi
|
grow in retrograde direction from point of attachment
|
|
|
venous thrombi
|
extend in the direction of blood flow
|
|
|
grossly apparent lamination of a thrombosis called
|
lines of zahn
|
|
|
lines of Zahn are formed from
|
layers of platelets mixed with fibrin and darker layers containing more red cells
|
|
|
thrombi that adhere to wall of heart chamber or aortic lumen
due to abnormal myocardial contraction |
mural thrombi
|
|
|
the most common sites of arterial thrombi
|
coronary arteries
cerebral arteries femoral arteries |
|
|
arterial thrombi
|
injured arterial wall
on atherosclerotic plaque usually occlusive |
|
|
venous thrombosis or phlebothrombosis
|
usually occlusive
usually form in static environment tend to contain enmeshed erythrocytes- why aka red or stasis thrombi |
|
|
How can you tell the difference between a postmortem clot and a venous thrombi
|
Postmortem clots
-gelatinous -dark red dependent portion where cells have settled -yellow chicken fat supernatant -usually not attached to underlying wall venous thrombi -firmer -point of attachment -reveal strands of pale gray fibrin on transection |
|
|
fates of a thrombus
|
1. propagation (toward heart)
2. embolization 3. dissolution 4. organization and recanalization (form new channels through vessel) |
|
|
disseminated intravascular coagulation (DIC)
|
widespread fibrin thrombi in microcirculation
can cause diffuse circulatory insufficency (esp. to brain, heart, kidneys) rapid consumption of platelets and coagulation proteins at the same time that fibrinolytic mechanisms are activated- can become a serious bleeding disorder not a primary disease but a widespread activation of thrombin |
|
|
embolism
|
detached intravascular solid, liquid, or gasseous mass that is carried in blood to a new site
aka thromboembolism (usually contain part of thrombus) |
|
|
rare forms of emboli
|
droplets of fat
bubbles of air/Nitrogen atherosclerotic debris (cholesterol) tumor fragments bits of bone marrow foreign bodies |
|
|
pulmonary embolism
|
200,000 deaths/year
95% originate from deep leg vein thrombi above the level of the knee usually pass through the R side of heart to the pulmonary vasculature (may be multiple emboli) 60-80% are clinically silent can cause right heart failure (cor pulmonale) when 60% or more of the pulmonary circulation is obstructed with emboli obstruction of medium size arteries may result in pulmonary hemorrhage but usually not pulmonary infarction due to dual blood flow |
|
|
systemic thromboembolism
|
emboli traveling in arterial circulation
most from intracardiac mural thrombi most from L ventricle walls infarcts (then L atria, then aortic aneurysms, ulcerated atherosclerotic plaques) can lodge anywhere but mainly the Lower extremities and 2ndly the brain outcome depends on collateral vascular supply to the tissue, tissue vulnerability to ischemia, and the caliber of the vessel occluded |
|
|
amniotic fluid embolism
|
1 in 50000 deliveries
mortality rate of 20-40% caused by infusion of fluid or tissue into the maternal circulation by a tear in the placental membranes or rupture of uterine veins sudden severe dyspnea, cyanosis, hypotensive shock, seizures, coma pulmonary edema and DIC develop |
|
|
infarction
|
area of ischemic necrosis caused by occlusion of the arterial supply or venous drainage
|
|
|
classification of infarcts
|
based on color and the presence or absence of microbial infection
red- hemorrhagic white- anemic septic or bland |
|
|
red hemorrhagic infarcts occur
|
1. venous occlusion
2. loose tissues (lung), blood collects 3. tissues with dual circulation 4. tissues with sluggish venous outflow 5. when flow is re-established to a previous site of occlusion and necrosis |
|
|
white (anemic) infarcts occur
|
1. arterial occlusions in solid organs with end arterial circulation (solidity limits hemorrhage)
|
|
|
dominant histological characteristic of infarction
|
ischemic coagulative necrosis
(if occulusion occurs minutes to hours before death there might be no histologic changes, if the patient survives 12-18hours the only change might be hemorrhage) |
|
|
How does the body deal with infarction
|
inflammatory response begins in a few hours and is well defined in 1-2 days
gradual degradation of dead tissue with phagocytosis most are replaced with scar tissue the brain is the exception- ischemic injury-> liquefactive necrosis |
|
|
septic infarction
|
when embolism occurs by fragmentation of bacterial vegetation from a heart valve when microbes seed an area of necrotic tissue
infarct is converted to an abscess |
|
|
factors that influence development of an infarct
|
1. nature of the vascular supply
2. rate of development of the occlusion 3. vulnerability of a given tissue to hypoxia 4. blood oxygen content |
|
|
organs with single blood supply
|
kidney
spleen obstruction causes infarction |
|
|
areas with dual blood supply
|
lungs
liver hand forearm insensitive to infarction |
|
|
rate of development of occlusion
|
slow developing occlusions allow for time to develop alternative perfusion pathways
collateral circulation |
|
|
vulnerability to hypoxia
|
neurons- irreversible damage after 3-4 minutes
myocardial cells- damage after 20-30 minutes fibroblasts- viable after hours of ischemia |
|
|
oxygen content of blood
|
partial flow obstruction in an anemic or cyanotic patient might lead to infarction
|
|
|
shock
|
cardiovascular collapse
final common pathway for many potentially lethal events systemic hypoperfusion due to reduction in CO or low circulating blood flow hypotension, impaired tissue perfusion, cellular hypoxia |
|
|
5 categories of shock
|
cardiogenic: myocardial pump failure
hypovolemic: loss of blood/plasma volume septic: systemic microbial infection neurogenic: spinal cord injury, loss of vascular tone and peripheral pooling of blood anaphylactic shock: IgE mediated hypersensitivity, associated with systemic vasodilation and increased vascular permeability |
|
|
1st cause of mortality in intensive care units
|
shock
|
|
|
classification of infarcts
|
based on color and the presence or absence of microbial infection
red- hemorrhagic white- anemic septic or bland |
|
|
red hemorrhagic infarcts occur
|
1. venous occlusion
2. loose tissues (lung), blood collects 3. tissues with dual circulation 4. tissues with sluggish venous outflow 5. when flow is re-established to a previous site of occlusion and necrosis |
|
|
white (anemic) infarcts occur
|
1. arterial occlusions in solid organs with end arterial circulation (solidity limits hemorrhage)
|
|
|
dominant histological characteristic of infarction
|
ischemic coagulative necrosis
(if occulusion occurs minutes to hours before death there might be no histologic changes, if the patient survives 12-18hours the only change might be hemorrhage) |
|
|
How does the body deal with infarction
|
inflammatory response begins in a few hours and is well defined in 1-2 days
gradual degradation of dead tissue with phagocytosis most are replaced with scar tissue the brain is the exception- ischemic injury-> liquefactive necrosis |
|
|
septic infarction
|
when embolism occurs by fragmentation of bacterial vegetation from a heart valve when microbes seed an area of necrotic tissue
infarct is converted to an abscess |
|
|
factors that influence the severity of an infarct
|
1. nature of the vascular supply
2. rate of development of the occlusion 3. vulnerability of a given tissue to hypoxia 4. blood oxygen content |
|
|
organs with single blood supply
|
kidney
spleen obstruction causes infarction |
|
|
areas with dual blood supply
|
lungs
liver hand forearm insensitive to infarction |
|
|
rate of development of occlusion
|
slow developing occlusions allow for time to develop alternative perfusion pathways
collateral circulation |
|
|
vulnerability to hypoxia
|
neurons- irreversible damage after 3-4 minutes
myocardial cells- damage after 20-30 minutes fibroblasts- viable after hours of ischemia |
|
|
oxygen content of blood
|
partial flow obstruction in an anemic or cyanotic patient might lead to infarction
|
|
|
shock
|
cardiovascular collapse
final common pathway for many potentially lethal events systemic hypoperfusion due to reduction in CO or low circulating blood flow hypotension, impaired tissue perfusion, cellular hypoxia |
|
|
5 categories of shock
|
cardiogenic: myocardial pump failure
hypovolemic: loss of blood/plasma volume septic: systemic microbial infection neurogenic: spinal cord injury, loss of vascular tone and peripheral pooling of blood anaphylactic shock: IgE mediated hypersensitivity, associated with systemic vasodilation and increased vascular permeability |
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Main cause of mortality in intensive care units
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shock
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septic shock
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results from spread and expansion of an initially localized infection into the bloodstream
most caused by endotoxin, gram negative bacilli- endotoxic shock |
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what is an endotoxin
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bacterial wall lipopolysaccharides that are released when the cell walls are degraded
from gram negative bacilli |
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How does septic shock occur after LPS exposure?
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1. LPS attaches to LPS binding protein
2. LPS-LPS binding protein complex binds to cell surface receptor (CD14) and then binds a signaling transducing protein (mammalian toll like receptor protein 4) 3. signals from TLR4 activate vascular wall cells and leukocytes and initiate a cascade of cytokine mediators 4. TLR-4 down regulates anticoagulation mechanisms including tissue factor pathway inhibitor and thrombomodulin 5. TLR4 engagement on monocytes and macrophages causes mononuclear cell activation with production of cytokines IL-1 and TNF |
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LPS
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at low doses: activate monocytes and macrophages, enhance ability to eliminate bacteria
activate complement produce cytokines: TNF, IL-1, Il-6, chemokines TNF and IL-1 act on endothelial cells to stimulate the expression of cytokines and chemokines |
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endotoxic shock
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higher levels of LPS and augmentation of cycokine cascade cause cytokine induced secondary effectors (NO) to become significant
cytokines TNF and Il-1 cause fever and increased synthesis of acute phase reactants diminished cell production of thrombomodulin and tissue factor pathway inhibitor |
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results of cytokines and secondary mediators in endotoxic shock
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systemic vasodilation (hypotension)
diminished myocardial contractility widespread endothelial injury and activation causing systemic leukocyte adhesion and pulmonary alveolar capillary damage activation of coagulation system- culminating in DIC |
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low quantities of lipopolysaccharide
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monocyte/macrophage neutrophil activation
endothelial cell activation complement activation (C3a, C5a) local inflammation |
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moderate quantities of lipopolysaccharides
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fever
liver releases acute phase reactants bone release leukocytes |
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high quantities of lipopolysaccharides
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low cardiac output
low peripheral resistance blood vessel injury thrombosis DIC (disseminated intravascular coagulation) ARDS (adult respiratory distress syndrome) |
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endotoxic shock
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hypoperfusion from widespread vasodilation, vasodilation, myocardial pump failure, DIC
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superantigens
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bacterial proteins that can cause syndromes similar to septic shock
toxic shock syndrome toxin 1 made by staphlococci polyclonal T-lymphocyte activators that induce systemic inflammatory cytokine cascades effects: diffuse rash, vasodilation, hypotension, death |
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3 stages of shock
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1. initial nonprogressive
2. progressive stage 3. irreversible stage |
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initial nonprogressive stage of shock
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reflex compensatory mechanisms are activated and maintain perfusion to vital organs
baroreceptor reflexes, catecholamine release, activation of renin-angiotensin axis, ADH release, sympathetic stimulation tachycardia, peripheral vasoconstriction (cool skin), renal conservation of fluid |
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progressive stage of shock
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hypoperfusion and onset of worsening circulation and metabolic imbalances including acidosis
widespread tissue hypoxia glycolysis- lactic acid low tissue pH-> blunts vasomotor response, arterioles dilate, blood pools in microcirculation (risk for DIC) confusion, urine output declines |
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irreversible stage of shock
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body has incurred cellular and tissue injury so severe that survival is not possible
lysosomal enzyme leakage myocardial contractile function worsens (NO synthesis) if ischemic bowel flora enters circulation endotoxic shock may be superimposed complete renal shutdown, acute tubular necrosis |
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manifestations of shock depend on precipitating insult
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hypovolemic and cardiogenic: hypotension, weak, rapid pulse, tachypnea, cool, clammy, cyanotic skin
septic shock: warm, flushed skin due to peripheral vasocilation |
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exacerbate shock
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electrolyte disturbances
metabolic acidosis cardiac, cerebral, pulmonary changes renal insuffiency |
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cardiogenic shock associated with extensive MI and gram - shock
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75% mortality rate even with the best care possible
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Most common cancer diagnoses
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prostate
breast |
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most cancer deaths
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lung
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neoplasm means
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new growth
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neoplasm
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abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues and persists in the same excessive manner after cessation of the stimuli which evoked the change
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oncology
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study of tumors or neoplasms
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cancer
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term for all malignant tumors
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2 basic components of tumors
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1. proliferating neoplastic cells that constitute their parenchyma
2. supportive stroma made of CT and blood vessels |
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desmoplasia
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parenchymal cells can stimulate the formation of abundant collagenous stroma
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classification of benign epithelial tumors
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based on cells of origin
microscopic architecture macroscopic patterns |
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adenoma
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benign epithelial neoplasm that forms glandular patterns
and tumors derived from glands |
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benign epithelial neoplasm producing visible finger-like projections
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papillomas
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macroscopically visible projection above mucosal surface that projects into gastric or colonic lumen
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polyp
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malignant tumors arising from mesenchymal tissue and contain little CT
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sarcoma
fibrosarcoma liposarcoma leiomyosarcoma rhabdomyosarcoma |
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malignant neoplasms of epithelial cell origin derived from any of the 3 germ layers
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carcinoma
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carcinoma with a glandular growth pattern
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adenocarcinoma
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carcinoma producing squamous cells
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squamous cell carcinoma
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cancer composed of undifferentiated cells
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undifferentiated malignant tumor
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pleomorphic adenoma tumors
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mixed tumors with epithelial components scattered in a myxoid stroma with more than one neoplastic cell type, derived from 1 germ layer
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teratoma or dermoid cysts
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from totipotential cells in gonads, usually more than one neoplastic cell type derived from more than one germ layer
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melanocarcinoma
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carcinoma of melanocytes
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seminoma
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carcinoma of testicular origin
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hepatoma
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hepatocellular carcinoma
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hamartoma
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benign tumor indigenous to the particular site
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anaplasia
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lack of differentiation
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malignant tumors
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usually poorly differentiated
primitive, unspecialized cells anaplasia: to form backward, revert to a lower level of differentiation |
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benign tumors
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usually well differentiated
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leiomyoma
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neoplastic cell in a benign smooth muscle tumor
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dysplasia
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disordered growth
loss in uniformity pleomorphism more mitotic figures changes involve entire thickness of the epithelium |
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4 phases of tumor growth
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1. malignant change in the target cell- transformation
2. growth of transformed cells 3. local invasion 4. distant metastases |
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pleomorphism
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variation in size and shape
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changes in anaplasia
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hyperchomatic nuclei- abundant DNA
nuclei are disproportionately large nuclear shape is very variable chromatin- coarsely clumped large nucleoli mitoses: higher proliferative activity loss of polarity: orientation is disturbed formation of tumor giant cells: single huge polymorphic nucleus and other with 2 or more nuclei |
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time for a tumor to become detectable
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30 population doublings with a cell cycle time of 3 days- 90 days
10^9 weighs 1 gram really the period before a tumor becomes detectable is unpredictable due to latent phase |
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maximal tumor size compatible with life
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1 kg,
10^12 cells |
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3 factors that determine the rate of tumor growth
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1. doubling time of tumor cells
2. fraction of tumor cells in the replication pool 3. rate at which cells are shed and lost in the growing lesion |
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growth fraction
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the proportion of cells within the tumor population that are in the proliferative pool
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as tumors grow: cells leave the proliferative pool due to
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shedding
lack of nutrients apoptosis by differentiating by reversion to G0 |
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tumor facts
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derived from single cell
by the time it is detectable, most cells are not in the replicative pool often diagnosed when fairly advanced in life cycle |
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rates of tumor growth
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is faster with less differentiated tissues
depends on blood supply hormonal stimulation depends on doubling time |
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benign tumors
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cohesive expansile masses
remain localized at site of origin do not have the capacity to infiltrate, invade or metastasize |
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malignant tumors
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poorly demarcated from the surrounding tissue
lack well-defined cleavage plane slowly expanding malignant tumors may develop an enclosing capsule that may push into normal structures |
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2 main features that differentiate malignant from benign tumors
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development of metastases
invasiveness |
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carcinoma in situ
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preinvasive stage
cytologic features of malignancy without invasion of the basement membrane |
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metastases
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tumor implants discontinuous with the primary tumor
marks tumor as malignant |
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all cancers can metastasize except
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malignant neoplasms of glial cells in CNS- gliomas
basal cell carcinomas of the skin |
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3 pathways that disseminate cancer
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1. direct seeding of body cavities or surfaces
2. lymphatic spread 3. hematogenous spread |
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3 categories of genetic predisposition to cancer
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1. autosomal dominant inherited syndromes
2. defective DNA repair syndromes 3. familial cancers |
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nonhereditary predisposing conditions to cancer
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chronic inflammation
precancerous conditions |
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molecular basis of cancer
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nonlethal genetic damage lies at the heart of carcinogenesis
mutation due to environmental agents (any acquired defect caused by exogenous agents) or inherited in germ line some mutations are spontaneous and stochastic a tumor is formed by the clonal expansion of a single precursor cell that has incurred the genetic damage |
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most common method to determine tumor clonality
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analysis of methylating patterns adjacent to the polymorphic locus of the human androgen receptor gene (HUMARA)
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4 classes of normal regulatory genes that are the principle targets of genetic damage
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1. growth promoting oncogenes (mutants are considered dominant because they transform cells despite normal counterpart)
2. growth inhibiting tumor suppressor genes (both alleles must be damaged) 3.genes that regulate programmed cell death (apoptosis) 4. genes involved in DNA repair |
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phenotypic attributes of a malignant neoplasm
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excessive growth
local invasiveness ability to form distant metastases characteristics are acquired- tumor progression |
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p53
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guardian of the genome
most common target for genetic alteration in human tumors homozygous loss of p53 gene activity can occur in virtually every kind of cancer in most cases the inactivating mutations affect both p53 alleles and are acquired in somatic cells sometimes people inherit one mutant p53 gene |
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7 fundamental changes in cell physiology that determine malignant phenotype
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1. self sufficiency in growth signals
2. insensitivity to growth-inhibitory signals 3. evasion of apoptosis 4. defects in DNA repair 5. limitless replicative potential 6. sustained angiogenesis 7. ability to invade and metastasize |
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steps involved in cell proliferation
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1. binding of growth factor to its receptor on the cell membrane
2. transient and limited activation of the growth factor receptor which activates signal transducing proteins 3. transmission of the transduced signal across the cytosol to the nucleus by second messengers or that directly activate transcription 4. induction and activation of nuclear regulatory factors that initiate DNA transcription 5. entry and progression of the cell into the cell cycle resulting in cell division |
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tumor suppressor genes
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proteins that apply brakes to cell proliferation
regulate cell growth (not prevent tumor formation) discovered in retinoblasoma |
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Knudson's "two hit hypothesis"
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in hereditary cases:
1 genetic change (1st hit) is inherited from parent and present in all somatic cells 2nd mutation (second hit) occurs in one of retinal cells sometimes both mutations hit a single retinal cell whose progeny form the tumor |
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retinoblastoma
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60% Sporadic
40% inherited predisposition autosomal dominant trait |
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evasion of apoptosis
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characteristic of neoplastic cells
BCL2 reduced cell death |
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3 types of DNA repair
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1. mismatch repair
2. nucleotide excision repair 3. recombinant repair defects in these result in neoplasia |
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a clock that counts cell divisions
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telomere shortening
tumor cells have unrestricted proliferative capacity, maintain telomere length and function may have defects in cell-cycle checkpoints |
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sustained angiogenesis
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tumors secrete vascular endothelial growth factor (VEGF)
tumors cannot enlarge beyond 1-2mm in diameter unless vascularized |
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tumor blood vessels
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tortuous
irregular shaped leaky probably due to vascular endothelial growth factor tumor cells may line structures that resemble capillaries: vasculogenic mimicry |
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ability to invade and metastasize
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metatastic cascade
1. invasion of extracellular matrix 2. vascular dissemination and homing of tumor cells |
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invasion of extracellular matrix
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a. breach basement membrane
b. traverse interstitial CT c. gain access to circulation |
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vascular dissemination and homing of tumor cells
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vulnerable to destruction by innate and adaptive immune defenses in circulation
b. must adhese to endothelium and pass through BM c. need adhesion molecules (integrins, laminin receptors, fibronectin) and proteolytic enzymes |
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organ tropism
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1. tumor cells may have adhesion molecules whose ligands are expressed preferentially on endothelial cells of the target organ
2. target organs may liberate chemoattractants that recruit tumor cells to the site 3. the target tissue may be an unpermissive environment for the tumor to grow |
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type 4 collagen
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component of basement membranes
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cadherins
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cell-cell adhesion
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