1. ischemia 2. hypoxemia 3. decreased O2-carrying capacity of blood

Pathoma 1 Flashcards by Kyra Porter

basic principles of growth adaptations

*an organ is in homeostasis with physiologic stress placed on it
*an increase, decrease, or change in stress on an organ can result in growth adaptations
*examples: hyperplasia, hypertrophy, atrophy, metaplasia, dysplasia

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hyperplasia and hypertrophy - overview

*increase in stress → increase in organ size
*occurs via increase in: 1) SIZE (hypertrophy) and/or 2) NUMBER OF CELLS (hyperplasia)
*generally occur together (ex. uterus during pregnancy)

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hypertrophy - mechanism

*increase in size of cells in an organ
*involves gene activation, protein synthesis, and production of organelles

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hyperplasia - mechanism

*increase in number of cells in an organ
*involves production of NEW CELLS from stem cells

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exception to hyperplasia and hypertrophy occurring together

*PERMANENT tissues (eg. cardiac myocytes, skeletal muscle, nerves) CANNOT MAKE NEW CELLS and therefore undergo hypertrophy only

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progression of pathologic hyperplasia

*pathologic hyperplasia can progress to dysplasia → cancer
*example: endometrial hyperplasia
*exception: BPH (no increased risk of prostate cancer)

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atrophy - overview

*a decrease in stress on an organ (eg. decreased hormonal stimulation, disuse, or decreased nutrient/blood supply) leads to a decrease in organ size
*occurs via a decrease in the size and number of cells

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atrophy - mechanisms

*decrease in cell number occurs via apoptosis
*decrease in cell size occurs via: 1) ubiquitin-proteosome degradation of the cytoskeleton; and 2) autophagy of cellular components

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mechanism of ubiquitin-proteosome degradation in atrophy

*intermediate filaments of the cytoskeleton are “tagged” with ubiquitin and destroyed by proteosomes

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mechanism of autophagy in atrophy

*autophagy of cellular components involves generation of autophagic vacuoles
*the vacuoles fuse with lysosomes whose hydrolytic enzymes breakdown cellular components

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metaplasia - overview

*a change in stress on an organ leads to a change in CELL TYPE
*most commonly involves change of one type of surface epithelium (squamous, columnar, urothelial) to another
*metaplastic cells are better able to handle the new stress

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Barrett esophagus as an example of metaplasia

*esophagus is normally lined by nonkeratinizing squamous epithelium (suited to handle friction of a food bolus)
*acid reflux from the stomach causes metaplasia to nonciliated, mucin-producing columnar cells (better able to handle the stress of stomach acid)

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metaplasia - mechanism

*occurs via reprogramming of stem cells, which the produces the new cell type
*REVERSIBLE with removal of the driving stressor
*ex: treatment of GERD may reverse Barrett esophagus

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progression of long-standing metaplasia

*under persistent stress, metaplasia can progress to dysplasia and eventually result in cancer
*example: Barrett esophagus may progress to adenocarcinoma of the esophagus
*exception: apocrine metaplasia (type of fibrocystic change of the breast) does NOT increase risk for breast cancer

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Vitamin A deficiency → metaplasia

*vitamin A is necessary for differentiation of specialized epithelial surfaces such as the conjunctiva covering the eye
*in Vit A deficiency, the thin squamous lining of the conjunctiva undergoes metaplasia into stratified keratinizing squamous epithelium
*note - this change = keratomalacia

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metaplasia of mesenchymal (connective) tissues

*myositis ossificans: connective tissue within muscle changes to bone during healing after trauma

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dysplasia - overview

*disordered cellular growth
*most often refers to proliferation of precancerous cells (ex. CIN is a precursor to cervical cancer)
*often arises from longstanding pathologic hyperplasia or metaplasia
*REVERSIBLE with alleviation of inciting stress
*if stress persists, dysplasia progresses to carcinoma (irreversible)

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aplasia - overview

*failure of cell production during embryogenesis
*ex: unilateral renal agenesis

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hypoplasia - overview

*decrease in cell production during embryogenesis, resulting in a relatively small organ
*ex: streak ovary in Turner syndrome

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basic principles of cellular injury

*occurs when a stress exceeds the cell’s ability to adapt
*likelihood of injury depends on type of stress, severity, and type of cell affected
*common causes of injury include: inflammation, nutritional deficiency or excess, hypoxia, trauma, and genetic mutations

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hypoxia - overview/mechanism

*an important cause of cellular injury due to low oxygen delivery to tissue
*mechanism of hypoxia → cellular injury:
1. oxygen is the final electron acceptor in the ETC of oxidative phosphorylation
2. decreased O2 impairs ox. phos. → decreased ATP production
3. lack of ATP (essential energy source) → cellular injury

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causes of hypoxia

ischemia
hypoxemia
decreased O2-carrying capacity of blood

ischemia → hypoxia → cellular injury

*ischemia = decreased blood flow through an organ
*arises with:
1. decreased arterial perfusion (eg. atherosclerosis)
2. decreased venous drainage (eg. Budd-Chiari syndrome)
3. shock: generalized hypotension resulting in poor tissue perfusion

hypoxemia → hypoxia → cellular injury

*hypoxemia = a low partial pressure of oxygen in the blood (PaO2 < 60 mmHg, SaO2 < 90%)
*arises with:
1. high altitude (decreased barometric pressure results in decreased PAO2)
2. hypoventilation (increased PACO2 results in decreased PAO2)
3. diffusion defect (PAO2 not able to push as much O2 into the blood due to a thicker diffusion barrier)
4. V/Q mismatch (blood bypasses oxygenated lung or oxygenated air cannot reach blood)

decreased O2-carrying capacity of blood → hypoxia → cellular injury

*arises with hemoglobin loss or dysfunction *examples: 1. anemia (decrease in RBC mass): PaO2 normal, SaO2 normal 2. carbon monoxide poisoning

mechanism of carbon monoxide poisoning → decreased O2-carrying capacity

*CO binds Hb more avidly than oxygen *PaO2 normal, SaO2 decreased *exposures include: smoke from fires, exhaust from cars or gas heaters *classic finding = cherry-red appearance of skin *early sign of exposure is headache; significant exposure can lead to coma and death

methemoglobinemia - overview

*iron in heme is oxidized to Fe3+, which cannot bind oxygen *PaO2 normal, SaO2 decreased *seen with oxidant stress (sulfa and nitrate drugs) or in newborns *classic finding = **cyanosis with chocolate-colored blood** *treatment is IV methylene blue, which helps reduce Fe3+ back to Fe2+ state

effects of low ATP (resulting from hypoxia) on cellular functions

1. **disruption of Na+/K+ pump** → sodium and water buildup in cell 2. disruption of Ca2+ pump → buildup of calcium in the cytosol of the cell, activating enzymes 3. disruption of aerobic glycolysis → switch to anaerobic glycolysis; lactic acid buildup results in low pH, which denatures proteins and precipitates DNA

REVERSIBLE (initial) phase of cellular injury due to low ATP

*hallmark = **cellular swelling** *cytosol swelling results in loss of microvilli and membrane blebbing *swelling of rough endoplasmic reticulum → dissociation of ribosomes and decreased protein synthesis

IRREVERSIBLE (late) phase of cell injury due to low ATP

*hallmark = **membrane damage** *plasma membrane damage results in: 1) cytosolic enzymes leaking into the serum and 2) additional calcium entering the cell *mitochondrial membrane damage results in: 1) loss of electron transport chain; 2) cytochrome c leaking into cytosol (activates apoptosis) *lysosome membrane damage results in: hydrolytic enzymes leaking into the cytosol, which are activated by the high intracellular calcium *end result of irreversible injury = cell death

basic principles of cell death

*morphologic hallmark of cell death = **loss of the nucleus,** which occurs via: 1. condensation (pyknosis) 2. fragmentation (karyorrhexis) 3. dissolution (karyolysis) *2 mechanisms of cell death = necrosis and apoptosis

necrosis - overview

*death of large groups of cells followed by acute inflammation *due to some underlying pathologic process; NEVER physiologic *divided into several types, based on gross features

coagulative necrosis - overview

*necrotic tissue that remains firm *cell shape and organ structure are preserved by coagulation of cellular proteins, but the nucleus disappears *characteristic of **ischemic infarction of ANY ORGAN except the brain**

coagulative necrosis - gross appearance

*area of infarcted tissue is often **wedge-shaped** (pointing to focus of vascular occlusion) and **pale** *red infarction arises if blood re-enters a loosely organized tissue (eg. pulmonary or testicular infarction)

liquefactive necrosis - overview

*necrotic tissue that becomes liquified ***enzymatic lysis of cells and protein result in liquefaction** *characteristic of: 1. brain infarction - proteolytic enzymes from microglial cells liquify the brain 2. abscess - proteolytic enzymes from neutrophils liquify tissue 3. pancreatitis - proteolytic enzymes from pancreas liquify parenchyma

gangrenous necrosis - overview

*coagulative necrosis that resembles mummified tissue (dry gangrene) *characteristic of **ischemia of the lower limb** & GI tract *if superimposed infection of dead tissues occurs, then liquefactive necrosis ensues (wet gangrene)

caseous necrosis - overview

*soft and friable tissue with "cottage-cheese like" appearance *combination of coagulative and liquefactive necrosis *characteristic of **granulomatous inflammation due to TB or fungal infection**

fat necrosis - overview

*necrotic adipose tissue with chalky-white appearance due to deposition of calcium *characteristic of **trauma to fat (eg. breast) or pancreatitis-mediated damage of peripancreatic fat**

fat necrosis - mechanism

*fatty acids released by trauma or lipase join with calcium via a process called **saponification** *saponification is an example of dystrophic calcification (in which calcium deposits on dead tissues)

fibrinoid necrosis - overview

*necrotic damage to blood vessel wall *leaking of proteins (including fibrin) into vessel wall → bright pink staining of the wall microscopically *characteristic of malignant hypertension or vasculitis

apoptosis - overview

*energy (ATP)-dependent, genetically programmed cell death involving single cells or small groups of cells *examples include: -endometrial shedding during menstrual cycle -removal of cells during embryogenesis -CD8+ T cell-mediated killing of virally infected cells

apoptosis - morphology

*dying cell shrinks → cytoplasm becomes more eosinophilic (pink) *nucleus condenses and fragments in an organized manner *apoptotic bodies fall from the cell and are removed by macrophages; note that apoptosis is not followed by inflammation

apoptosis - mechanism

*mediated by caspases that activate: 1. proteases → break down of cytoskeleton 2. endonucleases → break down DNA

intrinsic mitochondrial pathway for activation of caspases in apoptosis

1. cellular injury, DNA damage, or decreased hormonal stimulation **inactivates Bcl2** 2. lack of Bcl2 allows **cytochrome c to leak** from the inner mitochondrial matrix into the cytoplasm and activate caspases

extrinsic receptor-ligand pathway for activation of caspases in apoptosis

1. FAS ligand binds FAS death receptor (CD95) on the target cell, activating caspases (eg. negative selection of thymocytes in thymus) OR 2. tumor necrosis factor (TNF) binds TNF receptor on the target cell, activating caspases

cytotoxic CD8+ T cell-mediated pathway for activation of caspases in apoptosis

1. perforins secreted by CD8+ T cells create pores in membrane of target cell 2. granzyme from CD8+ T cell enters pores and activates caspases *example: CD8+ T cell killing of virally infected cells

free radicals - overview

*chemical species with an unpaired electron in their outer orbit *3 key free radicals: superoxide, hydrogen peroxide, hydroxyl free radical *note - hydroxyl free radical is the most dangerous free radical

physiologic generation of free radicals

*occurs during oxidative phosphorylation: 1. cytochrome c oxidase (complex IV) transfers electrons to oxygen 2. partial reduction of O2 yields: superoxide (O2 with an unpaired electron), hydrogen peroxide (H2O2), and hydroxyl radicals (OH with an unpaired electron)

pathologic generation of free radicals

*arises with: 1. **ionizing radiation** - water hydrolyzed to hydroxyl free radical 2. **inflammation** - NADPH oxidase generates superoxide ions during oxygen-dependent killing by neutrophils 3. **metals (copper, iron**) - Fe2+ generates hydroxyl free radicals (Fenton reaction) 4. **drug and chemicals** - P450 system of liver metabolizes drugs, generating free radicals

mechanism of free radicals → cellular injury

*free radicals cause cellular injury via peroxidation of lipids and oxidation of DNA and proteins *DNA damage is implicated in aging and oncogenesis

mechanisms for elimination of free radicals

1. antioxidants (eg. glutathione and vitamins A, C, and E) 2. enzymes: -superoxide dismutase -glutathione peroxidase -catalase 3. metal carrier proteins (eg. transferrin, ceruloplasmin)

basic principles of amyloidosis

*amyloid is a **misfolded protein that deposits in the extracellular space, thereby damaging tissues** *multiple proteins can deposit as amyloid; shared features include: 1. beta-pleated sheet configuration 2. congo red staining & apple-green birefringence when view microscopically under polarized light *deposition can be systemic or localized

classic clinical findings of systemic amyloidosis

1. nephrotic syndrome; kidney is most commonly involved organ 2. restrictive cardiomyopathy or arrhythmia 3. tongue enlargement, malabsorption, and hepatosplenomegaly