Test 1: review questions Flashcards
list the causes of cell injury
chemical, lack of O2, physical agent, workload, age
Oxygen/energy deprivation (hypoxia, anoxia, ischemia, etc.)
Physical agents (heat, cold, radiation, etc.)
Infectious agents
Immunologic dysfunction
Genetic derangements
Nutritional imbalances
Workload imbalances
Chemicals, drugs, toxins
Age
How does decreased ATP lead to cell injury and possible death? What is the role of Ca2+ in this process?
lack of ATP, leads to decrease in Na/K pump. Therefore Na floods cell and water follows causing swelling.
Ca will also flood into cell increasing enzymes activity
Membranes will start to breakdown due to PLA activation which will cause mitochondria to release cytochrome C, which leads to apoptosis.
Cell will use glycogen as energy source, this will cause build up of lactic acid, decrease in pH will cause enzymes not to work.
Increased Ca, cause activation of proteases, ATPases and endonucleases. Ribosomes will fall off and cause protein misfolding
ATP is synthesized via oxidative phosphorylation (using oxygen in mitochondria) or the glycolytic pathway (in absence of oxygen using glucose). With decreased synthesis or depletion of ATP, a number of cell systems are affected:
- The plasma membrane Na+ K+ ATPase pump fails and Na+ enters the cell and water follows leading to cell swelling and dilation of the RER.
- Failure of the Ca2+ pump causes excess calcium to enter the cell; that damages a number of systems by increased enzyme activity.
- If cells switch to glycolysis, glycogen is depleted and lactic acid and inorganic phosphates accumulate which decreases intracellular pH, resulting in decreased activity of some cellular enzymes.
- As ATP depletion continues, ribosomes detach from the RER leading to decreased protein synthesis.
- Protein misfolding occurs leading to further cell injury
Influx of Ca2+ leads to: Activation of phospholipase A, which breaks down the normal phospholipids of the inner mitochondrial membrane and other cell membranes, generating arachidonic acid (substrate for many lipid mediators of inflammation); Activation of proteases (cause cytoskeleton and membrane damage, ATPases, and endonucleases that degrade chromatin).
In cell injury, cell membranes can become defective. What are mechanisms of cell membrane damage? How can we as veterinarians use this process to aid us in making a diagnosis in our patients?
- Cell membranes can be damaged by a variety of insults including some of those above (ATP depletion, free radicals, calcium influx, and activation of phospholipases) as well as being directly damaged by infectious agents, complement, killer T cells, and physical and chemical agents.
- Membrane damage allows cell contents to leak into the plasma and these can be detected in blood samples. This is a common laboratory method of detecting injury in a variety of organs with acute injury leading to cell death (elevated creatine kinase with muscle damage, transaminases (ALT, AST) in liver damage, trypsin-like and lipase-like molecules in pancreatic damage).
Compare and contrast necrosis and apoptosis. How can a pathologist distinguish the two microscopically?
necrosis- messy, 3 steps- shrinks(pyknosis), explodes(karyorrhexis), fades(karyolysis). dilated mitochondria. Will cause outside factors to react, more pink(eosin)
Necrosis refers to the spectrum of morphologic changes (gross, histologic, and ultrastructural) that follow cell death in a living tissue. Microscopically, we see hypereosinophilic cytoplasm, nuclear changes (pyknosis, karyorrhexis, karyolysis) and inflammatory cells (e.g. neutrophils) to clean up debris.
apoptosis- controlled steps- blebbing, shrinks, gets eaten by macrophage.
Apoptosis is one group of pathways of cell death that are the result of a regulated intracellular program that activates intracellular enzymes to cause degradation of cell proteins and DNA, cell shrinkage, and death. Microscopically, we may see macrophages neatly phagocytizing condensed apoptotic bodies without other inflammatory cells.
pyknosis
karyolysis
karyorrhexis
Give a clinical example in which we would see the following types of necrosis: coagulative, liquefactive.
coagulative- ischemia- gangrene - still have cell wall
liquefactive- bacteria- wet gangrene- no cell wall- cells replaced by neurophils and macrophages/pus
Coagulative necrosis occurs most often with ischemia or toxins and for a few days the cells maintain their basic outline. Coagulative necrosis can be seen in cases of an infarct (e.g. renal, cardiac); severe anemia (e.g. centrilobular hepatic necrosis in cases of blood loss or hemolytic anemia). Liquefactive necrosis occurs most commonly with bacterial, fungal, or lytic viral infections and the cells are digested by their own enzymes, bacterial toxins, or the enzymes of leukocytes (e.g. abscess in any tissue/organ).
Define autolysis.
breakdown of tissue after death by bodies enzymes if not presevered
Autolysis is the degradation of a cell by its own enzymes after it has died. We usually use the term autolysis to refer to postmortem autolysis the changes that occur in dead cells after that death of the whole organism.
A patient dies suddenly of a suspected cardiac arrhythmia and undergoes an autopsy. Why can’t the pathologist see any histologic changes in the heart (e.g. myocardiocyte degeneration or necrosis)?
it takes 6-12 hours to see microscopic changes in the tissue after cell injury. Because they died so quickly the cells did not have time to react
Cell function is lost before cell death occurs and the visible effects of cell death lag behind. Ultrastructural changes are the first to be visible (by electron microscopy), but light microscopic evidence of cell death cannot usually be seen of 6 to 12 hours after cell death, and gross changes often take even longer.
Compare and contrast the following terms and provide an example of each:
- Atrophy vs Hypoplasia
- Hypertrophy vs Hyperplasia
atrophy break down of cells from injury or lack of use- foot in cast
hypoplasia- never grew to full size- tiny kidney
hypertrophy- increase in the size of a cell from hormonal or compensatory factors- big muscles
Increase in size of cells by virtue of an increase in number and size of organelles. Tissues or organs are often subsequently enlarged. Hypertrophy often accompanies hyperplasia due to cellular proliferation, but as a stand-alone adaptation is observed mainly in organs made up of predominantly terminally differentiated/post-mitotic cells (e.g. heart, skeletal muscle)
hyperplasia- increase in the number of cells - hepatocyte regeneration
Increase in the number of cells in an organ or tissue. Only possible in a cell population that is capable of mitosis (labile and quiescent cells, not terminally differentiated/post-mitotic cells).
metaplasia
Dysplasia – “disordered growth” – may be used in certain congenital disease (e.g. renal dysplasia, hip dysplasia). We also apply the term to epithelium as an acquired change. Discuss the clinical significance of this acquired change.
acquired change- hyperplasia of cells in the wrong order can lead to neoplasm
Dysplasia has two meanings. It may refer to abnormal tissue development (renal dysplasia) or hyperplasia with atypical cell shape, size, and orientation in fully developed tissues (epithelium). Disordered growth of tissues due to chronic irritation without an apparent host advantage and may be a precursor to malignant neoplasia (precancerous).e.g. Solar (UV light)-induced changes in the cornea and conjunctiva in Hereford cattle and the skin of the pinnae of white cats.
Both hepatocellular lipid accumulation (lipidosis, steatosis) and hepatocellular glycogen accumulation can cause diffuse enlargement and discoloration of the liver. Match the gross pictures below to the correct condition. What is the microscopic difference between the two? When would you see these gross changes clinically?
red- glycogen accumilation due to excess steroid- in cytoplasm- steroid use- swelling and clearing
yellow- lipidosis due to starvation or other overuse of fat- inside vacules in the cell- starvation
Steroid hepatopathy (left); glycogen accumulation associated with increased corticosteroids (e.g. hyperadrenocorticism). Glycogen vacuoles are less define and irregular, leading to the appearance of cytoplasmic swelling and clearing. Hepatic lipidosis (right); accumulation of fat in clear/crisp vacuoles in the cytoplasm. Associated with excessive entry of fatty acids due to excessive dietary intake or increased mobilization (due to starvation) of fat.
light chain
primary amyloid
Made up of monoclonal immunoglobulin light chains, seen with plasma cell dyscrasias and plasma cell tumors and equine nodular cutaneous amyloidosis; NOT related to inflammation
reactive AA
secondary amyloid
Made up of serum amyloid-associated (SAA) protein (an acute phase protein produced by the liver during inflammation and seen after chronic antigenic stimulation and chronic inflammation. Familial in Shar Pei dogs and Abyssinian and some Siamese cats
islet amyloid (IAPP)
Precursor polypeptide is co-secreted with insulin by the Beta cells in the pancreatic islets; deposited in pancreatic islets in aged cats; has been associated with diabetes mellitus; however, many old cats have islet amyloidosis and do NOT have diabetes mellitus.
Provide a clinical scenario in which you would observe DYSTROPHIC CALCIFICAITON and METASTATIC CALCIFICATION.
dystrophic calcification- caused when cells die and can’t control amount of calcium in the cell- leads to calcification
- Dystrophic calcification (mineralization) is calcification of necrotic tissue in an animal with normal serum calcium. Calcium accumulates in the mitochondria, since dead cells cannot regulate influx of calcium into cytosol. Examples include necrotic skeletal muscle, granulomas, dead parasites, and necrotic abdominal tissue secondary to pancreatitis.
metastatic- caused by too much calcium in the blood and leads to calcification in alive cells- anal gland carcinoma leading to increase in PTH rP
Metastatic calcification (mineralization) occurs in living tissues as a result of hypercalcemia. Usually begins in the interstitium (extracellular space) of organs affected (kidney, lung, blood vessels, stomach). Hypercalcemia of malignancy (LSA, Anal Sac Carcinoma), functional parathyroid adenoma, Vit D toxicity, uremia).
The two main pigments derived from hemoglobin (hemotogenous pigments) are HEMOSIDERIN and BILIRUBIN. Define each and explain their clinical importance.
hemosiderin- yellow- contains iron, heme breaks down into iron(hemosidersin) and bilirubin
bilirubin- green/brown- waste product- no iron, heme breaks down into (hemosidersin) and bilirubin. 3 main types of bilirubin: prehepatic(in RBC- unconjugated bilirubin), hepatic (in liver- un and conjugated) and posthepatic (bile duct- conjugated)
Hemosiderin is a hemoglobin-derived globular golden-yellow to yellow-brown pigment. It is most often found in macrophages at sites of erythrocyte lysis or breakdown. Small amounts of hemosiderin are normally present in the bone marrow, spleen and liver due to erythrocyte turnover; accumulation also indicated prior hemorrhage. Following lysis of red blood cells, iron is sequestered by macrophages and eventually converted to hemosiderin in lysosomes. Hemosiderin is positive with Prussian blue iron stain.
Bilirubin is a green brown, amorphous, globular pigment. It is the major component of bile. It is a waste product, and must be excreted. The majority of bilirubin is derived from the breakdown of senescent erythrocytes. It does NOT contain iron. Bilirubin is formed by RBC breakdown→ heme portion of hemoglobin is converted to biliverdin and then bilirubin by a series of biochemical reactions. Jaundice (icterus) is the clinical manifestation of hyperbilirubinemia and is a yellowish staining of the integument, sclera, and deeper tissues with bile pigments resulting from increased levels of bilirubin in the plasma. The three types of icterus are:
-
Pre-hepatic (Hemolytic)
- Due to massive breakdown of erythrocytes; many different causes (immune-mediated, infectious, metabolic, trauma, etc.)
- Causes increased unconjugated bilirubin; quickly converted into conjugated
-
Hepatic
- Hepatocellular disease compromises the liver’s ability to uptake unconjugated bilirubin and/or excrete conjugated bilirubin into bile canaliculus
- Increase in both unconjugated and conjugated bilirubin
-
Post-Hepatic
- Bile duct obstruction
- Increase in conjugated bilirubin
Define lipofuscin and ceroid pigments.
lipofuscin- brownish- yellow- formed in lysosomes- shows past damage- group of damaged organelles
ceroid- made by macrophages- vit E defeciency
Lipofuscin is a brownish-yellow intracellular pigment. This pigment increases with age and atrophy; and thus, has been termed the “wear and tear” or “aging” pigment. Can be found in the cells of the liver, heart, brain, thyroid gland and adrenal glands as well as macrophages. Formed in lysosomes and thought to be derived from the free radical oxidation of unsaturated lipids; consists of proteins complexed with lipids with little carbohydrate; Not harmful to the cell but is a marker of past free radical injury. Ceroid shares common histologic and histochemical features with lipofuscin; can accumulate in disease states (Vit E deficiency); produced by macrophages.
in dogs is it common to see hyperplastic nodules where?
liver, pancreas, spleen and adrenal cortex
in cats it is common to see nodular hyperplasia in what organs
pancreas and adrenal cortex
dysplasia- disorder of the cells- should be in a specific order but get confused
metaplasia
what cell injury?
fatty change (lipidosis).
distribution and severity?
severe diffuse hepatic lipidosis (hepatocellular fatty change)
what type of necrosis
: coagulative.
What are some features (cytoplasmic and nuclear) that differentiate necrotic from viable cells?
cytoplasmic:
- increased eosinophilia
nuclear:
- small dark nuclei (pyknosis)
- nuclear fragments (karyorrhexis)
- missing nuclei (karyolysis)
How can you differentiate necrosis from autolysis?
- secondary inflammatory reaction
- multifocal distribution (autolysis is usually diffuse)
- intact red blood cells
What one word would best describe these lesions?
infarcts
What etiologic category of disease fits this best (from the VITAMIN D, MINI VAN DITTI lists)?
vascular
What differentiates necrotic from viable hepatocytes?
Increased cytoplasmic eosinophilia, pyknosis, karyorrhexis, karyolysis. (None of the viable hepatocytes are normal either; the toxins have increased the size of the cells and their nuclei).
What morphologic type of necrosis is this?
coagulative.
what kind of necrosis
iquefactive.
What is the predominant inflammatory cell type in the center of the necrosis?
neutrophils
what kind of exudate?
Catarrhal- tissue response comprised of secretion or accumulation of thick gelatinous fluid containing mucus from mucous membranes (goblet cells and mucous glands). Seen with allergic and chronic airway inflamation and autoimmune GI disease
what kind of exudate
Suppurative- composed of neutrophils and dead cells (pus). Purulent is a synonym of suppurative. An abscess is a localized form of suppurative inflammation
what kind of exudate
Fibrinous - increased vascular permeability during acute inflammation and accumulation of fluid with high protein and low cell numbers with S.G > 1.02. Associated with endothelial cell injury and leakage of larger MW proteins such as fibrinogen. Fibrinogen is a homogenous extracellular pink material with H & E stain. Typically seen in areas lined by pleura, pericardium, peritoneum, alveoli, meninges, synovia
what kind of exudate
Serous- lesions characterized by accumulation of fluid rich in protein on body surfaces e.g. oozing of fluid from burns. Blisters are an example of a serous exudate.
Anti-inflammatory drugs are used widely in medical practice. Arachidonic Acid (AA) is generated from membrane phospholipids by PLA2. Products of AA metabolism, including prostaglandins, leukotrienes, and lipoxins, are potent pro- and anti-inflammatory mediators. Consequently, the enzymes that convert arachidonic acid into these molecules represent important targets for modulating the inflammatory response. List some commonly used anti-inflammatory drugs that target the AA pathway that act to modulate inflammation and pain.
AA is metabolized in one of three pathways: (1) the COX pathway for the formation of prostaglandins and thromboxanes, (2) the lipoxygenase pathway for the formation of leukotrienes and lipoxins, and (3) the cytochrome p450 pathway for the formation of epoxyeicosatrienoic acids.
- Aspirin, indomethacin, ibuprofen, and naproxen are COX-1 inhibitors. Aspirin, naproxen, and ibuprofen also inhibit COX-2, as do the highly selective COX-2 inhibitor drugs celecoxib, rofecoxib, valdecoxib, lumiracoxib, and etoricoxib.
- Acetaminophen may inhibit COX-2 to a minor degree and also slightly inhibit COX-3 (COX-1b), and yet have other activity/activities.
- Corticosteroids inhibit of phospholipase A2, the enzyme that releases arachidonic acid from membrane phospholipids. Corticosteroids signal the cell to synthesize a polypeptide known as lipocortin (lipomodulin), which then acts to inhibit phospholipase A2. Therefore the antiinflammatory effect of corticosteroids is delayed.
morphologic
There are multifocal, 2mm-1.5cm in diameter, dark red, soft, circular masses disseminated throughout all liver lobes.
The loss of renal parenchyma associated with severe hydronephrosis in a patient with an obstructive ureterolith, as illustrated below, is an example of which cell adaptation?
atrophy
What is the type of necrosis observed in centrilobular hepatocellular death due to ischemia?
coagulative (keeps cell membrane)
Coagulative necrosis occurs most often with ischemia or toxins and for a few days the cells maintain their basic outline. Eventually enzymatic action and entering leukocytes leads to proteolysis and loss of the cell outline.
this category of neoplasia elicits a specific tumor-stromal interaction (see picture).
- What is this reaction called?
- Briefly summarize this process.
Desmoplasia.
Platelet-derived growth factor (PDGF) released by tumor cells stimulates tumor-associated fibroblasts to increase the production of collagen. In some cases this process leads to an extensive fibrous reaction, termed a “scirrhous” or “desmoplastic” response.
What is the amorphous eosinophilic material that is intimately associated with the neoplastic cells?
Osteoid.
