Cell Adaptations, Injury, and Death Flashcards
An increase in stress leads to an increase in organ size. This occurs by one of two mechanisms.
______ is an increase in cell size.
______ is an increase in number of cells.
Hypertrophy
Hyperplasia
Of hyperplasia and hypertrophy, _______ involves gene activation, protein synthesis, and production of organelles
Hypertrophy
Of hyperplasia and hypertrophy, _____ involves production of new cells from stem cells
Hyperplasia
T/F: Hyperplasia and hypertrophy generally occur together
True; example: uterus in pregnancy
What type of tissue does not have the ability to undergo hyperplasia?
Permanent tissues — cardiac myocytes, skeletal muscle, and nerve tissue
THESE UNDERGO HYPERTROPHY ONLY
Pathologic hyperplasia can progress to ____ and ____
Dysplasia; cancer
[examples: endometrial hyperplasia progessing to endometrial carcinoma]
Pathologic hyperplasia can progress to dysplasia and cancer…with the exception of _________
Benign prostatic hyperplasia
A decrease in stress on an organ leads to a decrease in size — a process called _____ in which there is a decrease in cell size and cell number. The decrease in cell number occurs via _______.
The decrease in cell size occurs via ____________ and _________________
Atrophy; apoptosis
Ubiquitin-proteosome degradation of cytoskeleton; autophagy of cell components
A change in stress on an organ leads to a change in cell type, called _______
Metaplasia
Metaplasia most commonly involves _______ epithelium Metaplastic cells are better able to handle new stress
Surface
Barrett esophagus is a classic example of what growth adaptation? What change has taken place?
Metaplasia
Squamous epithelium —> columnar epithelium
Mechanism of metaplasia and its reversal
Metaplasia occurs by a reprogramming of stem cells
Typically reversible with removal of driving stressor (ex: treatment of GERD)
Like hyperplasia, metaplasia can progress to dysplasia and cancer. An example of this is Barrett esophagus progressing to adenocarcinoma of the esophagus. An exception to this process is ______ metaplasia, which is seen with fibrocystic change of the breast and is not associated with increased risk of cancer
Apocrine
________ deficiency can result in metaplasia (i.e., keratomalacia)
Vitamin A
Myositis ossificans is an example of ______ of mesenchymal tissue
Metaplasia
[bone being produced in the place of muscle tissue; important to distinguish from osteosarcoma in that imaging of adjacent bone will be normal with myositis ossificans]
______ = disordered cellular growth referring to proliferation of precancerous cells (e.g., CIN); arises from longstanding pathologic hyperplasia or metaplasia
Dysplasia
T/F: dysplasia is irreversible
False — Dysplasia is reversible with alleviation of inciting stress. If stress persists, dysplasia progresses to carcinoma which is irreversible
_____ = failure of cell production during embryogenesis
Aplasia (classic example is unilateral renal agenesis)
______ = decrease in cell production during embryogenesis resulting in a relatively small organ
Hypoplasia
Streak ovary in turners syndrome is an example of
A. Metaplasia B. Dysplasia C. Hypertrophy D. Hyperplasia E. Hypoplasia
E. Hypoplasia
Common causes of cell injury include inflammation, nutritional deficiency or excess, hypoxia, trauma, genetic mutations, etc.
Hypoxia occurs when there is low oxygen delivery to tissue. What are the 3 major causes of hypoxia?
Ischemia
Hypoxemia
Decreased O2 carrying capacity of the blood
_______ = decreased blood flow through an organ
Ischemia
Define hypoxemia
Low partial pressure of O2 in the blood (PaO2 < 60 mm Hg, SaO2 < 90%)
[Remember FiO2 is partial pressure of O2 in the atmosphere. PAO2 is partial pressure of oxygen in alveolar air sacs, while PaO2 is partial pressure of oxygen in the arterioles. SaO2 is the partial pressure of oxygen associated with Hb. So the sequence is FiO2 —> PAO2 —> PaO2 —> SaO2]
Anemia is a decrease in RBC mass. This is associated with a _____ PaO2 and a ______ SaO2
Normal; normal
[PaO2 reflects the ability of oxygen to cross from alveolar air sacs into capillaries. SaO2 reflects the percentage of Hb is bound by oxygen. Neither of these is altered by anemia]
Carbon monoxide binds Hb more avidly than O2, resulting in CO poisoning. CO poisoning is associated with a ____ PaO2 and a ______ SaO2. Exposures include smoke from fires and exhaust from cars or gas heaters
Normal; decreased
[Hb can’t hold as much oxygen bc some spaces are now taken up by CO]
Classic finding is cherry red appearance of the skin
Early sign of exposure is headache; significant exposure can lead to coma and death
CO poisoning
_______ refers to the situation in which iron in heme is oxidized to Fe3+, which cannot bind O2
Methemoglobinemia
[REMEMBER Fe2+ binds O2]
Methemoglobinemia refers to the situation in which iron in heme is oxidized to Fe3+, which cannot bind O2. This is associated with a ______ PaO2 and a ______ SaO2.
Normal; decreased
In what conditions might you see methemoglobinemia?
Methemoglobinemia is associated with oxidant stress (e.g., sulfa and nitrate drugs) or in newborns
Classic findings are cyanosis with chocolate-colored blood
Methemoglobinemia
Treatment for Methemoglobinemia
IV methylene blue — helps reduce Fe3+ back to Fe2+ state
Hypoxia impairs ______ _____ —> decreased ATP
Oxidative phosphorylation
[O2 is final acceptor in electron transport chain]
Low ATP resulting from hypoxia disrupts what 3 key cell functions?
Na/K pump — lack of ATP results in buildup of Na in cell, water follows, cell swelling
Ca2+ pump — usually keeps intracellular Ca low; increased Ca activates enzymes in the cell that you don’t want activated
Aerobic glycolysis — leads to lactic acid buildup
Initial phase of cell injury due to hypoxia is cellular ______ which leads to loss of microvilli, membrane blebbing, and swelling of RER
Swelling
[remember that consequence of swelling of RER is that ribosomes will disassociate and protein can no longer be synthesized]
The initial phase of cell damage due to hypoxia is cell swelling which is reversible. Eventually, the damage becomes irreversible and the hallmark of this is membrane _______
Damage
Example: a sign of irreversible damage is plasma membrane damage, so that is what you’re testing when you look for cardiac enzymes, liver enzymes, etc.
3 main cell membranes that are damaged by longstanding hypoxia
Plasma membrane — release of enzymes; calcium floods in
Mitochondrial membrane — Cyt C escape and cell death
Lysosomal membrane — calcium flooding in activates escaped lysosomal enzymes causing further cell damage
Morphologic hallmark of cell death
Loss of nucleus
[occurs via pyknosis, karyorrhexis, and karyolysis]
Pyknosis
Shrinkage of nucleus
Karyorrhexis
Breakage of nucleus into pieces
Karyolysis
Pieces of nucleus are further broken down
Death of a large group of cells followed by acute inflammation; due to underlying pathologic process and is NEVER physiologic
Necrosis
Characteristic type of necrosis for ischemic infarction of any organ except the brain
Coagulative necrosis
Describe tissue changes associated with coagulative necrosis (i.e., shape, structure, nuclear changes, etc)
Necrotic tissue remains firm; area of infarcted tissue is usually wedge-shaped and pale
Cell shape and organ structure are preserved by coagulation of cellular proteins
Nucleus disappears
How does a “red” infarction occur?
Red infarction arises if blood reenters tissue and tissue is loosely organized
Example: testicular infarction
Type of necrosis characteristic of brain infarction, abscess, and pancreatitis
Liquefactive necrosis
[enzymatic lysis of cells and proteins results in liquefaction]
NOTE: pancreatitis results in liquefactive necrosis of the pancreatic parenchyma and fat necrosis of the peripancreatic fat
Type of necrosis characteristic of ischemia of lower limb and GI tract
Gangrenous necrosis
Gangrenous necrosis is coagulative necrosis that resembles mummified tissue (dry gangrene). What happens to this type of necrosis if superimposed infection occurs?
Liquefactive necrosis (wet gangrene)
Characteristic type of necrosis associated with granulomatous inflammation due to TB or fungal infection
Caseous necrosis
Fat necrosis appears as necrotic adipose tissue with chalky-white appearance due to deposition of ______
Calcium (due to saponification)
Trauma to the breast may result in ____ necrosis
Fat
[classic scenarios of fat necrosis = trauma to fat (i.e., breast), pancreatitis-mediated damage of peripancreatic fat]
_______ = example of dystrophic calcification in which fatty acids released by trauma or lipase join with calcium
Saponification
Characteristic type of necrosis associated with malignant hypertension or vasculitis
Fibrinoid necrosis
______ necrosis involves damage to blood vessel wall resulting in leaking of proteins into that vessel wall, characterized by bright pink staining
Fibrinoid necrosis
Hypertension associated with pre-eclampsia in a pregnant female may be lead to ______ necrosis of the placenta
Fibrinoid
Energy-dependent, genetically programmed cell death that involves single cells or small groups of cells
Apoptosis
Endometrial shedding during menstrual bleeding: Necrosis or Apoptosis?
Apoptosis
Removal of cells during embryogenesis: Necrosis or Apoptosis?
Apoptosis
[failure results in syndactyly]
CD8+ T cell-mediated killing of virally infected cells: Necrosis or Apoptosis?
Apoptosis
Morphology of apoptosis
Dying cell shrinks and becomes eosinophilic
Nucleus condenses and fragments
Apoptotic bodies fall from cell and are removed by macrophages — NOT followed by inflammation! [contrast with necrosis]
Apoptosis is mediated by _____ which activate proteases that break down the cytoskeleton. They also activate ______ which break down the DNA
Caspases; endonucleases
Intrinsic mitochondrial pathway for caspase activation in apoptosis
Cell injury, DNA damage, or decreased hormone stimulation inactivates Bcl2
Cytochrome C leaks from inner mitochondrial matrix into cytoplasm
[Bcl2 role is to stabilize mitochondrial membrane]
2 primary examples of extrinsic receptor-ligand pathway for caspase activation in apoptosis
FAS ligand binds FAS death receptor (CD95) on target cell [mechanism for negative selection of T cells that react too strongly to self-antigen]
TNF binds TNF receptor on target cell
Cytotoxic CD8+ T-cell pathway for caspase activation in apoptosis
Perforins create pores in membrane of target cell
Granzyme enters pores and activates caspases
Define free radical
Chemical species with unpaired electron in outer orbit
Generation of free radicals occurs during what physiologic process?
Oxidative phosphorylation
[cytochrome C oxidase transfers electrons to O2; partial reduction yields O2, H2O2, and OH radicals]
NOTE: of all the free radicals, OH* is most damaging
Examples of things that cause pathologic generation of free radicals
Ionizing radiation (typically produces OH*)
Inflammation
Metals (e.g., copper and iron)
Drugs and chemicals (e.g., acetaminophen)
NOTE: underlying pathologic mechanism of Wilson’s disease, Hemochromatosis, etc. is generation of free radicals
How do free radicals damage cells?
Peroxidation of lipids
Oxidation of DNA and proteins
[oxidation of DNA introduces mutations that may result in oncogenesis — this is the basis of taking anti-oxidants]
3 general mechanisms of eliminating free radicals = antioxidants, enzymes, and metal carrier proteins.
What are the 3 major enzymes involved in eliminating free radicals?
Superoxide dismutase (SOD): converts O2* —>H2O2
Catalase: converts H2O2 —> OH*
Glutathione peroxidase: converts OH* —>H2O
Free radical injury most commonly seen in dry cleaning industry
CCl4
[CCl4 is converted to CCl3 in the P450 system of the liver. CCl3 is a free radical that damages hepatocytes. The initial stage of damage is reversible — evidenced by cellular swelling. Recycling of fat by apolipoproteins cannot occur because protein synthesis has been affected by cell/RER swelling. Thus the primary change seen is fatty change of the liver]
Pathophysiology of reperfusion injury
When blood (containing inflammatory cells) returns to organ —> oxygen allows inflammatory cells react to dead tissue by generating free radicals leading to further damage
Classic vignette is continued rise in cardiac enzymes after occluded vessel is reopened — this is due to FREE RADICAL injury
Misfolded protein that deposits in extracellular spaces, damaging tissues
Amyloid
Multiple proteins can deposit as amyloid. Misfolded proteins depositing as amyloid often deposit in _______________ configuration.
They exhibit ____________ and _________ under polarized light
Beta-pleated sheet
Congo red staining; apple-green birefringence
Deposition of amyloid can be systemic or localized. Systemic amyloidosis is divided into primary and secondary types.
Primary amyloidosis is systemic deposition of ____ amyloid, derived from _________
AL; Ig light chain
Type of amyloidosis associated with plasma cell dyscrasias
Primary amyloidosis (AL amyloid derived from Ig light chains)
Secondary amyloidosis refers to systemic deposition of ___ amyloid derived from _________, an acute phase reactant that is increased in chronic inflammatory states, malignancies, and Familial Mediterranean fever
AA; SAA
Autosomal recessive dysfunction of neutrophils that presents with episodes of fever and acute serosal inflammation
Familial Mediterranean Fever (high SAA during attacks deposits as AA amyloid — secondary amyloidosis)
Note: mimics various conditions depending on what serosa is affected — so if serosa of heart is affected, may look like an MI
Most common organ affected in amyloidosis
Kidney — presents with nephrotic syndrome
Classic clinical findings in amyloidosis
Nephrotic syndrome
Restrictive cardiomyopathy or arrhythmia
Tongue enlargement, malabsorption, and hepatosplenomegaly
Diagnosis of amyloidosis requires _______
Tissue biopsy
[abdominal fat pad and rectum are easily accessible targets]
T/F: Amyloid cannot be removed, so damaged organs must be removed
True
Localized amyloidosis refers to amyloid deposition that is usually localized to a single organ. Examples of this phenomenon include senile cardiac amyloidosis and familial amyloid cardiomyopathy. What is the difference between these 2 conditions in terms of pathology, symptoms, and pt population affected
In senile cardiac amyloidosis, a NON-MUTATED serum transthyretin deposits in the heart. It is usually ASYMPTOMATIC and present in 25% of individuals >80 years of age.
In familial amyloid cardiomyopathy, a MUTATED serum tranthyretin deposits in the heart and leads to RESTRICTIVE CARDIOMYOPATHY. 5% of African Americans carry the mutated gene
Describe the localized amyloidosis associated with type II diabetes
Amylin deposits in islets of pancreas
Derived from insulin
Describe amyloidosis associated with Alzheimer disease
AB amyloid deposits in brain, forming amyloid plaques
Derived from beta-amyloid precursor protein (on Chr 21) — important because there is increased risk of early onset Alzheimers in Down Syndrome
In dialysis-associated amyloidosis, _______ deposits in the ______
B2-microglobulin; joints
[beta-2 microglobulin provides structural support to MHC class I molecules; in dialysis it is not filtered from the blood so it deposits as amyloid]
In what condition is there localized amyloidosis in which calcitonin deposits within tumor?
Medullary carcinoma of the thyroid
[tumor of C-cells —> overproduction of calcitonin, which then deposits as amyloid. Histology is classically described as “tumor cells on an amyloid background”]
