Chapter 1 Flashcards
Note; ALL CAPS = either means high yield, or just making it easier to tell the difference between to words (like ABduction vs ADduction)
Which permanent tissues only undergo hypertrophy and not hyperplasia?
-Cardiac muscle, skeletal muscle, and nerve
How does hyperplasia lead to cancer? Is there an exception to this rule?
- When hyperplasia occurs secondary to a pathologic process
- Pathologic hyperplasia (ex. Endometrial hyperplasia) can progress to dysplasia and eventually cancer.
- EXCEPTION: BPH - NO increase risk for prostate cancer
Name of process that results in a decrease in cell #
apoptosis
Name of processes that results in decrease cell size
Ubiquitin-proteosome degradation of the cytoskeleton and autophagy of cellular components
What is Metaplasia?
A change in stress on an organ leads to a change in cell type.
Barret esophagus is a classic example of what type of growth adaptation?
Metaplasia
What type of tissue changes occur most commonly in metaplasia?
Change of one type of surface epithelium (squamous, columnar, urothelial) to another
What type of metaplasia do we see with Barret esophagus?
Non-keratinizing squamous epthelium –> nonciliated, mucin-producing columnar cells
Metaplasia is (reversible or irrreversible)?
reversible - in theory, with removal of the driving stressor
Can metaplasia progress to cancer?
Yes - under persistent stress:
-metaplasia –> dysplasia –> cancer
ex) Barret’s –> adenocarcinoma of the esophagus
EXCEPTION:apocrine metaplasia of breast - no increased risk for cancer
What vitamin deficiency can result in metaplasia?
Vitamin A.
-is necessary for differentiation of specialized epithelial surfaces such as the conjunctiva covering the eye
How will a Vitamin A deficiency manifest?
Night blindness
Thin squamous lining of the conjunctiva undergoes metaplasia into stratified keratinizing squamous epithelium. Change = KERATOMALACIA
MYOSITIS OSSIFICANS is an example of what?
- Mesenchymal (connective) tissue undergoing metaplasia
- muscle tissue changes to bone during healing after trauma (inflammation)
Define Dysplasia in 3 words
Disordered cellular growth
Cervical intraepithelial neoplasia (CIN) is an example of what growth adaptation?
Dysplasia
- refers to a proliferation of precancerous cells (as most dysplasias do).
- Represents dysplasia and is a precursor to cervial cancer
How does dysplasia arise?
-often from longstanding pathologic hyperplasia (endometrial hyperplasia) or metaplasia (Barrett)
IS DYSPLASIA REVERSIBLE?
Yes, in theory, with alleviation of inciting stress
-if the stress persists and it progresses to carcinoma –> that is irreversible
Define Aplasia:
Failure of cell production during embryogenesis
Define Hypoplasia
Decrease in cell production during embryogenesis resulting in a relatively small organ (ex streak ovary in turner syndrome)
What type of cells are highly susceptible to ischemic injury?
NEURONS (occurs after 3-5 minutes)
What does slowly developing ischemia result in?
Results in atrophy
In contrast to acute ischemia - which results in cellular injury
Define Hypoxia
Low oxygen delivery to tissue
What are the 3 causes of hypoxia?
- Ischemia (decreased blood flow through an organ)
- Hypoxemia (low partial pressure of oxygen in the blood)
- Decreased O2 - carrying capacity
What are 3 causes of ischemia?
- Decreased arterial perfusion (atherosclerosis)
- Decreased venous drainage (Budd-Chiari syndrome - from Polycythemia vera or Lupus causing a thrombosis in hepatic vein)
- Shock:
What lab values constitute Hypoxemia?
PaO2 < 60 mmHg;
SaO2 <90%
4 Causes of hypoxemia:
- High altitude
- Hypoventilation [Increased PACO2 –> Decreased PAO2)
- Diffusion Defect (Interstitial pulmonary fibrosis)
- V/Q mismatch (right-to-left shunt; atelectasis)
How does a decreased O2 carrying capacity of the blood occur?
Arises with hemoglobin (Hb) loss or dysfunction.
What are 3 examples of decreased O2-carrying capacity?
- Anemia [PaO2 normal; SaO2 normal]
- CO poisoning [PaO2 normal; SaO2 decreased]
- Methemoglobinemia [PaO2 normal; SaO2 decreased]
**What is the classic physical finding in CO poisoning?
Cherry-red appearance of skin
-Headache =early sign; then lead to coma and death
Explain Methemoglobinemia
Iron in heme is oxidized to Fe3+, which cannot bind O2
-Seen with oxidant stress (sulfa and nitrate drugs) or in newborns [‘cause babies suck at reducing Fe3+ to Fe2+]
What is a classic finding in methemoglobinemia?
Cyanosis with chocolate-colored blood
What is the treatment for Methemoglobinemia?
Intravenous methylene blue
- helps reduce Fe3+ back to Fe2+ state
What is the hallmark of reversible injury?
Cellular swelling
What is the hallmark of irreversible injury?
Membrane damage:
Where does the electron transport chain occur?
INNER MITOCHONDRIAL MEMBRANE
What is cytochrome C?
an enzyme found in the mitochondria used in oxidative phosphorylation. When this leaks into the cytosol (when mitorchondrial membrane is damaged), will activate apoptosis
What is the morphologic hallmark of cell death?
loss of the nucleus:
-Nuclear condensation (pyknosis) –> Fragmentation (Karyorrhexis) –> Dissolution (Karyolysis)
In general, describe Necrosis (i.e. - how it will be differentiated from the other form of cell death)
- Death of LARGE group of cells followed by ACUTE inflammation
- Due to some underlying pathologic process; never physiologic
What are the 6 gross patterns of necrosis?
- Coagulative
- Liquefactive
- Gangrenous
- Caseous
- Fat
- Fibrinoid necrosis
Which pattern of necrosis is characteristic of ischemic infarction of any organ (except the brain)?
Coagulative
What is a red infarction?
Coagulative necrosis: arises if blood re-enters a lossely organized tissue (pulmonary or testicular infarction)
How would coagulative necrosis appear? (i.e firm, squishy, circular….?)
Tissue remains firm (cell shape preserved)
- Wedge-shaped (pointing to focus of vascular occlusion)
- Pale
What type of necrosis is characteristic of brain infarction?
Liquefactive
Proteolytic enzymes from microglial cells liqeufy the brian
What type of necrosis is characteristic of Abscess and Panceatitis?
Liquefactive
- Abscess: Proteolytic enzymes from neutrophils
- Pancreatitis: Proteolytic enzymes from pancreas liquefy parenchyma
What type of necrosis is characteristic of ischemia of lower limb and GI tract?
Gangrenous necrosis
What is wet gangrene?
When there is gangrenous necrosis with superimposed infection of dead tissues ( and liquefactive necrosis ensues)
How would you describe a gangrenous necrosis?
Coagulative necrosis that resembles mummified tissue
How would you describe a Caseous necrosis?
Soft and friable necrotic tissue with “cottage cheese-like” appearance
-A combination of coagulative and liquefactive
What type of necrosis is characteristic of granulomatous inflammation due to tuberculous or fungal infections?
Caseous necrosis
What is saponification?
Fatty acids released by trauma or lipase join with calcium
-Is an example of dystrophic calcification
What is dystrophic calcification?
Calcium deposits on dead tissues.
- necrotic tissue acts as a nidus for calcification
- occurs in setting of NORMAL serum calcium and phosphate
What is metastatic calcification?
HIGH serum Ca or P levels lead to Ca deposition in normal tissue (hyperparathyroidism leading to nephrocalcinosis)
What type of necrosis is characteristic of trauma to fat and pancreatitis-mediated damage of peripancreatic fat?
Fat necrosis
-Will have a chalky-white appearance due to deposition of Ca
What type of necrosis is characteristic of malignant hypertension and vasculitis?
Fibrinoid necrosis
Define fibrinoid necrosis
Necrotic damage to blood vessel wall
-Leaking of proteins (fibrin) into vessel wall resulting in bright pink staining of the wall microscopically
Define apoptosis:
ATP-dependent, genetically programmed cell death involving single cells or small groups of cells
Give 3 examples of apoptosis
- Endometrial shedding during menstrual cycle
- Removal of cells during embryogenesis (digits)
- CD8 T cell-mediated killing of virally infected cells
After apoptotic bodies are removed by macrophages, what type of inflammation occurs?
NONE - apoptosis is not followed by inflammation (BUT necrosis does have inflammation!)
What mediates apoptosis?
Caspases: activate proteases and endonucleases
- Proteases break down cytoskeleton
- Endonucleases break down DNA
How are caspases activated by the intrinsic mitochondrial pathway?
- Inactivation of Bcl2 via cellular injury/DNA damage/loss of hormonal stimulation allows CYTOCHROME C to leak from the inner mitochondrial matrix into the cytoplasm and activate caspases
How are caspases activated by the extrinsic receptor-ligand pathway?
FAS ligand binds FAS death receptors (CD95) on the target cell –> activating caspases (negative selection of thymocytes in thymus)
-TNF binds TNF receptors on target cell, also activating caspases
How are caspaces activated by the Cytotoxic CD8 T cell-mediated pathway?
- Perforins secreted by CD8 T cells create pores in membrane of target cells
- Granzyme (really) from CD8 T cell enters pores and activates caspases
How are free radicals generated physiologically?
Oxidative phosphorylation
- Cytochrome c oxidase (complex IV) transfers electrons to oxygen
- Partial reduction of O2 yeilds Superoxide (O2 -), hydrogen peroxide (H2O2), and Hydroxyl radicals (OH-)
Which oxygen free radical is the devil of free radicals?
Hydroxyl radicals are the most dangerous
What are 4 ways free radicals are generated pathologically?
- Ionizing radiation: Water –> Hydroxyl free radical
- Inflammation: NADPH oxidase generates superoxide ions during oxygen-dependent killing by neutrophils
- Metals: Fenton reaction (Fe2+ generates hydroxyl)
- Drugs and chemicals: during metabolism via P450
How do free radicals cause cellular injury?
Via peroxidation of lipids and oxidation of DNA and proteins
DNA damage is implicated in aging and oncogenesis
What are 3 enzymes that eliminate free radicals?
Superoxide dismutase (in mitochondira): Superoxide –> H2O2
- Glutathione peroxidase (in mitochondria): Hydroxyl –> water
- Catalase (in peroxisomes): H2O2 –> H2O
What is Carbon Tetrachloride (CCl4), and why is it bad?
- organic solvent used in dry cleaning
- Converted to CCl3 by P450
- Results in cell injury with swelling of rER –> ribosomes detach, impairing protein synthesis
- Decreased apolipoproteins leads to FATTY CHANGE IN THE LIVER
What are 2 shared features of proteins that can be deposited as amyloid?
- Beta-pleated sheet configuration
2. Congo red staining and apple-green birefringence when viewed microscopically under polarized light
Define Primary amyloidosis
Systemic deposition of AL amyloid, which is derived from Ig light chain
-Associated with plasma cell dyscrasia (multiple myeloma)
Define Secondary amyloidosis
Systemic deposition of AA amyloid, which is derived from serum amyloid-associated protein (SAA)
What is serum amyloid-associated protein (SAA)?
an acute phase reactant that is increased in chronic inflammatory states, malignancy, and familial mediterranean fever (FMF - rare)
What are the clinical findings of systemic amyloidosis?
- NEPHROTIC SYNDROME: KIDNEY IS THE MOST COMMON ORGAN INVOLVED
- Restrictive cardiomyopathy or arrhythmia
- Tongue enlargement, malabsorption, hepatosplenomegaly
How do you diagnosis Systemic Amyloidosis:
Tissue biopsy
Abdominal fat pad and rectum are easily accessible biopsy targets. If you think convincing a patient sticking a needle up their butt will be easy anyway…
What is the treatment for systemic amyloidosis?
Damage organs must be transplanted. Amyloid cannot be removed
What is senile cardiac amyloidosis?
Localized amyloidosis
- NON-MUTATED serum transthyretin deposits in the heart
- usually asymptomatic. Common (25% of pts >80 years old)
What is Familial amyloid cardiomyopathy?
- Localized amyloidosis
- MUTATED serum transthyretin deposits in the heart leading to restrictive cardiomyopathy
When would you see Amylin depsoited in the islet of the pancreas?
Type II diabetes mellitus.
Amylin is derived from insulin
What amyloid is present in Alzheimer disease?
- Abeta amyloid (derived from Beta-amyloid precursor protein) deposits in the brain forming amyloid plagues.
- Gene for beta-APP is present on Chromosome 21 - which is where the association with Down syndrome comes from
What do you see in Dialysis-assoicated amyloidosis
B2-microglobulin deposits in joints
How is Medullary carcinoma of the thyroid associated with amyloidosis
Calcitonin (Produced by tumor cells) deposits within the tumor
-“TUMOR CELLS IN AN AMYLOID BACKGROUND”
