Basics of Pathology Flashcards
In what way to permanent tissues respond to stress?
hypertrophy only since they are incapable of hyperplasia
Why is pathologic hyperplasia dangerous?
it may progress to dysplasia and eventually to cancer
Most pathologic hyperplasias carry a risk of dysplasia and eventually cancer. What is the exception to this?
BPH does not carry a risk for prostate cancer
Define atrophy.
a response to stress characterized by a decrease in the size and number of cells
What mechanisms underly the decrease in cell number and size that define atrophy?
- decline in cell number is mediated by apoptosis
- decline in cell size occurs via ubiquitin-proteasome degradation of the cytoskeleton and autophagy of cellular components
What is metaplasia?
a change in cell type due to a change in the stress on an organ or tissue
Metaplasia most commonly involves what change?
change of one type of surface epithelium to another
What is a classic example of metaplasia?
Barrett esophagus
What is Barrett esophagus? What transition occurs? What cancer is it associated with?
- a classic example of metaplasia
- the esophagus is normally lined by nonkeratinizing squamous epithelium suitable for the friction of a food bolus
- acid reflux induces a metaplasia to a non-ciliated, mucin-producing columnar epithelium better able to handle the stress of acid
- poses a risk for adenocarcinoma
Through what mechanism does metaplasia occur?
via reprogramming of stem cells
Most metaplasias carry a risk for dysplasia and malignant transformation. What is the exception to this?
apocrine metaplasia of the breast carries no increased risk for cancer, rather it is associated with fibrocystic change
Apocrine metaplasia of the breast carries a risk for what?
- not cancer like most other metaplasias
- instead, it is associated with fibrocystic change
What vitamin deficiency can result in metaplasia?
Vitamin A
What is Keratomalacia? What specific change does it involve?
- a form of metaplasia arising from a vitamin deficiency
- VitA is necessary for the differentiation of specialized epithelial surfaces
- this is particularly true for the conjunctiva covering the eye
- the thin squamous lining of the conjunctiva undergoes a change called keratomalacia to stratified keratinizing squamous epithelium
What is a classic example of mesenchymal connective tissue metaplasia?
- myositis ossificans
- CT within muscle changes to bone during healing after trauma in part due to sustained inflammation
What is myositis ossificans?
- a classic example of mesenchymal metaplasia
- CT within muscle changes to bone during the healing process after trauma thanks to sustained inflammation
At what point along the progression from hyperplasia and metaplasia to dysplasia to cancer, does the process become irreversible.
- hyperplasia, metaplasia, and dysplasia are all reversible in theory
- only a cancerous transformation is irreversible
What is aplasia?
a failure of cell production during embryogenesis
When does cellular injury occur?
when stress exceeds the cell’s ability to adapt (either in magnitude, duration, or rate of onset)
Neurons are highly susceptible to what kind of injury?
ischemic injury more than others
Through what mechanism does hypoxia lead to cellular injury?
- oxygen is needed for energy production since it is the final electron acceptor
- low oxygen delivery to tissue impairs oxidative phosphorylation and results in diminished ATP levels
- low ATP disrupts key cellular functions such as Na/K-pump activity and calcium-pump activity
- furthermore there is a switch to anaerobic glycolysis and the resulting build up of lactic acid denatures proteins and precipitates DNA
What is hypoxemia?
a cause of hypoxia in which there is a low partial pressure of oxygen in the blood (PaO2 <60 mmHg or SaO2 <90%)
List four causes of hypoxemia.
- high altitude reduces FiO2 and affects PaO2
- hypoventilation increases PACO2 and results in a decreased PAO2
- a diffusion defect (e.g. interstitial pulmonary fibrosis), limits PaO2
- a V/Q mismatch (e.g. right-to-left shunt or atelectasis) reduces PaO2
What are the two most significant causes of decreased O2-carrying capacity, which contribute to hypoxia?
- anemia
- CO poisoning
CO Poisoning
- CO binds hemoglobin more avidly than oxygen so while PaO2 is normal, SaO2 is diminished
- this causes hypoxia and cellular injury
- exposure usually comes from smoke or exhaust inhalation
- classically, there is a cherry-red appearance of the skin and the most signficant sign of exposure is headache
- ultimately it leads to coma and death
What is Methemoglobinemia?
- a cause of hypoxia in which iron in heme is oxidized to the Fe3+ state, which cannot bind oxygen
- usually due to oxidant stress (e.g. exposure to nitrites) or in newborns
- classically presents with cyanosis and chocolate-colored blood
- treatment is IV methylene blue which helps generate mediators of iron reduction
The hallmark of reversible cellular injury is what? How can this be identified?
cellular swelling, which results in loss of microvilli and membrane blabbing as well as dissociation of ribosomes from the swelling RER, which causes a decline in protein synthesis
The hallmarks fo reversible and irreversible cellular injury are what? What is the hallmark of cell death?
- reversible: swelling
- irreversible: membrane damage
- death: loss of the nucleus
Irreversible cellular injury is defined by membrane damage. What does membrane damage result in and why is it irreversible?
- plasma membrane damage causes cytosolic enzymes to leak into serum and additional calcium to enter the cell
- mitochondrial membrane damage triggers a loss of the electron transport chain and leakage of cytochrome c into the cytosol
- lysosome membrane damage result in hydrolytic enzymes leaking, where they are activated by the elevated intracellular calcium
- mitochondrial membrane damage is the most significant because the loss of electron transport chain means even restoring O2 delivery can’t save the cell and cytochrome c release, induces apoptosis
Describe how hypoxia leads to irreversible cell injury.
- hypoxia is low oxygen delivery to tissue
- since oxygen is the final electron acceptor, it impairs oxidative phosphorylation and results in a lack of ATP
- without ATP, the Na/K and Ca pumps stop working and there is a switch to anaerobic glycolysis
- sodium, water, and calcium build up in the cell while lactic acid denatures proteins and precipitates DNa
- the cell begins to swell (hallmark of reversible injury), which results in a loss of microvilli, dissociation of ribosomes from the RER, and membrane damage
- membrane damage then marks irreversible injury
- cytosolic enzymes leak into the serum while additional calcium enters the cell
- lysosomal enzymes leak into the cytosol and are activated by the elevated calcium
- mitochondrial membrane damage results in a loss of electron transport chain so that even if O2 delivery is restored, ATP production can’t continue
- mitochondrial membrane damage also causes a leakage of cytochrome c, which induces apoptosis
The hallmark of cellular death is loss of the nucleus. Through what stages does this occur?
- pyknosis = condensation
- karyorrhexis = fragmentation
- karyolysis = dissolution
What are the two mechanisms of cell death?
necrosis and apoptosis
What is necrosis?
death of large groups of cells followed by acute inflammation (neutrophil infiltrate) due to some underlying pathologic process
How does necrosis compare to apoptosis?
- necrosis is the death of large groups of cells while apoptosis usually involves single cells or smaller groups
- apoptosis, in contrast to necrosis, is an energy-dependent process
- apoptosis can be physiologic whereas necrosis is always pathologic
What are the six types of necrosis?
- coagulative
- liquefactive
- gangrenous
- caseous
- fat
- fibrinoid
Describe coagulative necrosis? What is it typically characteristic of?
- a form of necrosis in which the necrotic tissue remains firm and cell shape and organ structure are preserved while the nucleus disappears
- typically characteristic of ischemic infarction of any organ except the brain
- seen as a wedge-shaped area pointing to teh focus of vascular occlusion
- a subset is red infarction, which arises if blood re-enters a loosely organized tissue (e.g. after a testicular torsion disrupts the vein causing necrosis but continues to be supplied by the artery)
What is red infarction?
- a subset of coagulative necrosis (the other being pale infarction)
- occurs when blood re-enters loosely organized necrotic tissue (i.e. tissues with multiple blood supplies)
- for example, testicular torsion may collapse the vein without disrupting the artery so blood continues to flow in
Describe liquefactive necrosis. What is it characteristic of?
- necrotic tissue that becomes liquefied due to enzymatic lysis of cells and proteins
- characteristic of brain infarction, abscesses, and pancreatitis because of microglial enzymes, neutrophil enzymes, and pancreatic enzymes, respectively
Describe gangrenous necrosis? What is the difference between wet and dry gangrene? What is it characteristic of?
- coagulative necrosis that resembles mummified tissue is called dry gangrene
- if a superimposed infection of the dead tissue occurs, then liquefactive necrosis ensues and this is called wet gangrene
- it is characteristic of chronic ischemia in the lower limb and GI tract, particularly in diabetics?
Describe caseous necrosis? What is it characteristic of?
- consists of soft, friable necrotic tissue with a “cottage cheese-like” appearance
- a combination of coagulative and liquefactive necrosis
- characteristic of granulomatous inflammation due to TB or fungal infection
Describe fat necrosis and the mechanism that contributes to it. What is it characteristic of?
- necrotic adipose tissue with a chalky-white appearance due to the deposition of calcium
- calcium is deposited as fatty acids are released and bind calcium, a process called saponification
- characteristic of trauma to fat and pancreatitis-mediated damage of peripancreatic fat
- appears dark blue on histology
What is saponification?
- an example of dystrophic calcification
- the process whereby, free fatty acids bind calcium and precipitate as calcium deposits
- a feature of fat necrosis
Pancreatitis will lead to what kind(s) of necrosis?
- the parenchyma will undergo liquefactive necrosis due to the presence of pancreatic enzymes
- the peripancreatic fat undergoes fat necrosis as lipase is released and frees fatty acids
What is the difference between dystrophic and metastatic calcification? Give examples of each.
- dystrophic is calcification of abnormal tissue in the setting of normal serum calcium and phosphate levels (e.g. saponification of fat necrosis) and tends to be localized
- metastatic calcification occurs when high serum calcium or phosphate levels lead to calcium deposition in normal tissue (e.g. hyperparathyroidism leading to nephrocalcinosis) and tends to be more widespread
Describe fibrinoid necrosis. What two conditions is it highly characteristic of?
- necrotic damage to the blood vessel wall
- leaking of proteins like fibrin into the vessel wall result in bright pink, thick staining of the wall microscopically
- characteristic of malignant hypertension (e.g. pre-eclapsia resulting in fibrinoid necrosis of the placenta) and vasculitis
Give three examples of physiologic apoptosis.
- endometrial shedding
- removal of cells during embryogenesis
- CD8 T cell-mediated killing of virally infected cells
Describe the changes seen in a cell undergoing apoptosis.
- the dying cell shrinks, leading the cytoplasm to become more eosinophilic while the nucleus condenses and fragments in an organized manner and is extremely basophilic
- apoptotic bodies fall from the cell and are removed by macrophages
- it is not followed by inflammation
Apoptosis is mediated by what group of proteins? How do they function?
capsases, which activate proteases and endonucleases
How is apoptosis triggered? In other words, how do caspases become activated?
- intrinsic pathway: damage leads to inactivation of Bcl2; Bcl2 normally prevents cytochrome c release by binding and inhibiting APAF-1 and without it cytochrome c is free to activate caspase 9
- extrinsic receptor-ligand pathway: FasL binds Fas or TNF binds the TNF receptor, activating caspases
- cytotoxic CD8 T cell-mediated pathway: perforin create pores through which granzyme enters and activates caspases
Which free radical is most damaging?
the hydroxyl radical
How are free radicals generated physiologically?
during oxidative phosphorylation, partial reduction of O2 yields superoxide, hydrogen peroxide, and hydroxyl radicals
Describe four mechanisms for the pathologic generation of ROS and the species they create.
- ionizing radiation produces hydroxyl free radicals
- inflammation generates superoxide ions during the oxidative burst
- metals like iron and copper are normally bound, but when free they generate hydroxyl free radicals
- drugs and chemicals are metabolized by the P450 system, generating free radicals
The damage associated with Wilson’s disease and hemochromatosis is mediated by what?
the free radicals species produced by free copper or iron
How do free radicals cause cellular injury?
they peroxidate lipids and oxidate DNA and proteins
Which enzymes are responsible for the elimination of free radicals?
- superoxide dismutase reduces superoxide to hydrogen peroxide
- catalase reduces hydrogen peroxide to oxygen and water
- glutathione peroxidase reduces primarily hydroxyl radicals by oxidizing two molecules of glutathione
What is carbon tetrachloride? How does exposure manifest?
- CCl4 an organic solvent used in the dry cleaning industry
- P450 converts it to a CCl3 free radical
- this results in hepatocyte injury, which in turn contributes to decreased apolipoprotein synthesis and fatty change in the liver
What is reperfusion injury?
- damage to tissue that follows restoration of blood for to an ischemic tissue
- repefusion results in the formation of oxygen-derived free radicals
An individual presents with an MI and is treated; however, his cardiac enzymes are continuing to rise. What is occurring?
he is experiencing a repercussion injury mediated by free radicals
Define and describe amyloid. How can we identify it?
- a misfolded protein that deposits in the extracellular space
- typically has a beta-pleated sheet configuration
- it is identified using Congo red stain which then demonstrates apple-green birefringence under polarized light
Primary Systemic Amyloidosis
- systemic deposition of AL amyloid, which is derived from immunoglobulin light chain
- associated with plasma cell dyscrasias like multiple myeloma
Secondary Systemic Amyloidosis
- a systemic deposition of AA amyloid, which is derived from serum amyloid-associated protein, a positive acute phase reactant
- levels increase during a chronic inflammatory state, malignancy, and Familial Mediterranean Fever
- clinical findings depending on the tissue affect but the kidney is most commonly involved, producing a nephrotic syndrome, and the heart is often involved, producing a restrictive cardiomyopathy or arrhythmia
- diagnosis requires a tissue biopsy and damaged organs must be transplanted
Familial Mediterranean Fever
- an autosomal recessive condition due to dysfunctional neutrophils
- occurs in persons of Mediterranean origin
- presents with episodes of fever and acute serial inflammation, which may mimic appendicitis, arthritis, or MI
- SSA becomes elevated during the course, contributing to a secondary systemic amyloidosis (nephrotic syndrome and restrictive cardiomyopathy likely)
Senile Cardiac Amyloidosis
- non-mutated serum transthyretin deposits in the heart
- usually asymptomatic
- seen in more than 25% of people over 80 years old
Familial Amyloid Cardiomyopathy
- mutated serum transthyretin deposits in the heart
- contributes to a restrictive cardiomyopathy
- prevalent amongst African Americans
Diabetes-Associated Amyloidosis
- amylin, a derivative of insulin, is deposited in the islets of the pancreas
- also known as islet amyloid polypeptide
Dialysis-Associated Amyloidosis
- B2-microglobulin (a structural support for MHC-I) deposits in the joints
- may present as carpal tunnel syndrome
Give six examples of localized amyloidosis and the protein that is deposited.
- senile cardiac amyloidosis: non-mutated transthyretin
- familial amyloid cardiomyopathy: mutated transthyretin
- non-insulin-dependnent diabetes mellitus: amylin
- Alzheimer disease: AB amyloid
- Dialysis-Associated amyloidosis: B2-microglobulin
- Medullary carcinoma of the hyoid: calcitonin
Medullary Carcinoma of the Thyroid
- a tumor derived form C-cells, which produce calcitonin
- calcitonin deposits within the tumor, causing an amyloidosis
- classically described as “tumor cells in an amyloid background”
What is DNA laddering?
fragments in multiples of 180 bp that are a sensitive indicator of apoptosis
What are the roles of Bcl-2, BAX, and BAK?
- BAX and BAK are proapoptotic
- Bcl-2 inhibits APAF-1 and cytochrome release and is anti-apoptotic
What kind of apoptosis mediates negative selection of T cells in the thymic medulla?
Fas-FasL (extrinsic death receptor pathway)
Which regions of the brain, heart, kidney, liver, and colon are most susceptible to ischemic injury?
- brain: ACA, MCA, PCA boundary areas
- heart: subendocardium of the LV
- kidney: straight segment of the proximal tubule and thick ascending limb
- liver: zone III (around the central vein)
- colon: splenic flexure and rectum
What are watershed zones?
- areas that receive blood supply from the most distal branches of two arteries with limited collateral vascularity, leaving them highly susceptible to hypo perfusion ischemia
- primary examples are in the brain and at the splenic flexure and rectum in the GI tract
Which neurons in the brain are most vulnerable to hypoxic-ischemic insult?
- Purkinje cells of the cerebellum
- pyramidal cells of the hippocampus
- neocrotex
In which organs does metastatic calcification tend to predominate? Why?
- interstitial tissues of the kidney, lung, and gastric mucosa are most affected
- this is because these tissues lose acid quickly and a basic pH favors deposition
Describe inhalation injury (causes, presentation, sequelae)
- a pulmonary complication associated with smoke and fire
- caused by heat, microscopic particles, or irritants
- leads to chemical tracheobronchitis, edema, pneumonia, and ARDS
- many patients present secondary to buns, CO inhalation, or arsenic poisoning
Describe lipofuscin. What is it indicative of? How does it form?
- it is a yellow-brown pigment associated with normal aging
- it is associated with “wear and tear”
- formed by oxidation and polymerization of autophagocytosed organelle membranes
Chromatolysis
- a histologic reaction of neuronal cell body to axonal injury
- the changes reflect increased protein synthesis as the cell attempts to repair a damaged axon
- the cell swells and rounds, the nucleus is displaced to the periphery, and Nissl substance disperses throughout the cytoplasm
- accompanies Wallerian degeneration (degeneration of axon distal to site of injury)
Hyperacute Rejection
- a type II hypersensitivity that occurs within minutes
- mediated by preformed recipient antibodies against donor antigens
- leads to widespread necrosis of graft vessels and thus ischemia and necrosis of the transplant
- requires graft removal
Acute Rejection
- a type IV hypersensitivity that occurs in weeks to months
- there is a cellular (CD4 and CD8) and a humoral component
- causes vasculitis with a dense lymphocytic interstitial infiltrate
- this is what immunosuppression is used to prevent
Chronic Rejection
- a type II and IV hypersensitivity in months to years
- mediated by CD4 cells responding to donor peptides being presented on recipient MHCs
- results in proliferation of vascular smooth muscle, parenchymal atrophy, and interstitial fibrosis
GvHD
- most common in bone marrow and liver transplants
- due to engrafted T cells attacking donor antigens, making it a type IV hypersensitivity
- presents with a maculopapular rash, hepatosplenomegaly, jaundice, and diarrhea
What is the difference between type I, II, and IV renal tubular acidosis?
- type I: due to inability of a-intercalated cells to secrete protons, so no new bicarb is produced; urine pH > 5.5; serum potassium low
- type II: due to inability of PCT to adequately reabsorb bicarb; urine pH < 5.5 because a-intercalated cells attempt to compensate; serum potassium low
- type IV: due to hypoaldosteronism or aldosterone resistance; urine pH < 5.5; serum potassium high
What would cause a type I, II, or IV renal tubular acidosis?
- type I: amphotericin B toxicity, analgesic nephropathy, congenital anomalies of the urinary tract, SLE
- type II: fanconi syndrome, multiple myeloma, carbonic anhydrase inhibitors
- type IV: low aldosterone or aldosterone resistance
Trisomy 21
- caused by meiotic non-dysjunction due to maternal age, unbalanced Robertsonian translocation, or mitotic non-dysfunction
- presents with nuchal translucency and hypoplasia of the nasal bone on ultrasound in the first trimester
- amniotic fluid in the first trimester demonstrates elevated B-hCG and diminished PPAP-A
- amniotic fluid in the second trimester demonstrates low AFP, elevated B-hCG, low estriol, and elevated inhibin A
- presents with intellectual disability, risk for Alzheimer’s, duodenal atresia, Hirschsprung disease, risk of ALL or AML, prominent epicanthal folds, Brushfield spots, and AV septal defects
Trisomy 18
- the second most common cause of trisomy, known as Edward’s syndrome
- in utero, B-hCG and PPAP-A are low in the first trimester; AFP, B-hCG, estriol, and inhibin A are low in the second
- findings described by “PRINCE Edward”: prominent occiput, rocker bottom feet, intellectual disability, nondisjunction, clenched fists with overlapping fingers, low-set ears
- plus micrognathia and congenital heart disease
Trisomy 13
- known as Patau syndrome
- B-hCG and PPAP-A are low in the first trimester
- microcephaly, holoprosencephaly, intellectual disability
- microphthalmia, cleft lip/palate
- congenital heart disease
- PKD
- cutis aplasia, polydactyly, rocker bottom feet
What is the mechanism of action for tacrolimus?
it forms a complex with FKBP and inhibits calcineurin, preventing activation of NFAT, which is a pro-inflammatory transcription factor
What is the mechanism of action for cyclosporine?
it forms a complex with cyclophilin and inhibits calcineurin, preventing activation of NFAT, which is a pro-inflammatory transcription factor
What is the mechanism of action for sirolimus?
it forms a complex with FKBP and inhibits mTOR, a protein in the IL-2R signal cascade, which stimulates cell proliferation
Name two monoclonal antibodies that inhibit IL-2R.
daclizumab and basiliximab
How do tacrolimus, cyclosporine, and sirolimus compare in regards to toxicity?
- tacrolimus is most nephrotoxic
- cyclosporine is nephrotoxic
- sirolimus is not nephrotoxic (the kidneys “sir”vives)
What are the effects of dopamine, somatostatin, TRH, and CRH in the hypothalamic-pituitary axis?
- dopamine inhibits release of prolactin and TSH
- TRH promotes the release of prolactin and TSH
- somatostatin inhibits the release of GH and TSH
- CRH promotes the release of ACTH, MSH, and B-endorphin
Phenylalanine is a precursor for what?
- tyrosine
- thyroxin
- catecholamines
- melanin
Tryptophan is a precursor for what?
- serotonin and melatonin (requires B6/pyridoxine and BH4)
- niacin, NAD, and NADP (requires B2 and B6/pyridoxine)
Glycine is a precursor for what?
porphyrin
Glutamate is a precursor for what?
GABA and glutathione
Argining is a precursor for what?
NO, urea, and creatine
Describe proper verbal development.
- oratory by 10 months
- 200 words by age 2 with 2 word phrases
- 1000 words by age 3 with complete sentences
- full stories by age 4
Describe proper motor development.
- rolls and sits by 6 months
- crawls by 8 months
- stands by 10 months
- first steps by 12 months
- kicks ball by 24 months
- drives tricycle by 3 years
- copies lines and circles by 4 years
- hops on one foot by 4 years
- grooms and dresses by 5 years
What cartilage and nerves arise from branchial arches 1, 2, 3, and 4/6?
- 1: maxillary, mandible, malleus and incus plus CN V3
- 2: stapes, and lesser horn of hyoid plus CN VII
- 3: greater horn of hyoid plus CN IX
- 4/6: cricoid plus CN X
What are the derivatives of the 1st, 2nd, 3rd, and 4th branchial pouches?
- 1: eustachian
- 2: epithelial lining of palatine tonsils
- 3: inferior parathyroid and thymus
- 4: superior parathyroid and parafollicular C cells of thyroid
List the important CYP inducers.
- carbamazepine
- cyclophosphamide
- griseofulvin
- modafinil
- phenytoin
- rifampin
- St. John’s wort
List the important CYP inhibitors.
- Amiodarone
- Azoles
- Clarithromycin
- Cimetidine
- Fluoroquinolones
- Grape Fruit Juice
- Isoniazid
- Ritonavir
