Topics A6-11 - Cell Injury, Accumulations, Pigment, Calcification, Stones Flashcards
3 morphological kinds of cell injury (the reversible state between healthy cells and necrosis)
- Hydropic/Vacuolar Degeneration, aka Cellular Swelling. Low energy -> poor sodium/water pumping
- Parenchymal Degeneration. Mostly in liver, heart, kidney. Looks like boiled meat
- Fatty Degeneration. Also mostly parenchymal organs, but injured cells accumulate lipid droplets
5 causes of fatty degeneration / “steatosis”
- Starvation: increases fat mobilization from periphery
- Hypoxia: fat catabolism blocked
- Toxins, alcohol: Decrease in NAD, increase in NADH. NAD needed for beta oxidation
- Protein malnutrition: cannot produce ApoB-100 and thus cannot export TAG
- Obesity: fat overload
How does fat accumulation in cells look with H-E stain?
Looks like there are empty holes in the cell due to unstained fat deposits
What is the difference in morphology between fatty degeneration caused by toxins vs hypoxia?
Toxins -> diffuse fatty degeneration
Hypoxia -> mottled / spotty fat degeneration
What is steatoris diffuse hepatis?
What are 2 causes?
Diffuse liver fat accumulation, liver appears enlarged and yellow
Caused by obesity or alcoholism, with cirrhosis
What is nutmeg liver?
What part of the liver is most affected?
Aka Degeneratio adiposa insularis hepatis, occurs due to build up of pressure in the IVC (typically first due to increased pressure in lung, then right ventricle, then IVC, then liver). Increased pressure leads to decreased oxygenation.
The pericentral area around the central vein receives the least oxygen (it’s at the end of the arterial-venous gradient), and so it is affected the most by hypoxia. Makes a mottled appearance.
What is degeneratio adiposa diffusa myocardii?
Entire heart appears yellowish due to fat deposits, pumping failure occurs. More related to sepsis
What is degeneratio adiposa insularis myocardii?
Aka “Tiger Heart” - has stripes on it from hypoxia. There is subendocardial degeneration due to anemia, acute respiratory problems, decreased oxygen, or increased muscle effort. Subendocardium cells accumulate fat in a striped fashion.
What are 3 autosomal recessive diseases that cause glycogen accumulation?
- von Gierke’s disease (Hepatic glycogenosis), lacks glucose 6 phosphatase
- McArdle’s Disease (myopathic glycogenosis) - muscle phosphorylase missing
- Pompe Disease: lysosomal acid maltase deficiency, causes glycogen to accumulate in lysosomes
2 parts of the intimal plaque in atherosclerosis, and what do they contain?
What is the most dangerous part for rupture?
- Lipid/Necrotic Core: cholesterol crystals, EC matrix, cell debris, and foam cells. This is surrounded by inflammatory cells (lymphocytes, macrophages) and plasma proteins
- Fibrous Cap: new vascularization (proliferating blood vessels), endothelial cells, smooth muscle. The most dangerous part for rupture is the cap’s “shoulder” where it meets the vessel wall
Framingham Study: What are the 3 major constitutional risk factors for atherosclerosis?
(note: for the risks described in the Framingham study, each one when combined is not summative but multiplicative.. so having 2 risks increases your risk by 4x, and so on)
- Age. Risk increases after ~40 years old. Atherosclerosis takes a long time to become clinically significant.
- Sex: higher risk in males. Female hormones have a protective role. This benefit decreases after menopause though
- Genetics: no single gene, but some that influence obesity, hyperlipidemia, diabetes, etc.
Framingham Study: What are 4 major modifiable risk factors for atherosclerosis?
- Hyperlipidemia (more specifically hypercholesterolemia): High LDL / low HDL. Obesity and smoking increase LDL and decrease HDL. Small amount of alcohol increases HDL, but large amount is damaging.
- Hypertension: puts stress on endothelial cells
- Cigarete smoking
- Diabetes mellitus
Framingham Study: 5 additional risk factors to atherosclerosis, besides the major constitutional and modifiable ones
- Chronic Inflammation. Even something like poor dental hygiene can increase MI risk because oral bacteria stimulate inflammation
- Obesity
- Low physical activity
- Stressful life (related to hypertension)
- Type “A” Personality - competitive, also more common in men
How do endothelial non-denuding cell injuries relate to atherosclerosis?
What causes endothelial non-denuding injury? (2 main causes to know)
Endothelial cell injury doesn’t cause cell death but rather dysfunction with increased ROS and decreased NO produced by endothelial cells.
Injury occurs from hypertension (pressure and turbulent flow, especially on arterial branches) and hyperlipidemia (macrophages eat up oxLDL and die -> subendothelium has cholesterol with necrotic debris). Also cigarette smoke, infectious agents, etc.
What are the 3 morphological types of atherosclerosis?
- Fatty Streak: early atherosclerosis, reversible, begins in childhood. Does not impede flow
- Primary atherosclerotic plaque: classic description, has intimal thickening and blood flow impeded
- Complicated plaque: on top of primary plaque there are additional changes.. separate card for that
What are 6 changes to an atherosclerotic plaque that make it “complicated” versus primary?
- Aneurysm: plaque causes pressure atrophy on vessel wall
- Thrombus formation: via Ulceration, Erosion, or Rupture
- Bleeding: bleeding into plaque can cause hematoma and rupture. Bleeding can also occur from vaso vasorum
- Calcification
- Stenosis: (related to calcification)
- Cholesterol Embolism
What should be done for primary prevention of atherosclerosis (pt has no symptoms yet)?
- Quit or don’t start smoking. A pack a day increases risk by 200x
- Treat hypertension, diabetes, reduce LDL cholesterol, etc. Control all problems related to coronary artery disease.
Prevention should start in childhood, good health education, start good habits early
What should be done as secondary prevention of atherosclerosis? Pt already has atherosclerosis, maybe already had an MI
Again treat hypertension, diabetes, etc. Also give statins to lower LDL cholesterol (maybe the new PCSK9 inhibitors too). May need surgical intervention, such as stent placement.
What causes amyloidosis when it’s associated with hemodialysis?
Beta2 microglobulin (component of MHC class I) is retained in circulation because its not efficiently filtered out in hemodialysis machines.
What special type of histology staining is used for amyloidosis? What is the annoying buzzword that is used to describe it?
Congo staining
Congo red turns amyloid red, and polarizing microscope shows an “apple green birefringence”
What causes amyloidosis?
Protein misfolding and aggregation. Maybe 30 different compounds known to create amyloidosis. These look like a starch (amylose in particular) when stained, hence the name.
Have beta pleated sheet structure; linear non-branching filaments
What type of amyloidosis is related to Alzheimer’s disease?
Amyloid Beta (AB) - spherical plaques. The precursor is Amyloid Precursor Protein (APP)
What type of amyloidosis is seen in myelomas?
Amyloid light chain (AL) - made from immunoglobulin light chains, lambda or kappa.
(Note: not the same thing as Russell bodies)
What type of injury is created by amyloidosis?
Pressure injury, because amyloid deposits compress cells and block their functions. They’re insoluble, have a very bad prognosis. Do not evoke an inflammatory response.
Most important organ damaged is the kidney
What type of amyloidosis is associated with acute phase inflammation?
AA: Amyloid-Associated, precursor is SAA: Serum Amyloid A. If patient has chronic inflammation, the liver produces a lot of SAA, and misfolding creates amyloidosis
What type of amyloid is related to thyroid hormone? What important area can it deposit in?
Transthyretin: protein misfolding takes place in liver that transports thyroxine and retinol-binding protein. When it’s misfolded, it’s resistant to proteolysis, and deposits as amyloid. Mutation of gene encoding this causes familial amyloid polyneuropathies.
Can deposit in heart -> called Senile Systemic Amyloidosis
4 diseases of Hyaline accumulation
- Hyalinic arteriosclerosis: related to diabetes and hypertension. Kidney most affected: “nephrosclerosis”
- Hyaline membrane disease: relates to alveoli
- Hyalinic glomeruli: end-stage kidney disease
- Mallory Hyaline - hepatocytes get Mallory bodies with alcohol toxicosis
How does a kidney affected by nephrosclerosis look?
Surface is granular and shrunken, like grain leather
What is the pathogenesis of hyaline membrane disease? What 2 conditions does it occur in?
Hyaline membrane in alveoli results from leaky capillaries secreting protein-rich exudate
Causes:
- IRDS: infant respiratory distress syndrome, caused by hypoxia
- ARDS: adult version. Caused by sepsis, toxins
What are 2 types of spleen conditions resulting from splenic amyloidosis?
Nodular deposition -> “sago spleen”
Red pulp deposition -> “sausage spleen”
Both cause splenomegaly and are “clinically unimportant” but probably still have to know it
What are 2 important conditions caused by inhaled carbon/coal and its deposition?
- Anthracosis: macrophages eat carbon and deposit in lung’s lymphatic vessels, maybe even regional lymph nodes. Not very dangerous
- Coal Worker’s (and Stone Polisher’s) Pneumoconiosis: coal is mixed with Si, Fe, and other metals that are more dangerous. Si crystals get in lung -> macrophage rxn -> SiOH with toxic, fibrosis-stimulating effect. We are incapable of removing Si, get fibrotic lung, pulmonary hypertension, cor pulmonale, etc.
What pigment change might cause brown atrophy of the heart?
Lipofuscin: a wear-and-tear pigment common in old age, generated from breakdown and lipid peroxidation of intracellular membranes. In histo its yellow-brown granules, usually arranged around the nucleus
Brown atrophy of heart: heart is small, brown, angled downward, and coronaries are curvy
What makes hemosiderin?
What histo stain is used for it?
Macrophages trapping ferritin micelles together, making brownish-colored granular substance.
Prussian blue staining (has potassium ferrin) - stains iron blue or purple
What is the main difference between hemosiderosis and hemochromatosis that Matolcsy emphasized?
Hemosiderosis is still under control of macrophages, they are eating iron and it’s depositing in them in various organs
Hemochromatosis is out of control of the macrophages; they are overloaded because of the genetic mutation that allows uncontrolled absorption of iron
What are the 2 kinds of hemosiderosis?
Local: bruising after trauma, or brown-colored lung due to left-sided heart failure and congestion
Systemic: general breakdown of RBC’s, due to hemolysis. Have hemosiderin deposits all over organs
What is the mechanism behind hemochromatosis?
Autosomal recessive mutation of hepcidin, which regulates iron absorption. Mutation means iron absorption is uncontrolled, iron levels are way too high, the macrophages become saturated by iron and it deposits in other cells
What are some organ-specific consequences of hemochromatosis?
Pancreas, heart, and skin become fibrotic. Pancreas destruction causes diabetes and steatorrhea. Heart and skin become brown, heart failure develops.
Liver develops cirrhosis, portal hypertension develops. Person has 200x risk for hepatocarcinoma.
At what age do symptoms of hemochromatosis usually start? What is the difference in genders?
Women develop it later because of menstrual bleeding getting rid of some iron
What’s the rate-limiting enzyme for melanin production?
Tyrosinase
Melanin is made after many conversions of tyrosine, which is first converted to DOPA by tyrosinase
What is vitiligo? What are the two types?
Vitiligo = lack of melanocytes and melanin in epidermal layer
- Hereditary: albinism, occurs due to mutation of tyrosinase
- Autoimmune: autoantibody against melanocytes. More localized, get splotches. More noticeable in dark-skinned people
What is a melasma?
Dark brownish discoloration of the skin. More common in pregnant women, related to hormonal changes. Stimulation of melanocytes to produce more melanin.
What is an epidermal melanin unit?
Combination of melanocytes and the epithelial cells that absorb the melanin that is produced by melanocytes. These epithelial cells are mostly at the basal layer of epidermis
What is used as an identifying marker for immunohistochemistry of melanin? And for malignant melanoma?
S100+ for melanocytes
HMB45+ for malignant melanoma
What are the two types of melanocytic nevi?
- Compound nevus: the nevus accumulates downwards in both the epidermal and subepidermal area
- Dermal nevus: accumulates in the dermis
What’s the mnemonic for melanoma recognition?
A: asymmetrical
B: borders are irregular
C: color - more than one, or uneven distribution
D: diameter > 6mm (~size of pencil eraser)
E: evolution - recent growth or color change. This is the most important sign!
What are the 2 types of calcification?
- Dystrophic (normocalcemic) calcification: local calcification due to injury, necrosis, and aging. serum calcium is normal.
- Metastatic (hypercalcemic) calcification: serum calcium is increased, causes widespread calcification
How might calcium deposits appear?
Bluish-colored (calcium phosphate is basophilic)
Crystals, amorphous, or like lamellated spirals (psammoma body)
What are the two types of dystrophic calcification initiation?
- Extracellular: Calcium is located inside membrane-bound vesicles from necrotic cell fragments, and membrane-bound phosphatase generates Pi that binds to Ca2+ -> crystal precipitation (“propagation”)
- Intracellular initiation: initiated in mitochondria of dead/dying cells that cannot regulate intracellular Ca2+
Where does atherosclerosis show calcification?
In the central area, there is necrotic cell debris that accumulates calcium
What are two instances where valves undergo calcification?
- Calcifying aortic stenosis - from exit of the valve, necrotic tissue develops and calcifies. Remember this is associated with left ventricle hypertrophy
- Artificial valve: from necrotic area around sutures attaching the valve
Why are tumors prone to dystrophic calcification? What in this may be used as a sign of cancers?
Tumor cells outgrow their vascular supply and can die by necrosis, then become calficified.
The calcification is a tumor sign because it’s radiodense, and also may show up as psammoma bodies (concentric lamellated spirals) in histology. Psammoma body may be seen in ovarian or papillary thyroid cancer.
Why is there calcification in tuberculosis?
Inflammation -> granuloma with central caseation necrosis. The necrotic tissue forms calcifications.
Which organs see metastatic calcifications, and why?
The high serum Ca2+ precipitates in organs with alkaline cells, especially those that secrete acid and leaving remaining tissue alkaline. Calcium favors precipitation in alkaline environment
Microcalcifications occur the most in lung, kidney, and stomach. No significant functional loss.
Which two main conditions generate hypercalcemia?
- Hyperparathyroidism. PH mobilizes Ca2+ from bones. Could be from parathyroid adenoma or from kidney failure (kidney cannot excrete phosphate, so it stays in blood and binds Ca2+, and low calcium stimulates PH release)
- Bone distracting/ damaging diseases. Could be osteolytic bone cancer releasing Ca2+.
What are the two types of gallstones?
- Cholesterol stones: pale yellow to white, occasionally black. “ovoid and firm.” Contain crystalline cholesterol monohydrate. More common.
- Pigment stones: from bilirubin. There are black and brown forms.
(need to confirm which is harder, saw some conflicting info.. probably pigment stones are harder)
What’s more dangerous, small or big gallstones?
Small ones, because they’re more likely to go into the bile duct and clog it
What are 4 forms of kidney stones?
- Calcium stones: most common
- Magnesium Ammonium Phosphate Stones (aka Struvit or Staghorn) - fragile, brownish
- Hyperuricemia: associated with gout
- Cysteinuria: very rare, cysteine transport mutation
What is a long term complication of gallstones?
Chronic inflammation can cause tumors: carcinoma via chronic cholecystitis
What is a major consequence of kidney stones?
Hydronephrosis: downstream occlusion will increase pressure upstream, dilating the lumens. Creates pressure atrophy on renal tissue
Which gender is more likely to get gallstones?
Females (2x higher)
What is the different causes between black and brown pigment stones?
Black: hemolytic anemia or excess conjugated bilirubin
Brown: sign of infection in common bile duct. Infection unconjugates CB, increasing the UCB in bile and makes it browner
Need more on stones. There wasn’t a lecture that covered it very well
Yes
