Topics A6-11 - Cell Injury, Accumulations, Pigment, Calcification, Stones

Question 1

3 morphological kinds of cell injury (the reversible state between healthy cells and necrosis)

Answer 1

1. Hydropic/Vacuolar Degeneration, aka Cellular Swelling. Low energy -> poor sodium/water pumping
2. Parenchymal Degeneration. Mostly in liver, heart, kidney. Looks like boiled meat
3. Fatty Degeneration. Also mostly parenchymal organs, but injured cells accumulate lipid droplets

Question 2

5 causes of fatty degeneration / “steatosis”

Answer 2

1. Starvation: increases fat mobilization from periphery
2. Hypoxia: fat catabolism blocked
3. Toxins, alcohol: Decrease in NAD, increase in NADH. NAD needed for beta oxidation
4. Protein malnutrition: cannot produce ApoB-100 and thus cannot export TAG
5. Obesity: fat overload

Question 3

How does fat accumulation in cells look with H-E stain?

Answer 3

Looks like there are empty holes in the cell due to unstained fat deposits

Question 4

What is the difference in morphology between fatty degeneration caused by toxins vs hypoxia?

Answer 4

Toxins -> diffuse fatty degeneration

Hypoxia -> mottled / spotty fat degeneration

Question 5

What is steatoris diffuse hepatis?

What are 2 causes?

Answer 5

Diffuse liver fat accumulation, liver appears enlarged and yellow
Caused by obesity or alcoholism, with cirrhosis

Question 6

What is nutmeg liver?

What part of the liver is most affected?

Answer 6

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.

Question 7

What is degeneratio adiposa diffusa myocardii?

Answer 7

Entire heart appears yellowish due to fat deposits, pumping failure occurs. More related to sepsis

Question 8

What is degeneratio adiposa insularis myocardii?

Answer 8

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.

Question 9

What are 3 autosomal recessive diseases that cause glycogen accumulation?

Answer 9

1. von Gierke’s disease (Hepatic glycogenosis), lacks glucose 6 phosphatase
2. McArdle’s Disease (myopathic glycogenosis) - muscle phosphorylase missing
3. Pompe Disease: lysosomal acid maltase deficiency, causes glycogen to accumulate in lysosomes

Question 10

2 parts of the intimal plaque in atherosclerosis, and what do they contain?

What is the most dangerous part for rupture?

Answer 10

1. Lipid/Necrotic Core: cholesterol crystals, EC matrix, cell debris, and foam cells. This is surrounded by inflammatory cells (lymphocytes, macrophages) and plasma proteins
2. 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

Question 11

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)

Answer 11

1. Age. Risk increases after ~40 years old. Atherosclerosis takes a long time to become clinically significant.
2. Sex: higher risk in males. Female hormones have a protective role. This benefit decreases after menopause though
3. Genetics: no single gene, but some that influence obesity, hyperlipidemia, diabetes, etc.

Question 12

Framingham Study: What are 4 major modifiable risk factors for atherosclerosis?

Answer 12

1. 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.
2. Hypertension: puts stress on endothelial cells
3. Cigarete smoking
4. Diabetes mellitus

Question 13

Framingham Study: 5 additional risk factors to atherosclerosis, besides the major constitutional and modifiable ones

Answer 13

1. Chronic Inflammation. Even something like poor dental hygiene can increase MI risk because oral bacteria stimulate inflammation
2. Obesity
3. Low physical activity
4. Stressful life (related to hypertension)
5. Type “A” Personality - competitive, also more common in men

Question 14

How do endothelial non-denuding cell injuries relate to atherosclerosis?

What causes endothelial non-denuding injury? (2 main causes to know)

Answer 14

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.

Question 15

What are the 3 morphological types of atherosclerosis?

Answer 15

1. Fatty Streak: early atherosclerosis, reversible, begins in childhood. Does not impede flow
2. Primary atherosclerotic plaque: classic description, has intimal thickening and blood flow impeded
3. Complicated plaque: on top of primary plaque there are additional changes.. separate card for that

Question 16

What are 6 changes to an atherosclerotic plaque that make it “complicated” versus primary?

Answer 16

1. Aneurysm: plaque causes pressure atrophy on vessel wall
2. Thrombus formation: via Ulceration, Erosion, or Rupture
3. Bleeding: bleeding into plaque can cause hematoma and rupture. Bleeding can also occur from vaso vasorum
4. Calcification
5. Stenosis: (related to calcification)
6. Cholesterol Embolism

Question 17

What should be done for primary prevention of atherosclerosis (pt has no symptoms yet)?

Answer 17

1. Quit or don’t start smoking. A pack a day increases risk by 200x
2. 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

Question 18

What should be done as secondary prevention of atherosclerosis? Pt already has atherosclerosis, maybe already had an MI

Answer 18

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.

Question 19

What causes amyloidosis when it’s associated with hemodialysis?

Answer 19

Beta2 microglobulin (component of MHC class I) is retained in circulation because its not efficiently filtered out in hemodialysis machines.

Question 20

What special type of histology staining is used for amyloidosis? What is the annoying buzzword that is used to describe it?

Answer 20

Congo staining

Congo red turns amyloid red, and polarizing microscope shows an “apple green birefringence”

Question 21

What causes amyloidosis?

Answer 21

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

Question 22

What type of amyloidosis is related to Alzheimer’s disease?

Answer 22

Amyloid Beta (AB) - spherical plaques. The precursor is Amyloid Precursor Protein (APP)

Question 23

What type of amyloidosis is seen in myelomas?

Answer 23

Amyloid light chain (AL) - made from immunoglobulin light chains, lambda or kappa.

(Note: not the same thing as Russell bodies)

Question 24

What type of injury is created by amyloidosis?

Answer 24

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

Question 25

What type of amyloidosis is associated with acute phase inflammation?

Answer 25

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

Question 26

What type of amyloid is related to thyroid hormone? What important area can it deposit in?

Answer 26

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

Question 27

4 diseases of Hyaline accumulation

Answer 27

1. Hyalinic arteriosclerosis: related to diabetes and hypertension. Kidney most affected: “nephrosclerosis”
2. Hyaline membrane disease: relates to alveoli
3. Hyalinic glomeruli: end-stage kidney disease
4. Mallory Hyaline - hepatocytes get Mallory bodies with alcohol toxicosis

Question 28

How does a kidney affected by nephrosclerosis look?

Answer 28

Surface is granular and shrunken, like grain leather

Question 29

What is the pathogenesis of hyaline membrane disease? What 2 conditions does it occur in?

Answer 29

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

Question 30

What are 2 types of spleen conditions resulting from splenic amyloidosis?

Answer 30

Nodular deposition -> “sago spleen”

Red pulp deposition -> “sausage spleen”

Both cause splenomegaly and are “clinically unimportant” but probably still have to know it

Question 31

What are 2 important conditions caused by inhaled carbon/coal and its deposition?

Answer 31

1. Anthracosis: macrophages eat carbon and deposit in lung’s lymphatic vessels, maybe even regional lymph nodes. Not very dangerous
2. 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.

Question 32

What pigment change might cause brown atrophy of the heart?

Answer 32

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

Question 33

What makes hemosiderin?

What histo stain is used for it?

Answer 33

Macrophages trapping ferritin micelles together, making brownish-colored granular substance.

Prussian blue staining (has potassium ferrin) - stains iron blue or purple

Question 34

What is the main difference between hemosiderosis and hemochromatosis that Matolcsy emphasized?

Answer 34

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

Question 35

What are the 2 kinds of hemosiderosis?

Answer 35

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

Question 36

What is the mechanism behind hemochromatosis?

Answer 36

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

Question 37

What are some organ-specific consequences of hemochromatosis?

Answer 37

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.

Question 38

At what age do symptoms of hemochromatosis usually start? What is the difference in genders?

Answer 38

Women develop it later because of menstrual bleeding getting rid of some iron

Question 39

What’s the rate-limiting enzyme for melanin production?

Answer 39

Tyrosinase

Melanin is made after many conversions of tyrosine, which is first converted to DOPA by tyrosinase

Question 40

What is vitiligo? What are the two types?

Answer 40

Vitiligo = lack of melanocytes and melanin in epidermal layer

1. Hereditary: albinism, occurs due to mutation of tyrosinase
2. Autoimmune: autoantibody against melanocytes. More localized, get splotches. More noticeable in dark-skinned people

Question 41

What is a melasma?

Answer 41

Dark brownish discoloration of the skin. More common in pregnant women, related to hormonal changes. Stimulation of melanocytes to produce more melanin.

Question 42

What is an epidermal melanin unit?

Answer 42

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

Question 43

What is used as an identifying marker for immunohistochemistry of melanin? And for malignant melanoma?

Answer 43

S100+ for melanocytes

HMB45+ for malignant melanoma

Question 44

What are the two types of melanocytic nevi?

Answer 44

1. Compound nevus: the nevus accumulates downwards in both the epidermal and subepidermal area
2. Dermal nevus: accumulates in the dermis

Question 45

What’s the mnemonic for melanoma recognition?

Answer 45

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!

Question 46

What are the 2 types of calcification?

Answer 46

1. Dystrophic (normocalcemic) calcification: local calcification due to injury, necrosis, and aging. serum calcium is normal.
2. Metastatic (hypercalcemic) calcification: serum calcium is increased, causes widespread calcification

Question 47

How might calcium deposits appear?

Answer 47

Bluish-colored (calcium phosphate is basophilic)

Crystals, amorphous, or like lamellated spirals (psammoma body)

Question 48

What are the two types of dystrophic calcification initiation?

Answer 48

1. 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”)
2. Intracellular initiation: initiated in mitochondria of dead/dying cells that cannot regulate intracellular Ca2+

Question 49

Where does atherosclerosis show calcification?

Answer 49

In the central area, there is necrotic cell debris that accumulates calcium

Question 50

What are two instances where valves undergo calcification?

Answer 50

1. Calcifying aortic stenosis - from exit of the valve, necrotic tissue develops and calcifies. Remember this is associated with left ventricle hypertrophy
2. Artificial valve: from necrotic area around sutures attaching the valve

Question 51

Why are tumors prone to dystrophic calcification? What in this may be used as a sign of cancers?

Answer 51

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.

Question 52

Why is there calcification in tuberculosis?

Answer 52

Inflammation -> granuloma with central caseation necrosis. The necrotic tissue forms calcifications.

Question 53

Which organs see metastatic calcifications, and why?

Answer 53

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.

Question 54

Which two main conditions generate hypercalcemia?

Answer 54

1. 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)
2. Bone distracting/ damaging diseases. Could be osteolytic bone cancer releasing Ca2+.

Question 55

What are the two types of gallstones?

Answer 55

1. Cholesterol stones: pale yellow to white, occasionally black. “ovoid and firm.” Contain crystalline cholesterol monohydrate. More common.
2. 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)

Question 56

What’s more dangerous, small or big gallstones?

Answer 56

Small ones, because they’re more likely to go into the bile duct and clog it

Question 57

What are 4 forms of kidney stones?

Answer 57

1. Calcium stones: most common
2. Magnesium Ammonium Phosphate Stones (aka Struvit or Staghorn) - fragile, brownish
3. Hyperuricemia: associated with gout
4. Cysteinuria: very rare, cysteine transport mutation

Question 58

What is a long term complication of gallstones?

Answer 58

Chronic inflammation can cause tumors: carcinoma via chronic cholecystitis

Question 59

What is a major consequence of kidney stones?

Answer 59

Hydronephrosis: downstream occlusion will increase pressure upstream, dilating the lumens. Creates pressure atrophy on renal tissue

Question 60

Which gender is more likely to get gallstones?

Answer 60

Females (2x higher)

Question 61

What is the different causes between black and brown pigment stones?

Answer 61

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

Question 62

Need more on stones. There wasn’t a lecture that covered it very well

Answer 62

Yes