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STEP 1: Growth Adaptations Cellular Injury PATHOMA > Cellular Death and Amyloidosis > Flashcards

Cellular Death and Amyloidosis Flashcards

1
Q

What is the morphological hallmark of CELL DEATH? Name the underlying mechanisms responsible for this.

A

LOSS OF NUCLEUS
Step 1: PYKNOSIS = Nuclear condensation
Step 2: KARYORRHEXIS = Nuclear fragmentation
Step 3: KARYOLYSIS = Nuclear dissolution

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2
Q

What are the 2 mechanisms of cell death?

A

NECROSIS (Murder of LARGE GROUP of cells)

APOPTOSIS (Suicide of SINGLE cell or SMALL GROUP of cells)

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3
Q

Name the 6 types of NECROSIS.

A
  1. COAGULATIVE NECROSIS
  2. LIQUEFACTIVE NECROSIS
  3. GANGRENOUS NECROSIS
  4. CASEOUS NECROSIS
  5. FAT NECROSIS
  6. FIBRINOID NECROSIS
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4
Q

NECROSIS TYPE 1: Describe the pathology of COAGULATIVE NECROSIS.

A

Coagulation of cellular proteins -> Retain cell shape + organ structure -> Necrotic tissue is FIRM
Loss of nuclei

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5
Q

Ischemic infarcts of any organ result in COAGULATIVE NECROSIS except for which organ?

A

BRAIN

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6
Q

What are the two appearances of COAGULATIVE NECROSIS INFARCTED TISSUE?

A
  1. WEDGE-SHAPED PALE INFARCT: Pointing to focus of vascular origin
  2. RED INFARCT: 2 requirements - Blood re-enters + Tissue is loosely organized
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7
Q

What are the two requirements of a RED HEMORRHAGIC INFARCT, characterized by COAGULATIVE NECROSIS? Name two classic organs where a HEMORRHAGIC INFARCT presents itself.

A

REQUIREMENT 1: Blood has to be able to re-enter via artery
REQUIREMENT 2: Tissue is loosely organized

TESTICULAR HEMORRHAGIC INFARCT: When the spermatic cord is twisted, the thin-walled vein is blocked but thick-walled artery remains patent. Arterial blood re-enters without blood able to leave via vein

PULMONARY HEMORRHAGIC INFARCT

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8
Q

NECROSIS TYPE 2: What is the pathology of LIQUEFACTIVE NECROSIS?

A

Necrotic tissue that becomes LIQUIFIED -> Enzymatic LYSIS of cells and protein

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9
Q

What are the two types of necrosis associated with PANCREATITIS?

A

LIQUEFACTIVE NECROSIS of pancreatic parenchyma

FAT NECROSIS of peri-pancreatic fat

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10
Q

What are 3 characteristic hallmarks of LIQUEFACTIVE NECROSIS?

A
  1. BRAIN INFARCTION: Ischemic infarcts of all organs are COAGULATIVE NECROSIS except for the brain. Proteolytic enzymes from MICROGLIAL CELLS (macrophages) liquify the brain.
  2. ABSCESS: Proteolytic enzymes from NEUTROPHILS liquify tissue
  3. PANCREATITIS: Proteolytic enzymes from PANCREAS liquify PARENCHYMA
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11
Q

NECROSIS TYPE 3: What is the pathology of GANGRENOUS NECROSIS?

A

Coagulative necrosis that resembles MUMMIFIED TISSUE

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12
Q

What is the typical characteristic of GANGRENOUS NECROSIS? What is the less likely characteristic?

A

ISCHEMIA OF LOWER LIMB - particularly in diabetic pts: Atherosclerosis of popliteal artery -> Occlusion of blood supply to lower limb -> GANGRENOUS NECROSIS

ISCHEMIA OF GI TRACT

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13
Q

What is the difference between DRY GANGRENE and WET GANGRENE?

A

DRY GANGRENE = Gangrenous necrosis by itself
WET GANGRENE = Gangrenous necrosis + Liquefactive necrosis (infection of the dead grangrenous tissue) - Wet portion = PUS (neutrophils) + inflammatory exudate

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14
Q

NECROSIS TYPE 4: What is the pathology of CASEOUS NECROSIS?

A

Soft, friable necrotic tissue - “COTTAGE CHEESE-like appearance”

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15
Q

What is characteristic of CASEOUS NECROSIS?

A

Think of caseous necrosis as NECROSIS + adding a little bit of “flour” to batter - FLOUR being TB-causing mycobacterium or fungal wall

GRANULOMATOUS CHRONIC INFLAMMATION - Due to TB or FUNGAL INFECTION

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16
Q

COAGULATIVE NECROSIS + LIQUEFACTIVE NECROSIS = ?

GANGRENOUS NECROSIS + LIQUEFACTIVE NECROSIS = ?

A

CASEOUS NECROSIS = COAGULATIVE + LIQUEFACTIVE

WET GANGRENE = GANGRENOUS + LIQUEFACTIVE

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17
Q

Female pt presents with a palpable mass on the breast. Upon biopsy, giant cells + fat + calcification is seen. What is the underlying process?

A

FAT NECROSIS

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18
Q

NECROSIS TYPE 5: What is the pathology of FAT NECROSIS? What are the two most common characteristics of FAT NECROSIS?

A

DEATH of adipose tissue -> Release of fatty acids -> Ca2+ binds to fatty acids = SAPONIFICATION
2 general causes of SAPONIFICATION:
1. BREAST ADIPOSE TISSUE: Trauma to the breast (e.g. car accident) or female who plays softball with a hit to the chest -> Death of fat tissue -> FA Release -> Ca2+ binds
2. PERI-PANCREATIC FAT: Pancreatitis -> Release of LIPASE -> FA release -> Ca2+ binds

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19
Q

Calcium normally does NOT deposit within normal tissues. What are the two scenarios when CALCIFICATION presents itself? How are these two differentiated based on lab values (Hint: Think Ca and phosphate)

A
  1. SAPONIFICATION - Ex of dystrophic calcification when DEAD FAT tissue becomes a nidus for Ca2+ deposition
    NORMAL Ca2+/NORMAL phosphate
  2. METASTATIC CALCIFICATION - Due to HIGH ca or phosphate -> Calcium deposition all over the body
    HIGH Ca2+/HIGH phosphate
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20
Q

SAPONIFICATION is a type of dystrophic calcification that occurs in a setting of NORMAL Ca2+/Phosphate. What pathologies are associated with saponification
(HINT: Think 3 for breast saponification, Think 4 for a unifying histological feature)

A

BREAST SAPONIFICATION: Trauma-related fat necrosis (BENIGN) + Sclerosing Adenosis Fibrocystic Change (BENIGN, too many glands in lobular unit) + Ductal Carcinoma in situ (MALIGNANT)

PSAMMOMA BODIES = SAPONIFICATION: Mesothelioma + Serous carcinoma of ovary + Papillary carcinoma of thyroid + Meningioma

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21
Q

Does METASTATIC CALCIFICATION imply METASTATIC CANCER? Name a scenario with a metastatic cancer to the bone.

A

NO - Metastatic in the sense that calcium can deposit anywhere in the body
COINCIDENTLY: Metastatic cancer to the bone -> Usually OSTEOCLASTIC or OSTEOLYTIC lesion (unless PROSTATE ADENOCARCINOMA = osteoblastic) -> Hypercalcemia -> Metastatic calcification

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22
Q

What endocrine abnormality can result in METASTATIC CALCIFICATION?

A

HYPERPARATHYROIDISM: High Ca2+ and PO4 -> Increases calcium deposition in normal tissues -> Results in NEPHROCALCINOSIS

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23
Q

NECROSIS TYPE 6: What is the pathology of FIBRINOID NECROSIS?

A

Fibrinoid Necrosis = Necrotic damage to BV wall

Leakage of proteins (INCLUDING FIBRIN) to vessel wall -> Bright pink staining

24
Q

What are 2 main and 1 extra characteristic circumstances of FIBRINOID NECROSIS?

A
  1. MALIGNANT HTN - Diastolic BP >120-130, Presents with HEADACHE, RENAL FAILURE, PAPILLEDEMA = medical emergency
  2. VASCULITIS
    These two are scenarios of HYPERPLASTIC ARTERIOLOSCLEROSIS: Onion skin appearance (SM hyperplasia in attempt to contain the high BP)
  3. PRE-ECLAMPSIA: Cause of very elevated BP
25
Q

Pt is a 30yo woman with FIBRINOID NECROSIS. What is the most likely underlying etiology of her fibrinoid necrosis?

A

PRE-ECLAMPSIA: Cause of VERY HIGH BP. 30yo woman unlikely to have malignant HTN. Presents with proteinuria as well

26
Q

What are 3 classical scenarios of apoptosis? (Think menstrual cycle, embryogenesis, infection)

A
  1. ENDOMETRIAL SHEDDING during menstrual cycle
  2. Removal of CELLS (e.g. spacing between fingers, toes) during embryogenesis
  3. CD8+ T-cell mediated killing of VIRALLY INFECTED cells
27
Q

What are the two morphological changes of APOPTOSIS? What is the biochemical mechanism underlying each change

A
  1. EOSINOPHILIC SHRINKAGE OF DYING CELL: Dying cell fragments and shrinks -> Cytoplasm (eosinophilic) becomes more concentrated
    MECH: Apoptosis mediated by CASPASE -> Activates PROTEASES -> Breaks down cytoskeletal elements that maintain cell size and architecture
  2. NUCLEAR CONDENSATION: Nucleus condenses and fragments in an organized manner
    MECH: Apoptosis mediated by CASPASE -> Activates ENDONUCLEASE -> Fragments DNA
28
Q

When apoptotic bodies fall from the cell, how are they removed? Does inflammation follow or not follow? How is this unlike necrosis?

A

APOPTOTIC BODIES removed from MACROPHAGES

ACUTE INFLAMMATION does NOT follow, unlike tissue necrosis being 1 of 2 main stimuli for acute inflammation

29
Q

Apoptosis is mediated by which key molecule? What two molecules get activated as a result?

A

APOPTOSIS mediated by CASPASES

Caspases -> Activate PROTEASE (Cell shrinkage) + ENDONUCLEASE (Nuclear condensation/fragmentation)

30
Q

What are the 3 pathways of apoptosis. Describe molecules involved in each.

A
  1. INTRINSIC PATHWAY (MITOCHONDRIAL): Due to inactivation of BCL-2 (Stabilizer of inner mitochondrial membrane) = Leakage of cytochrome c -> Activation of caspases -> Activation of proteases/endonucleases
  2. EXTRINSIC PATHWAY (RECEPTOR-LIGAND): Due to CD95 (Fas ligand) binding to CD95-R (Fas death receptor) of target cell OR TUMOR NECROSIS FACTOR binding TNF-alpha receptor on target cell-> Activates caspases -> Activates proteases/endonucleases
  3. CD8+ T-cell mediated killing of APC (expressing MHC Class I) - CD8+ T-cell binds MHC Class I with self-Ag -> Secretes perforins -> Creates pores on target cell -> Secretes granzymes that enters pores -> Activates caspases -> Activates proteases/endonucleases
31
Q

What is the typical immunologic example of the EXTRINSIC RECEPTOR LIGAND PATHWAY of apoptosis?

A
  1. **NEGATIVE SELECTION of thymocytes in thymus medulla during maturation (CENTRAL TOLERANCE)
  2. PERIPHERAL TOLERANCE: Self-reactive lymphocytes that escaped central tolerance have inherent CD95-R (Fas death receptor) -> Will upregulate its own CD95 (Fas ligand) -> Binds its own CD95-R and those of other self-reactive lymphocytes

Sidenote: + Selection of thymocytes and B-cell apoptosis is mostly via intrinsic mitochondrial pathway.

32
Q

What are the free radicals? Of all the free radicals, which is the most damaging?

A

O2 (accepts 1e-) = O2-
O2 (accepts 2e-) = H2O2
O2 (accepts 3e-) = OH- **MOST DAMAGING of all free radicals
O2 (accepts 4e-) = H2O - NO longer free radical

33
Q

How do free radicals cause cellular injury?

A
  1. LIPID PEROXIDATION
  2. DNA OXIDATION and DNA protein damage
  3. DNA mutations implicated in AGING and ONCOGENESIS
34
Q

How does CCl4 (carbon tetrachloride) result in free radical injury? Where is it most commonly found in?

A

Organic solvent used in dry cleaning (CCl4) is converted to CCl3- free radical by HEPATOCYTE P450 enzymes -> Initial phase of REVERSIBLE INJURY (RER swelling) -> Ribosomes detach -> Impaired protein synthesis (DECREASED APOLIPOPROTEIN)

35
Q

After CCl4 poisoning, what does the liver look like?

A

FATTY LIVER**
CCl4 poisoning -> Hepatocyte P450 enzymes convert CCl4 into CCl3- -> Reversible injury -> Cellular swelling -> Ribosomes freely detach -> Decreased protein (apolipoprotein) synthesis -> Fat can enter liver but fat can NOT LEAVE the liver (VLDL synthesis requires ApoB100, C, E)

36
Q

What is AMYLOID? What are two shared characteristics? (1 configuration, 1 staining)

A

Misfolded protein that deposits in the extracellular space -> damages tissues

SHARED FEATURES: Multiple proteins can deposit as amyloid, but most are BETA PLEATED
Detected microscopically in CONGO RED STAIN + APPLE-GREEN BIREFRINGENCE under polarized light

37
Q

SYSTEMIC AMYLOIDOSIS TYPE 1: What is PRIMARY amyloidosis?

A

PRIMARY AMYLOIDOSIS = systemic deposition of AL AMYLOID - Derived from Ig LIGHT CHAIN

38
Q

What pathology is PRIMARY SYSTEMIC AMYLOIDOSIS associated with?

A

PLASMA CELL DYSCRASIA (e.g. MULTIPLE MYELOMA) - overproduction of Ig LIGHT CHAIN

39
Q

SYSTEMIC AMYLOIDOSIS TYPE 2: What is SECONDARY amyloidosis? Describe the pathophysiology.

A

Secondary amyloidosis = Deposition of AA amyloid, derived from SAA (serum amyloid-associated protein = acute phase reactant)

HIGH/CHRONIC INFLAMMATION -> Elevated SAA (Acute phase reactant) -> Elevated AA amyloid deposition

40
Q

SYSTEMIC AMYLOIDOSIS TYPE 2: What are 3 pathologies that are associated with SECONDARY AMYLOIDOSIS. [HINT: Think of what SAA is and what pathologies are related to it]

A

SAA = precursor of AA amyloid systemic deposition = ACUTE PHASE REACTANT
Associations:
1. CHRONIC INFLAMMATORY STATES: SLE/RA/Crohns/UC/hashimoto’s/Sjogren’s/chronic gastritis/BRONCHIECTASIS
2. MALIGNANCY: Low-grade chronic inflammatory state against tumor cells
3. FAMILIAL MEDITERRANEAN FEVER

41
Q

What is FAMILIAL MEDITERRANEAN FEVER that is commonly associated with SECONDARY SYSTEMIC AMYLOIDOSIS (AA amyloid deposits throughout tissues)? What is the inheritance pattern?

A

FMF = Autosomal recessive mutation of a protein that modulates inflammation (specifically neutrophils) = HYPER-INFLAMMATION

42
Q

How does FAMILIAL MEDITERRANEAN FEVER in association with SECONDARY SYSTEMIC AMYLOIDOSIS commonly present?

A

EPISODIC FEVERS + Acute serosal inflammation mimicking (APPENDICITIS, MYOCARDIAL INFARCTION - Inflammation of pericardium, ARTHRITIS)

43
Q

What is the most commonly involved organ in SYSTEMIC AMYLOIDOSIS (both primary and secondary)? How does it manifest?

A

KIDNEY = most commonly involved organ

Manifests as NEPHROTIC SYNDROME - Due to amyloid deposits in the MESANGIUM

44
Q

What are 2 possible cardiac clinical manifestations of SYSTEMIC AMYLOIDOSIS?

A
  1. RESTRICTIVE CARDIOMYOPATHY -> Diastolic dysfunction

2. ARRHYTHMIA

45
Q

What other clinical manifestations present with SYSTEMIC AMYLOIDOSIS (Think GI - upper GI tract (2) and liver)?

A

TONGUE ENLARGEMENT - Due to AL or AA amyloid deposits in tongue
MAL-ABSORPTION - Due to amyloid deposits in small bowel
HEPATOSPLENOMEGALY

46
Q

How is the diagnosis of SYSTEMIC AMYLOIDOSIS made?

A

TISSUE BIOPSY to do a CONGO RED STAIN or APPLE-GREEN BIREFRINGENCE under polarized light

47
Q

Where are the 2 most accessible sites of obtaining a tissue biopsy for SYSTEMIC AMYLOIDOSIS DIAGNOSIS?

A

Abdomen fat pad + Rectum

48
Q

What is the treatment of SYSTEMIC AMYLOIDOSIS? Can amyloid be resected?

A

TRANSPLANT OF DAMAGED ORGAN

Amyloid can NOT be removed

49
Q

LOCALIZED AMYLOIDOSIS: What is LOCALIZED AMYLOIDOSIS?

A

Amyloid deposits within a single organ

50
Q

List the 6 types of LOCALIZED AMYLOIDOSIS.

[HINT: 2 cardiac, 1 neuro, 1 renal, 2 endocrine]

A
  1. SENILE CARDIAC AMYLOIDOSIS
  2. FAMILIAL CARDIAC AMYLOIDOSIS
  3. ALZHEIMER’S
  4. DIALYSIS-ASSOCIATED AMYLOIDOSIS
  5. TYPE 2 DM
  6. MEDULLARY CARCINOMA OF THYROID
51
Q

What amyloid protein deposits in SENILE CARDIAC AMYLOIDOSIS? What is the typical classical presentation?

A

**UW: NATRIURETIC PEPTIDE-derived protein (localized amyloidosis in cardiac atria)

NON-MUTATED TRANSTHYRETIN (2nd most common protein in blood) deposits in HEART
Typically ASYPMTOMATIC - Generally 25% of individuals >80yo will have SENILE CARDIAC AMYLOIDOSIS

52
Q

What amyloid protein deposits in FAMILIAL CARDIAC AMYLOIDOSIS? What is the typical presentation?

A 
MUTATED TRANSTHYRETIN (opposed to senile cardiac amyloidosis which was a non-mutated form) deposits in HEART 
Typical presentation = Decreased myocardial compliance -> Diastolic heart failure ensues
53
Q

What amyloid protein deposits in ALZHEIMER’S? Which associated pathology increases the risk of developing Alzheimer’s earlier (

A

ABETA AMYLOID PROTEIN deposits - derivative from APP (amyloid precursor protein) in BRAIN and around VESSELS (cerebral amyloid angiopathy)
APP lies on chromosome 21, Trisomy 21 [DOWN SYNDROME] increases risk

54
Q

What amyloid protein deposits in TYPE 2 DM (NIDDM)?

A

Deposits of AMYLIN (derivative of insulin) in ISLET CELLS

Due to insulin resistance -> Burns out pancreatic islet cells

55
Q

What amyloid protein deposits in DIALYSIS-ASSOCIATED AMYLOIDOSIS? What is the normal function of this protein?

A

BETA-2 MICROGLOBULIN deposits in JOINTS
Nl function of beta-2 microglobulin = provides structural support for MHC Class I (Expressed on all nucleated cells + PLT)

56
Q

What is the pathophysiology of DIALYSIS-ASSOCIATED AMYLOIDOSIS?

A

Dialysis -> BETA-2 MICROGLOBULIN does NOT get filtered well -> Deposits in JOINTS

57
Q

Pt has an enlarged thyroid. Upon fine needle aspiration biopsy, there are CALCITONIN deposits (parafollicularly) in a background of stroma. What does the pt have?

A

MEDULLARY CARCINOMA OF THYROID = LOCALIZED AMYLOIDOSIS
Medullary carcinoma = malignant tumor of neuro-endocrine parafollicular C cells [spindle-shaped cells] that secrete CALCITONIN (opposes PTH and decreases Ca2+) + Background of amyloid stroma

STEP 1: Growth Adaptations Cellular Injury PATHOMA (3 decks)

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