Cellular Death and Amyloidosis Flashcards
What is the morphological hallmark of CELL DEATH? Name the underlying mechanisms responsible for this.
LOSS OF NUCLEUS
Step 1: PYKNOSIS = Nuclear condensation
Step 2: KARYORRHEXIS = Nuclear fragmentation
Step 3: KARYOLYSIS = Nuclear dissolution
What are the 2 mechanisms of cell death?
NECROSIS (Murder of LARGE GROUP of cells)
APOPTOSIS (Suicide of SINGLE cell or SMALL GROUP of cells)
Name the 6 types of NECROSIS.
- COAGULATIVE NECROSIS
- LIQUEFACTIVE NECROSIS
- GANGRENOUS NECROSIS
- CASEOUS NECROSIS
- FAT NECROSIS
- FIBRINOID NECROSIS
NECROSIS TYPE 1: Describe the pathology of COAGULATIVE NECROSIS.
Coagulation of cellular proteins -> Retain cell shape + organ structure -> Necrotic tissue is FIRM
Loss of nuclei
Ischemic infarcts of any organ result in COAGULATIVE NECROSIS except for which organ?
BRAIN
What are the two appearances of COAGULATIVE NECROSIS INFARCTED TISSUE?
- WEDGE-SHAPED PALE INFARCT: Pointing to focus of vascular origin
- RED INFARCT: 2 requirements - Blood re-enters + Tissue is loosely organized
What are the two requirements of a RED HEMORRHAGIC INFARCT, characterized by COAGULATIVE NECROSIS? Name two classic organs where a HEMORRHAGIC INFARCT presents itself.
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
NECROSIS TYPE 2: What is the pathology of LIQUEFACTIVE NECROSIS?
Necrotic tissue that becomes LIQUIFIED -> Enzymatic LYSIS of cells and protein
What are the two types of necrosis associated with PANCREATITIS?
LIQUEFACTIVE NECROSIS of pancreatic parenchyma
FAT NECROSIS of peri-pancreatic fat
What are 3 characteristic hallmarks of LIQUEFACTIVE NECROSIS?
- BRAIN INFARCTION: Ischemic infarcts of all organs are COAGULATIVE NECROSIS except for the brain. Proteolytic enzymes from MICROGLIAL CELLS (macrophages) liquify the brain.
- ABSCESS: Proteolytic enzymes from NEUTROPHILS liquify tissue
- PANCREATITIS: Proteolytic enzymes from PANCREAS liquify PARENCHYMA
NECROSIS TYPE 3: What is the pathology of GANGRENOUS NECROSIS?
Coagulative necrosis that resembles MUMMIFIED TISSUE
What is the typical characteristic of GANGRENOUS NECROSIS? What is the less likely characteristic?
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
What is the difference between DRY GANGRENE and WET GANGRENE?
DRY GANGRENE = Gangrenous necrosis by itself
WET GANGRENE = Gangrenous necrosis + Liquefactive necrosis (infection of the dead grangrenous tissue) - Wet portion = PUS (neutrophils) + inflammatory exudate
NECROSIS TYPE 4: What is the pathology of CASEOUS NECROSIS?
Soft, friable necrotic tissue - “COTTAGE CHEESE-like appearance”
What is characteristic of CASEOUS NECROSIS?
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
COAGULATIVE NECROSIS + LIQUEFACTIVE NECROSIS = ?
GANGRENOUS NECROSIS + LIQUEFACTIVE NECROSIS = ?
CASEOUS NECROSIS = COAGULATIVE + LIQUEFACTIVE
WET GANGRENE = GANGRENOUS + LIQUEFACTIVE
Female pt presents with a palpable mass on the breast. Upon biopsy, giant cells + fat + calcification is seen. What is the underlying process?
FAT NECROSIS
NECROSIS TYPE 5: What is the pathology of FAT NECROSIS? What are the two most common characteristics of FAT NECROSIS?
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
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)
- SAPONIFICATION - Ex of dystrophic calcification when DEAD FAT tissue becomes a nidus for Ca2+ deposition
NORMAL Ca2+/NORMAL phosphate - METASTATIC CALCIFICATION - Due to HIGH ca or phosphate -> Calcium deposition all over the body
HIGH Ca2+/HIGH phosphate
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)
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
Does METASTATIC CALCIFICATION imply METASTATIC CANCER? Name a scenario with a metastatic cancer to the bone.
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
What endocrine abnormality can result in METASTATIC CALCIFICATION?
HYPERPARATHYROIDISM: High Ca2+ and PO4 -> Increases calcium deposition in normal tissues -> Results in NEPHROCALCINOSIS
NECROSIS TYPE 6: What is the pathology of FIBRINOID NECROSIS?
Fibrinoid Necrosis = Necrotic damage to BV wall
Leakage of proteins (INCLUDING FIBRIN) to vessel wall -> Bright pink staining
What are 2 main and 1 extra characteristic circumstances of FIBRINOID NECROSIS?
- MALIGNANT HTN - Diastolic BP >120-130, Presents with HEADACHE, RENAL FAILURE, PAPILLEDEMA = medical emergency
- VASCULITIS
These two are scenarios of HYPERPLASTIC ARTERIOLOSCLEROSIS: Onion skin appearance (SM hyperplasia in attempt to contain the high BP) - PRE-ECLAMPSIA: Cause of very elevated BP
Pt is a 30yo woman with FIBRINOID NECROSIS. What is the most likely underlying etiology of her fibrinoid necrosis?
PRE-ECLAMPSIA: Cause of VERY HIGH BP. 30yo woman unlikely to have malignant HTN. Presents with proteinuria as well
What are 3 classical scenarios of apoptosis? (Think menstrual cycle, embryogenesis, infection)
- ENDOMETRIAL SHEDDING during menstrual cycle
- Removal of CELLS (e.g. spacing between fingers, toes) during embryogenesis
- CD8+ T-cell mediated killing of VIRALLY INFECTED cells
What are the two morphological changes of APOPTOSIS? What is the biochemical mechanism underlying each change
- 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 - NUCLEAR CONDENSATION: Nucleus condenses and fragments in an organized manner
MECH: Apoptosis mediated by CASPASE -> Activates ENDONUCLEASE -> Fragments DNA
When apoptotic bodies fall from the cell, how are they removed? Does inflammation follow or not follow? How is this unlike necrosis?
APOPTOTIC BODIES removed from MACROPHAGES
ACUTE INFLAMMATION does NOT follow, unlike tissue necrosis being 1 of 2 main stimuli for acute inflammation
Apoptosis is mediated by which key molecule? What two molecules get activated as a result?
APOPTOSIS mediated by CASPASES
Caspases -> Activate PROTEASE (Cell shrinkage) + ENDONUCLEASE (Nuclear condensation/fragmentation)
What are the 3 pathways of apoptosis. Describe molecules involved in each.
- 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
- 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
- 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
What is the typical immunologic example of the EXTRINSIC RECEPTOR LIGAND PATHWAY of apoptosis?
- **NEGATIVE SELECTION of thymocytes in thymus medulla during maturation (CENTRAL TOLERANCE)
- 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.
What are the free radicals? Of all the free radicals, which is the most damaging?
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
How do free radicals cause cellular injury?
- LIPID PEROXIDATION
- DNA OXIDATION and DNA protein damage
- DNA mutations implicated in AGING and ONCOGENESIS
How does CCl4 (carbon tetrachloride) result in free radical injury? Where is it most commonly found in?
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)
After CCl4 poisoning, what does the liver look like?
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)
What is AMYLOID? What are two shared characteristics? (1 configuration, 1 staining)
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
SYSTEMIC AMYLOIDOSIS TYPE 1: What is PRIMARY amyloidosis?
PRIMARY AMYLOIDOSIS = systemic deposition of AL AMYLOID - Derived from Ig LIGHT CHAIN
What pathology is PRIMARY SYSTEMIC AMYLOIDOSIS associated with?
PLASMA CELL DYSCRASIA (e.g. MULTIPLE MYELOMA) - overproduction of Ig LIGHT CHAIN
SYSTEMIC AMYLOIDOSIS TYPE 2: What is SECONDARY amyloidosis? Describe the pathophysiology.
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
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]
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
What is FAMILIAL MEDITERRANEAN FEVER that is commonly associated with SECONDARY SYSTEMIC AMYLOIDOSIS (AA amyloid deposits throughout tissues)? What is the inheritance pattern?
FMF = Autosomal recessive mutation of a protein that modulates inflammation (specifically neutrophils) = HYPER-INFLAMMATION
How does FAMILIAL MEDITERRANEAN FEVER in association with SECONDARY SYSTEMIC AMYLOIDOSIS commonly present?
EPISODIC FEVERS + Acute serosal inflammation mimicking (APPENDICITIS, MYOCARDIAL INFARCTION - Inflammation of pericardium, ARTHRITIS)
What is the most commonly involved organ in SYSTEMIC AMYLOIDOSIS (both primary and secondary)? How does it manifest?
KIDNEY = most commonly involved organ
Manifests as NEPHROTIC SYNDROME - Due to amyloid deposits in the MESANGIUM
What are 2 possible cardiac clinical manifestations of SYSTEMIC AMYLOIDOSIS?
- RESTRICTIVE CARDIOMYOPATHY -> Diastolic dysfunction
2. ARRHYTHMIA
What other clinical manifestations present with SYSTEMIC AMYLOIDOSIS (Think GI - upper GI tract (2) and liver)?
TONGUE ENLARGEMENT - Due to AL or AA amyloid deposits in tongue
MAL-ABSORPTION - Due to amyloid deposits in small bowel
HEPATOSPLENOMEGALY
How is the diagnosis of SYSTEMIC AMYLOIDOSIS made?
TISSUE BIOPSY to do a CONGO RED STAIN or APPLE-GREEN BIREFRINGENCE under polarized light
Where are the 2 most accessible sites of obtaining a tissue biopsy for SYSTEMIC AMYLOIDOSIS DIAGNOSIS?
Abdomen fat pad + Rectum
What is the treatment of SYSTEMIC AMYLOIDOSIS? Can amyloid be resected?
TRANSPLANT OF DAMAGED ORGAN
Amyloid can NOT be removed
LOCALIZED AMYLOIDOSIS: What is LOCALIZED AMYLOIDOSIS?
Amyloid deposits within a single organ
List the 6 types of LOCALIZED AMYLOIDOSIS.
[HINT: 2 cardiac, 1 neuro, 1 renal, 2 endocrine]
- SENILE CARDIAC AMYLOIDOSIS
- FAMILIAL CARDIAC AMYLOIDOSIS
- ALZHEIMER’S
- DIALYSIS-ASSOCIATED AMYLOIDOSIS
- TYPE 2 DM
- MEDULLARY CARCINOMA OF THYROID
What amyloid protein deposits in SENILE CARDIAC AMYLOIDOSIS? What is the typical classical presentation?
**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
What amyloid protein deposits in FAMILIAL CARDIAC AMYLOIDOSIS? What is the typical presentation?
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
What amyloid protein deposits in ALZHEIMER’S? Which associated pathology increases the risk of developing Alzheimer’s earlier (
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
What amyloid protein deposits in TYPE 2 DM (NIDDM)?
Deposits of AMYLIN (derivative of insulin) in ISLET CELLS
Due to insulin resistance -> Burns out pancreatic islet cells
What amyloid protein deposits in DIALYSIS-ASSOCIATED AMYLOIDOSIS? What is the normal function of this protein?
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)
What is the pathophysiology of DIALYSIS-ASSOCIATED AMYLOIDOSIS?
Dialysis -> BETA-2 MICROGLOBULIN does NOT get filtered well -> Deposits in JOINTS
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?
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
