Free radical injury and Amyloidosis Flashcards
What are physiologic generation of free radicals?
oxidative phosphorylation. cytochrome c oxidase transfers electrols to O2 during oxidative phsphorylation. O should accept 4 electrons. if it is only partially reduced, you get free radicals.
What are examples of pathologic free radical generation?
ionizing radiation: makes OHdot. Made by hitting water in tissues. this is the most damaging free radical (hydroxyl)
- inflammation: neutrophils can kill with an oxidative burst (activated by NADPH oxidase). makes supraoxide free radical.
- metals: copper and iron. these are usually bound in the body. Via fenton rxn when it involves iron; makes hydroxyl radical. Whenever iron or copper builds up, there is damage to the tissue.
- drugs and chemicals, like acetaminophen or carbon tetrachloride
What kinds of damage do free radicals cause?
peroxidize lipids, and can oxidize DNA and proteins. may be implicated in oncogenesis.
How does the body remove free radicals?
- antioxidants: vitamin A, C, E.
- Metal carrier proteins: transferrin in the blood, ferritin in the tissues.
- enzymes
What enzymes are good at eliminating free radicals?
remember: O2 to O2dot (superoxide) to H2O2 to hydroxyl radical to water.
superoxide is taken out by SOD
H2O2 is handled by catalase
hydroxyl radical is handled by glutathione peroxidase
What is carbon tetrachloride?
classically seen in dry cleaning industry
gets converted to carbon trichloride in the liver. this damages the hepatocytes. you will see cellular swelling with RER swelling and reduction of protein synthesis. Will cause lack of apolipoproteins. Fat comes into liver but can’t get out: classic change is fatty liver.
What should I know about reperfusion injury?
cells are damaged, cell membrane is damaged, and enzymes leak out. if blood is returned to the organ, oxygen and inflammatory cells also return to the tissue. together, this can cause generation of free radicals, which can further injure the tissue. classic vignette: continued rise in cardiac enzymes after reperfusing an MI pt.
What is amyloid?
misfolded protein that deposits in the extracellular space and causes damage. usually have beta sheet configuration. pick up congo red stain. green bifuringence.
What is primary amyloidosis?
systemic deposition of AL amyloid derived from Ig Light chain.
associated with plasma cell dyscrasias or associated with multiple myeloma: causes overproduction of light chain
causes widespread organ dysfunction: renal (nephrotic), cardiac (restrictive cardiomyopathy), hematologic, neurologic, and GI effects
What is secondary amyloidosis?
systemic deposition of AA amyloid derived from SAA
SAA is an acute phase reactant that is incr. in inflammatory states, malignancy, and familial mediterranean fever.
What is familial mediterranean fever?
dysfunction of neutrophils
presents with episodes of fever and acute serosal inflammation. can involve serosa of heart, abdomen.
high SAA during attacks deposit as AA amyloid.
What are the classic clinical findings for amyloidosis?
kidney is the most commonly involved organ: often causes nephrotic syndrome
can also cause restrictive cardiomyopathy (problem with filling the heart) or arrhythmia
tongue enlargement, malabsorption, and liver and spleen swelling
Dx of systemic amyloidosis
requires tissue biopsy. abdominal fat pad and rectum are easily accessible.
What is senile cardiac amyloidosis?
non-mutated serum transthyretin deposits in the heart
asymptomatic
seen in the elderly
What is familial amyloid cardiomyopathy?
mutated serum transthyretin that deposits in the heart. leads to restrictive cardiomyopathy
5% of African americans carry the mutated gene.
