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Dr. Dambach's last hour. she's migrating. metastasizing.

this lab we're doing, btw, is problem based/case based learning. these 
cases are supposed to hone our research skills. make sure we make 
critical comments on the evaluation form at the end of the course.

so, right now, some examples of mineralization

slide: section of cardiac tissue. some necrosis and inflammation present. 
separately, one cell with dark purple ring around it - it's mineralized. 
most likely this is dystrophic mineralization and serum calcium is 
normal.

slide: vitE/selenium deficiency, dystrophic mineralization of muscle

slide: serosal surface of dog stomach - metastatic calcification of 
stomach secondary to renal dz. "paintbrush" hemorrhages around white foci 
of necrosis and mineralization.

startle response of 9 banded armadillo slide is pretty cool ;)

AMYLOID:
refers to a diverse group of extracellular protein deposits
proteins share common properties that allow them to be called amyloid
-structural and morphologic properties-beta pleated sheet, fibrillar, 
linear
-staining properties
-stable, static proteins that resist complete degradation
amyloid deposition in tissue causes tissue dysfunction by mass effect
is often accompanied by influx of macrophages
amyloid precursor proteins may be a normal, improperly degraded protein 
or abnormal protein, or protein made by tumor
amyloid deposition can occur in any organ and cause its dysfunction which 
leads to clinical disease called AMYLOIDOSIS

because of immunohistochemistry we can tell what the protein is that 
makes amyloid, but we don't know WHY

know it is fairly inert, resistant to degradation, 
has three components:

made of that fibrillary protein and has an amyloid P aka AP component - a 
serum protein component no one knows the function of, and a 
glycosaminoglycan usually heparan sulfate.

the glomerulus is prone to developing amyloid because it already has 
glycosaminoglycan and AP component floating around.
the cause or "trigger" of amyloid deposition is unknown.

grossly, amyloid causes organ to be light tan. may start out multifocal 
but becomes diffuse. histologically it appears pink, amorphous, 
acellular, hyaline. 

staining properties: starts depositing along CT stroma and vessels 
because of available binding sites, and because of it being carried in 
blood. the parallel arryas of proteins stacked in beta pleated sheets 
bind and orient the stain Congo Red, which looks light pink. the 
orientation of congo red imparts the classic 'apple green" birefringence 
of the stain with polarized light.
only amyloid does that.

glycosaminoglycan is responsible for binding iodine so you can use iodine 
at gross post morten to look for brown spots of amyloid binding iodine.

animal with renal amyloidosis present with proteinuria, increased BUN, 
creat, etc. kidneys are diffusely light tan, firm, waxy. if you stain 
kidney with iodine, you see pinpoint little brown foci. why is kidney 
diffusely light tan?maybe due to restricted blood flow due to amyloid 
compressing the blood vessels. the color change in the kidney can't be 
due to amyloid.

liver amyloidosis...hepatocytes are separated by amyloid deposits which 
follow the space of Disse. the hepatocytes are now different sizes - 
they've atrophied. grossly the liver is diffusely mottled yellow/red due 
to amyloid build up and vascular compression.

lung arteriole filled with amyloid

kidney with diffuse glomerular amyloidosis. all the glomeruli have 
amyloid deposits. btw, collagen also has birefringence, but it's white.

cross section of fresh kidney, stained w/iodine. cortex shows pinpoint 
dark brown foci - those are the affected glomeruli. this is a diffuse 
change - ALL glomeruli are affected.

classification of amyloidosis:

-can be deposited in an isolated organ or systemically
-is deposited in many conditions
note: bob casey had hereditary amyloidosis, that's why he needed 
heart/lung transplant
-proteins which make up amyloid differ, but belong to only a few 
categories
-two major types of classification: by type of protein, or by clinical 
presentation.

people are now starting to use protein type classification more than 
clinical presentation. we didn't used to be able to tell anything about 
the type of protein.

major types of amyloid: four types are common, three are important (one 
is normal senile change). there are seven types total.

AL amyloid - light chain origin. made of the immunoglobulin light chains. 
is associated with plasma cell tumors (multiple myeloma) and B cell 
dyscrasias (uncontrolled functionality), or chronic inflammation.
pathogenesis of AL deposition: primary disorder of Ig 
production--->excess production of Ig--->release into 
circulation--->partial degradation by phagocytes--->partly digested 
protein-->she moved the lslide

most common type of amyloid in animals**** AA AMYLOID ***

AA amyloid is resultof mystery protein called serum AA protein, SAA, 
which we don't know anything about. it's produced by liver under 
influence of inflammatory process (the SAA is, that is). so this is 
always result of chronic inflammatory process, or inherited problem with 
inflammatory response so they make too much SAA or can't degrade it. most 
common kind of amyloidosis in animals. SAA is a normal acute phase 
protein made in liver. AA amyloid occurs secondary to problem with 
processing of SAA. whenever there is inflammation in the body, TNF1a and 
IL1 are upregulated, and they cause a chain reaction, activating IL6, 
which then tells hepatocytes to make more SAA. this amyloid is also a 
product of partial degradation, like AL amyloid. AA amyloid can be 
deposited systemically but most often kidney, liver.

AE amyloid: E= endocrine
derived from normal preprohormones or from hormone product secreted from 
endocrine tumor. commonly found in pancreatic islets of cats. not sure if 
that is a significant finding. in humans and macaques, it leads to 
diabetes mellitus. in cats, we commonly see this change in older cats w/o 
diabetes. so may be a matter of degree. in all species, this amyloid is 
made of normal endocrine secretion.

classification by presentation:

primary: refers to appearance of amyloid without preexisting dz. includes 
the spectrum of plasma cell and B cell disorders. plasma cell tumor 
amyloid is included. usually primary amyloidosis involves AL form.
however, multiple myeloma results in primary amyloidosis with a systemic 
manifestation. any disease process which is itself making the amyloid - 
usually a tumor - this is primary amyloidosis

secondary: most common form in animals.  a complication of previously 
existing chronic inflammatory process. AA form of protein is deposited. 
so cause of amyloidosis is TOTALLY unrelated to production of amyloid. 
can be deposited anywhere...mainly kidney and liver.
horses prone to getting it in nasal passages and skin. people who work 
with wild birds will see that birds will drop dead from severe splenic 
hepatic and renal amyloidosis after their fracture repairs. this is due 
to major inflammatory response

familial: cases with apparent heritable predisposition: abyssinian cats, 
shar pei dogs. AA amyloid usually involved. typically systemic. some shar 
pei have cyclic fever and inflammation, and something about that is 
predisposing them to have amyloid deposition. same thing w/abys and some 
other oriental breed cats.

slide: kidney with interstitial amyloid

amyloid is always present in a matrix, along a stroma, along a reticular 
network. won't be in a lumen, or in a cell. always in interstitium, wall 
of vessel, etc.

--------------the top three are all potentially systemic
isolated
isolated form is found in only one organ.
AE amyloid deposited in pancreatic islets in cats
AL amyloid deposited in cutaneous plasma cell tumors
the four types share the same protein types.
AA amyloid - 
AE amyloid


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