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dr. dambach:

what causes disease
what changes characterize disease
how does it relate to clinical signs

so far, we've talked about cellular injury mechanisms and the problems 
they cause. only four main things affected by them as discussed already.

now, we need to discuss cellular adaptation to injury and cell death.

celllular morphologic changes and adaptation to injury:

often, injury is reversible if the stressor is removed. if it persists, 
it tries to adapt if it can.

we talked already about swelling (hydropic change) and fatty change seen 
in early and reversible cell injury. swollen cells with clear vacuoles.

chronic persistent injury causes other changes: atrophy, hyperplasia, 
hypertrophy, metaplasia, and dysplasia, on the cellular level. 

in terms of organs, aplasia = never formed, hypoplasia = small

normal fat metabolism review: 

FFA enters liver, acetate joins, you get oxidation to ketone bodies, 
phospholipids, and cholesterol esters, via beta oxidation. these are used 
as energy for liver. but most FFA follows triglyceride pathway, and 
therefore need apoprotein from rough ER to bind triglyceride, to make 
lipoproteins, that can be sent into the circulation. in animals,there are 
three places where this can become deranged and cause fatty change. if FA 
levels in blood increase (eg, due to diet increase, pregnancy, or lack of 
glycogen or glucose) but apoprotein level does NOT increase, you have 
excess amt of triglycerides being produced, and lipid accumulates in 
hepatocytes. normal liver can upregulate apoprotein synthesis, but if FFA 
level elevation is persistent, backup will occur. Also, coudl have 
apoprotein synthesis problem. if animal has DNA problem, or toxin hurting 
rough ER, or protein starvation, etg...then triglycerides build up as 
well. also, if liver isn't oxidizing any fats, and shunts all FFA to 
triglyceride pathway, that could add to the burden. fatty change in 
miniponies and donkeys is due to not making enough apoprotein.

histologically, we see clear vacuoles, starting in central lobular area, 
due to amt of FFA processing in that region. periphery of acinus has more 
normal looking hepatocytes without the big fat vacuoles. triglyceride 
accumulates in the vacuoles. looks clear because of solvents used in 
slide prep.

in severe case, you can't see normal structures atall.. all hepatocytes 
areFULL of clear vacuole demarcated by cellmembrane.  all organelles are 
compressed. hepatocytes also swell, constricting the bile ducts and 
canaliculi, so bile movement is perturbed. these animals have systemic 
illness due to hepatic dysfunction. can kill them. they get hepatic 
encephalopathy since can't detoxify products of digestion. grossly, the 
liver is diffusely yellow orange, friable, with rounded edges indicating 
swelling/enlargement. if you see severe, diffuse, hepatocellular fatty 
change, the liver isalso swollen. the color is a "fat" color, and the 
liver will feel greasy. this is pathognomic for fatty change. sometimes 
will float in water. in center, you can see little red dots - it's a  
"reticulated pattern" accentuating the zonal pattern. looks like 
reticulated pattern on giraffe. 

fatty change can also occurin kidney, skeletal muscle, etc. it is 
accumulation of LIPID VACUOLES IN THE CYTOPLASM. do notconfuse this with 
deposition of adipocytes between other cells. 

slide: adipocytes between cardiac myocytes. this is "fatty infiltration" 
NOT fatty change. fatty infiltration is generally an incidental finding 
to muscle atrophy.

to understand fatty change,need to understand metabolism of fat in the 
liver. we don't understand pathogenesis of hepatic lipidosis in cats. 
usually happens in stressed fat cats. we don't know much about it. only 
about 60% live.

slide: lungs and trachea. multifocal black patches are present.NOT 
diffuse - not affectingentire lung. firmer than normal (blood and 
inflammatory cells cause this). morphologic dx: pneumonia, aka 
inflammation of lung. note the pattern of lesions at periphery of lung. 
this suggests an inhaled substance - aspiration pneumonia or 
bronchopneumonia. inflammation is mostly around bronchi. etiology 
bacterial or foreign material. pathogenesis: inhalation of 
substanceleading to inflammation.

cellular adaptations: occur if cell survives injury and injury is 
persistent.
associated with persistent, sublethal injury
reversible if injury is discontinued

ATROPHY: a decrease in cell size and function
occurs in a variety of conditions both pathologic and physiologic.
-reduced functional demand/lack of stimulation - eg, when limb casted, 
atrophies
eg, cells reduce their metabolic rate to that which is needed. they just 
maintain themselves. can be pathologic or physiologic. eg, if dog rips 
brachial plexus, no nerve stimulus exists to stimulate muscles of 
forearm, it atrophies.
-inadequate/reduced blood supply- surviving cells will shut down 
machinery to survive on reduced oxygen/nutrients.
-insufficient nutrients 
- interruption of trophic signals (endocrine/neuromuscular) can be 
normal, eg mammary gland atrophy post weaning. glands no longer get 
hormones, so they atrophy.

slide: liver section. can see central vein and portal area. in portal 
area, abundant pink cytoplasm,minimal space between hepatocytes. in 
central vein area, hepatocytes are thinner,more space, see RBCs more 
easilyl. there is central lobular ATROPHY. usually due to pressure from 
vena cava due to heart failure. blood backs up in vena cava, central 
veins increase in pressure, exerting pressure on local hepatocytes. can 
cause atrophy andeven necrosis overtime. 

slide: central lobular necrosis. all red patchy areas show that 
hepatocytes are gone and sinusoids are very dilated and blood filled. 
this iscase of pressure atrophy leading to cell death.

slide: adrenalgland: cortex and medulla. medulla under stress control, 
cortex under hormonal control. bilateral cortical atrophy present, here. 
secondary to exogenous steroids. pituitary stopped signalling cortex to 
make steroids, so it atrophied.

atrophy is ACQUIRED not congenital. if 12 yr old dog has cortical 
dysfunction, and adrenals look like that, it's ATROPHY not hypoplasia. if 
animal had conginital cortical HYPOPLASIA, would have had problems early 
in life. can be hard to differentiate hypoplasia from atrophy in some 
cases. 



HYPERTROPHY
an increase in size and functional capacity of cell.
stimulus for hypertrophy and hyperplasia is similar.
HyperPLASIA is an increase in NUMBER of cells.

some cells can't replicate. Cardiac muscle cells, if stimulated to work 
more, have to get bigger, can't increase in number. so they HYPERTROPHY. 
epithelial cells will do both - because they CAN.

stimuli leading to both:
-anything that increases metabolic function, physiologic (pubescence) or 
pathologic.
hormonal influences - maturation and puberty, lactational mammgland 
hyperplasia, exogneous supplementation - eg, testosterone supplementation 
-muscles get big, but testicles atrophy :)
also, when p450 system is induced, we get ER hypertrophy.
if one kidney is hypoplastic at birth, other one will HYPERTROPHY because 
nephrons can't replicate or get HYPERPLASTIC.

renal tubular epi can regenerate, but tubular epi cell will usually 
hypertrophy first. these cells should be kinda cuboidal. but, may see 
huge nucleus andbig puffy cells - hypertrophy.

weightlifting: muscles hypertrophy due to increased demand.
heart will hypertrophy, causing the lumen to decrease in size. slide: 
severe diffuse hypertrophy of left ventricle. what causes this? systemic 
hypertension. heart has to pump against a bigger pressure to eject blood. 
whenever the afterload is increased, heart will hypertrophy.

grossly, how to tell between hypertrophy and hyperplasia: well,skeletal 
muscle can't become hyperplastic. epithelium can. smooth muscle 
hypertrophies, epithelia get hyperplastic. glands, skin, intestinal villi 
- undergo hyperplasia, usually with hypertrophy. difference is can teh 
cells replicate.

slide: skin showing hyperplastic epithelium. there is an increased number 
of NORMAL cells.

slide: dog with verrucous nose. similar to lg dog with elbow callous. is 
result of pressure on elbow when lies down. epi cells increase in number. 
turns black b/c melanocytes undergo hyperplasia with chronic injury as 
well. grossly raised and bumpy.

hyperplasia occurs in many parenchymous organs, like liver and pancreas. 
cells increasein number but we don't know why.is incidental finding, 
usually age related or idiopathic. common in dog is idiopathic 
hepatocellular nodular hyperplasia. grossly multifocal, nodular, non 
encapsulated, pale mahogany lesions. cells are grossly hypertrophic and 
area is hyperplastic. some fatty change. not a compressing lesion. 
neoplasia is often encapsulated and compressing.

pancreatic acinar hyperplasia occurs as well. incidental finding - light 
tan nodules, probably due to increased number and clearing of cytoplasm.

METAPLASIA:
conversion of one differentiated cell type to another.
most often seen secondary to chronic inflammation of ductal or glandular 
epithelium which has epitheliumchanging to squamous epi: squamous 
metaplasia. seen in respiratory tract, cervix.
under chronic stress, ciliated cells in resp tract are damaged, so change 
to more protective state - squamous epi. 
canoccur incidentally or with age, eg osseus metaplasia, fibroplasia 
(scar)
if fibroplasia stays around, long time, can change to bone - osseus 
metaplasia.
when fibrous tissue changes to bone.

this is not totally harmless, esp in epithelium. if you change cell type, 
you chnagefunction. squam epi doesn't move stuff out of respiratory 
tract.

slide: monkey resp tract with lung mite: epi is now squamous. also 
accumulation of black mite feces. similar changes to epi are seen in 
smokers.

turtles with hypovitaminosis A get changes in respiratory epi. ciliated 
epi becomes squamous. also happens in eye mucosa, causes conjunctivitis. 


slide: lung tissue with well formed bone spicules. "heterotopic bone"
note that metaplasia involves NORMALLY FORMED cells, inthe wrong place.
in older animals, cartilage can ossify, eg in larynx.

DYSPLASIA:
an irregular alteration in size, shape, and organization of cells in a 
tissue.
we're talking about cellular dysplasia. the only reason this is in with 
otheradaptive categories is that it arises in cases of chronic 
irritation. cells start losing normal controls. different from 
hyperplasia, where cells are oriented NORMALLY but there areMORE of them. 
here, cells start to lose normal orientation and relation to normal 
cells. it is pre-neoplastic change. chronic injury can lead to cancer,eg 
with liver flukes in humans and cats. dysplasia often occurs in areas of 
hyperplasia andmetaplasia. this is NOT organ dysplasia. ORGAN DYSPLASIA 
means parts of organs are not organized normally. that is CONGENITAL and 
not pre-neoplastic.

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