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Reversiblecellular injury
Part 1Cellular swelling- vacuolar and hydropic degenerationIntracellular accumulation of lipids -atherosclerosis. Lipidoses.
Reversible cellular injury 1
Disorders in the cellular water balance. Lipid accumulation within the
parenchymal cells /lipid degeneration/. Lipid accumulation within the
mesenchymal cells. Lipid phagocytosis. Lysosomal storage diseases /
tesaurismoses/. Abnormal accumulation of complex lipids
in the cell - lipidosis.
CELLULAR RESPONSES TO STRESS AND PATHOGENIC FACTORS
hypertrophy, hyperplasia,atrophymetaplasia
REVERSIBLE CELL INJURY
Morphologic changes in early stages or mild forms of injury reversible if the damaging stimulus is
removed Some injuries can lead to death if
prolonged and or severe enough In the past
Degeneration (degenerare – changing) Dystrophia (dys+trophe –abnormal
feeding)
REVERSIBLE CELL INJURY
Two groups morphologic changes Disorders in the cellular water balance
Cellular swelling Abnormal intracellular accumulations
Lipids Glycogen, mucopolysacharides Proteins Pigments
Disorders in the cellular water balance
Cellular swelling
The first manifestation of almost all forms of injury to cells – hypoxia, infections, poisons Increased cellular water content Due to failure of energy-dependent ion
pumps in the plasma membrane, leading to an inability to maintain ionic and fluid homeostasis.
Disorders in the cellular water balance
Cellular swelling
It is difficult to appreciate with the light microscope
It may be more apparent at the level of the whole organ-macroscopy it causes some pallor, increased turgor, and
increase in weight of the organ. Site of localization
Renal tubular cells Hepatocytes Myocardial cells
Disorders in the cellular water balance
Cellular swelling Microscopic examination
Cells are swollen, deformed, pale
hydropic change or vacuolar degeneration –the presense of small, clear vacuoles within the cytoplasm
they represent distended and pinched-off segments of the ER.
Swelling of cells is reversible.
Degeneratio parenchymatosa renis
The epithelial cell of the proximal convoluted tubules are swollen and deformed, with pale and dull cytoplasm
Abnormal intracellular accumulations
Under some circumstances cells may accumulate abnormal amounts of various substances They may be harmless or associated
with varying degrees of injury. may be located in the cytoplasm,
within organelles (lysosomes), or in the nucleus
Abnormal intracellular accumulations
3 main pathways of intracellular accumulations
A normal substance is produced at a normal or an increased rate, but the metabolic rate is
inadequate to remove it. fatty change in the liver
A normal or an abnormal endogenous substance accumulates because of genetic or acquired
defects in its folding, packaging, transport, or secretion.
accumulation of proteins - α1-antitrypsin deficiency defect in an enzyme results to failure to degrade a
metabolite – storage diseases An abnormal exogenous substance is deposited
and accumulates because the cells has no enzymatic machinery to degrade the substance nor the ability
to transport it to other sites Accumulations of carbon or silica particles
Intracellular accumulations
Lipids Neutral Fat Cholesterol
Proteins “Hyaline” = any “proteinaceous” pink “glassy”
substance Glycogen Pigments
Endogenous exogenous
Intracellular lipid accumulations
Sites of localization within the parenchymal cells -lipid
degeneration within the fat cells – obesitas,
lipomatosis within the macrophages -lipid
phagocytosis.
Lipid accumulation within the parenchymal cells
Lipid degeneration
= Fatty Change (Steatosis) refers to any abnormal accumulation of
triglycerides within parenchymal cells. It is most often seen in the liver, since
this is the major organ involved in fat metabolism
It may also occur in heart, skeletal muscle, kidney, and other organs.
Steatosis may be caused by toxins, protein malnutrition, diabetes mellitus, obesity, and anoxia.
Pathogenesis of fatty liver Fat metabolism
Free fatty acids from adipose tissue or ingested food are normally transported into hepatocytes
they are esterified to triglycerides, converted into cholesterol or phospholipids, or oxidized to ketone bodies
Some fatty acids are synthesized from acetate within the hepatocytes as well.
Secretion of the triglycerides from the hepatocytes requires the formation of complexes with apoproteins to form lipoproteins, which are able to enter the circulation
Excess accumulation of triglycerides may result from defects at any step from fatty
acid entry to lipoprotein exit, thus accounting for the occurrence of fatty liver after diverse hepatic insults.
Overfeeding, obesitas, diabetes mellitus - FFA income
Starvation- fatty acid mobilization from peripheral stores.
Hypoxia and Hepatotoxins (e.g., alcohol) - fatty acid oxidation (alter mitochondrial, SER function)
CCl4 and protein malnutrition - synthesis of apoproteins
Morphology of fatty changes
In any site, fatty accumulation appears as clear vacuoles within parenchymal cells.
Special staining techniques are required to distinguish fat from intracellular water or glycogen, which can also produce clear vacuoles but have a different significance.
To identify fat microscopically, tissues must be processed for sectioning without the organic solvents typically used in sample preparation - frozen sections, by staining with Sudan IV or oil red O (stain fat orange-red).
Glycogen may be identified by staining for polysaccharides using the periodic acid-Schiff stain (stains glycogen red-violet).
If vacuoles do not stain for either fat or glycogen, they are presumed to be composed mostly of water.
LIPID LAW ALL Lipids are YELLOW grossly and WASHED out (CLEAR) microscopically
FATTY LIVER Gross appearance
Mild fatty change in the liver may not affect the gross appearance.
With increasing accumulation, the organ enlarges and becomes progressively yellow
it may weigh 3 to 6 kg (1.5-3 times the normal weight)
bright yellow, soft, and greasy.
FATTY LIVER
Microscopic features Microvesicular
steatosis Macrovesicular
steatosis mixed
Degeneratio Adiposa Hepatis
(HE, Sudan III)
Lipid degeneration of myocardium
In the heart, lipid is found in the form of small droplets, occurring in one of two patterns In prolonged moderate hypoxia (anemia)-
focal intracellular fat deposits (papillary muscles)
creating grossly apparent bands of yellowed myocardium alternating with bands of darker, red-brown, uninvolved heart ("tigered effect").
In more profound hypoxia or by some forms of toxic injury (e.g., diphtheria) – diffuse pattern of fatty change
uniformly affected myocytes.
Lipid degeneration of the ren
In the ren, lipid is found in the form of small droplets, occurring in the epithelial cells of convoluted tubules In severe hypoxia In nephrotic syndrome
Increases reabsorption of lipoproteins
FATTY CHANGES The significance of fatty change depends
on the cause and severity of the accumulation. When mild it may have no effect on cellular
function. More severe fatty change may transiently
impair cellular function - fatty change is reversible.
In the severe form, fatty change may precede cell death, and may be an early lesion in a serious liver disease called nonalcoholic steatohepatitis
Lipid accumulations within the fat cells
General obesitas within the fat cells of
adipose tissue Lipomatosis (local
obesitas) within the fat cells of
connective tissue of different organs, no functional disturbances
Heart – subepicardium of right chamber
Pancreas – interlobular connective tissue
Lipid accumulations within the macrophages
Lipid phagocytosis. Phagocytic cells may become overloaded with lipid
(triglycerides, cholesterol, and cholesterol esters) in several different pathologic processes.
Macrophages in contact with the lipid debris of necrotic cells or abnormal (e.g., oxidized) forms of lipoproteins may become stuffed with phagocytosed lipid.
foam cells - macrophages filled with minute, membrane-bound vacuoles of lipid, imparting a foamy appearance to their cytoplasm.
In atherosclerosis - smooth muscle cells and macrophages are filled with lipid vacuoles composed of cholesterol and cholesteryl esters
these give atherosclerotic plaques their characteristic yellow color and contribute to the pathogenesis of the lesion
Xantomas – fibromas (benign tumors, where tumor cells accumulate cholesterol esters)
xanthos – yellow, Xantelasmas
clusters of these foamy macrophages present in the subepithelial connective tissue of skin
In hereditary hyperlipidemic syndromes macrophages accumulate intracellular cholesterol - lipidoses
Arteriosclerosis Endothelial cell damage of muscular and elastic
arteries Abdominal aorta coronary artery, popliteal artery Internal carotid artery
Causes of endothelial cell injury Hypertension, smoking, LDL
Cell response to endothelial injury Macrophages and platelets adhere to damaged
endothelium. Released cytokines cause hyperplasia of medial
smooth muscle cells. Smooth muscle cells migrate to the tunica intima. Cholesterol enters smooth muscle cells and
macrophages (foam cells). Smooth muscle cells release cytokines that
produce extracellular matrix. collagen, proteoglycans, and elastin
Development of fibrous cap (plaque) Smooth muscle, foam cells, inflammatory cells,
extracellular matrix Fibrous cap overlies a necrotic center.
Cellular debris, cholesterol crystals (slit-like spaces), foam cells
Disrupted plaques may extrude underlying necrotic material leading to vessel thrombosis
Fibrous plaque becomes dystrophically calcified and ulcerated.
Arteriosclerosis Complications of atherosclerosis
Vessel weakness (e.g., abdominal aortic aneurysm)
Vessel thrombosis acute MI (coronary artery), Stroke (internal carotid artery,
middle cerebral artery), Small bowel infarction (superior
mesenteric artery), Hypertension
Renal artery atherosclerosis may activate the renin-angiotensin-aldosterone system.
Peripheral vascular disease Increased risk of gangrene Pain in the buttocks and when
walking (claudication) Cerebral atrophy
circle of Willis vessels or internal carotid artery
Atheromatosis Aortae (HE, SUDANIII)
Atheromatosis AortaeThe slit-like spaces are cholesterol clefts,
a classic feature of atherosclerosis
Tesaurismoses Lysosomal Storage Diseases
There is an inherited lack of a lysosomal enzyme, catabolism of its substrate remains incomplete, leading to accumulation of the partially degraded insoluble metabolites within the lysosomes
Lysosomes, contain a variety of hydrolytic enzymes that are involved in the breakdown of complex substrates into soluble end products.
Approximately 40 lysosomal storage diseases, divided into broad categories based on the biochemical nature of the substrates and the accumulated metabolites
Lipidosis Glycogenosis Mucopolysaccharidoses
Within each group are several entities, each resulting from the deficiency of a specific enzyme.
Despite this complexity, certain features are common to most diseases in this group
LIPIDOSIS
Autosomal recessive transmission of enzyme defects for lipid metabolism, leading to accumulation of undegraded lipid metabolites in the cells of different organs Gaucher Disease Tay-Sachs disease Niemann-Pick Disease, Types A and B
LIPIDOSISGaucher Disease
The disease results from mutation in the gene that encodes glucosylceramidase (glucocerebrosidosis)
an accumulation of glucosylceramide in the mononuclear phagocytic cells (liver, lien, bone marrow) and their transformation into so-called Gaucher cells
derived from the breakdown of senescent blood cells, particularly erythrocytes
Gaucher cells enlarged, (100 μm), because of the
accumulation of distended lysosomes, a pathognomonic cytoplasmic appearance
characterized as "wrinkled tissue paper“ EM –lysosomes with tubular structures
and fibrils Clinical features
hepatosplenomegaly Bones-osteopenia ± neurologic disorders
LIPIDOSISTay-Sachs disease
Characterized by a mutation in and consequent deficiency of the α subunit of the enzyme hexosaminidase A, involving in the degradaytion of gangliosides
CNS –neurons, ganglia, retina Neurologic disturbances,
amaurosis
Affected cells - swollen, possibly foamy
EM- a whorled configuration within lysosomes
LIPIDOSISNiemann-Pick Disease
A primary deficiency of acid sphingomyelinase and the resultant accumulation of sphingomyelin
Affected cells and organs phagocytic cells of spleen, liver, bone
marrow, lymph nodes, lungs stuffed with droplets or particles of the
complex lipid, imparting a fine vacuolation or foaminess to the cytoplasm
Neurons of CNS enlarged and vacuolated as a result of
the storage of lipids.
2 types Type A –manifests itself in infancy with
massive visceromegaly and severe neurologic deterioration
Type B – no neurologic disorders