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