04-Intracellular Accumulations 2008

8/12/2019 04-Intracellular Accumulations 2008

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INTRACELLULARACCUMULATIONSDr.Maha Arafah


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Overview Under some circumstances cells may

accumulate abnormal amounts of various

substances,. They may be harmless or associated with

varying degrees of injury .


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Overview May be found:

in the cytoplasm

within organelles (typically lysosomes)

in the nucleus

Came to the cell through:

Synthesis by affected cells

Produced elsewhere


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Pathways1. Normal or increased rateof production of a

normal substance, but metabolic rate isinadequate to remove it (e.g. fatty change inliver)


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Pathways

2. A normal or an abnormal endogenoussubstance accumulates because of geneticor acquired defectsin its folding, packaging,transport, or secretion.

e.g. In -1antitrypsin deficiency,1at accumulates in the liver causing cirrhosis)


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1antitrypsin deficiency


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Pathways3. An inherited defect in an enzyme may result in

failure to degrade a metabolite.

The resulting disorders are called storage

diseases.


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Lecture will include Overview of intracellular accumulations

Accumulation of Lipids Accumulation of Cholesterol

Accumulation of Proteins

Accumulation of Glycogen

Accumulation of Pigments

Pathologic Calcification


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Fatty Change(Steatosis)


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Fatty Change Fatty change refers to any abnormal

accumulation of triglycerides within

parenchymal cells. Site: liver, most common site

it may also occur in heart, skeletal muscle,

kidney, and other organs.


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Causes of Fatty Change Toxins(most importantly: Alcohol abuse)

diabetes mellitus

Protein malnutrition (starvation)

Obesity

Anoxia


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Hepatotoxins (e.g. alcohol) by disrupting

mitochondria and SER ; anoxia

CCl4 and protein malnutrition

Starvation will

increase this

Defects in any of the

steps of uptake,

catabolism, or

secretion can lead to

lipid accumulation.


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The significance of fattychange Depends on the cause and severity of the

accumulation.

Mildit may have no effect on cellular function.

Severefatty change may transiently impair cellularfunction

In the severe form, fatty change may precede cell

death, and may be an early lesion in a serious liverdisease called nonalcoholic steatohepatitis


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Morphology of fatty change Most common site:the liver and the heart.

With increasing accumulation, the organenlarges and becomes progressively yellow,

soft, and greasy.


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Light of microscopy fatty change Early: small fat vacuoles in the

cytoplasm around the nucleus.

Later stages: the vacuoles coalesce

to create cleared spaces that

displace the nucleus to the cell

periphery

Occasionally contiguous cells

rupture (fatty cysts)


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Is Fatty liver reversible? Fatty change is reversible

except if some vital intracellular process is

irreversibly impaired (e.g., in CCl4poisoning),


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Prognosis of Fatty liver Mild: benign natural history (approximately

3% will develop cirrhosis

Moderate to sever: inflammation,

degeneration in hepatocytes, +/- fibrosis

(30% develop cirrhosis)

5 to 10 year survival:67% and 59%


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Accumulation of Lipids

Accumulation of Cholesterol Accumulation of Proteins





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Cholesterol andCholesteryl Esters


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Cellular cholesterol metabolism is tightly

regulated to ensure normal cell

membrane synthesis without significantintracellular accumulation

Conditions associated with


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Cholesterol and Cholesteryl Esters

accumulation Several different pathologic processes:1. Macrophages in contact with the lipid debris

of necrotic cells or abnormal (e.g.,oxidized) forms of lipoproteins


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Foam cells


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2. Atherosclerosis:smooth muscle cells and macrophages are

filled with lipid vacuoles composed of

cholesterol and cholesteryl esters


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Atherosclerosis: These give

atherosclerotic

plaques their

characteristic yellowcolor and contribute

to the pathogenesis

of the lesion


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Cholesterol and Cholesteryl Esters

accumulation3. In hereditary and acquired

hyperlipidemic syndromes, macrophages

accumulate intracellular cholesterol

4.Xanthomas:clusters of foamy

macrophages present in the subepithelialconnective tissue of skin or in tendons


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ObjctivesTo study:

Overview of intracellular accumulations


Accumulation of Cholesterol

Accumulation of Proteins Accumulation of Glycogen




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Proteins


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Morphologically visible protein

accumulations are much less common

than lipid accumulations They may occur because excesses are

presented to the cells or because the

cells synthesize excessive amounts


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Protein accumulationsExample:

1. Nephrotic syndrome:

In the kidney trace amounts of albumin filtered

through the glomerulus are normallyreabsorbed by pinocytosis in the proximalconvoluted tubules

After heavy protein leakage, pinocytic vesiclescontaining this protein fuse with lysosomes,resulting in the histologic appearance of pink,hyaline cytoplasmic droplets


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Protein accumulationsExample:2. marked accumulation of newly

synthesized immunoglobulins that may

occur in the RER of some plasma cells,forming rounded, eosinophilic Russell

bodies.


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Protein accumulationsExample:3. Mallory body, or "alcoholic hyalin," is an

eosinophilic cytoplasmic inclusion in liver

cells that is highly characteristic ofalcoholic liver disease

These inclusions are

composed predominantly

of aggregated

intermediate filaments


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Protein accumulationsExample:4. The neurofibrillary tangle found in the

brain in Alzheimer disease is an

aggregated protein inclusion thatcontains microtubule-associated proteins


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Accumulation of Glycogen Accumulation of Pigments



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Glycogen


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Glycogen Associated with abnormalities in the

metabolism of either glucose or glycogen.

Examples:1. In poorly controlled diabetes mellitus, glycogen

accumulates in renal tubular epithelium, cardiacmyocytes, and cells of the islets of Langerhans.

2. Glycogen accumulates within cells in a group of

closely related genetic disorders collectively referredto as glycogen storage diseases, or glycogenoses


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Pigments


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Pigments are coloredsubstances that

are either:

exogenous, coming from outside the body,or

endogenous, synthesized within the body

itself.


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Exogenous pigment The most common is carbon

When inhaled, it is phagocytosed by

alveolar macrophages and transportedthrough lymphatic channels to the

regional tracheobronchial lymph nodes.


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Exogenous pigment

Aggregates of the pigment blacken the draining

lymph nodes and pulmonary parenchyma

(anthracosis).


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Heavy accumulations may

induce emphysema or a

fibroblastic reaction that can

result in a serious lungdisease ( coal workers'

pneumoconiosis)


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Asbestos bodies

Asbestos bodies


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ObjectivesTo study: Overview of intracellular accumulations





Accumulation of Pigments Pathologic Calcification


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Endogenous pigments include lipofuscin,

melanin, and certain derivatives of

hemoglobin.


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Lipofuscin "wear-and-tear pigment" is an insoluble brownish-

yellow granular intracellular material that seen in avariety of tissues (the heart, liver, and brain) as afunction of age or atrophy.

Consists of complexes of lipid and protein that derivefrom the free radical-catalyzed peroxidation ofpolyunsaturated lipids of subcellular membranes.

It is not injurious to the cell but is important as a marker

of past free-radical injury.

The brown pigment when present in large amounts,imparts an appearance to the tissue that is calledbrown atrophy.


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Lipofuscin By electron microscopy, the pigment appears

as perinuclear electron-dense granules


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Melanin is an endogenous, brown-black pigment

produced in melanocytes

Although melanocytes are the only source ofmelanin, adjacent basal keratinocytes in theskin can accumulate the pigment

(dermal macrophages)


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Melanin


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Hemosiderin is a hemoglobin-derived granular pigment

that is golden yellow to brown andaccumulates in tissues when there is alocal or systemic excess of iron.

Hemosiderin pigment represents largeaggregates of ferritin micelles, can be

seen by light and electron microscopy


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Hemosiderin Although hemosiderin accumulation is

usually pathologic, small amounts of this

pigment are normal in the mononuclearphagocytes of the bone marrow, spleen,

and liver, where there is extensive red

cell breakdown


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Hemosiderin Local excesses of iron, and consequently of

hemosiderin, result from hemorrhage.

Bruise: The original red-blue color ofhemoglobin is transformed to varying shadesof green-blue by the local formation ofbiliverdin (green bile) and bilirubin (red bile)from the heme


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HemosiderinThe iron ions of hemoglobin accumulate as golden-yellowhemosiderin.

The iron can be unambiguously identified by the Prussian

blue histochemical reaction


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Hemosiderosis

is systemic overload of iron, hemosiderin isdeposited in many organs and tissues

It is found at first in the mononuclear

phagocytes of the liver, bone marrow, spleen,and lymph nodes and in scatteredmacrophages throughout other organs.

With progressive accumulation, parenchymalcells throughout the body (principally the liver,pancreas, heart, and endocrine organs) will beaffected


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Hemosiderosis Hemosiderosis occurs in the setting of:

1.increased absorption of dietary iron

2.impaired utilization of iron3.hemolytic anemias

4.transfusions (the transfused red cellsconstitute an exogenous load of iron).

.


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Effect of hemosiderosis In most instances of systemic

hemosiderosis, the iron pigment does notdamage the parenchymal cells

However, more extensive accumulationsof iron are seen in hereditaryhemochromatosis with tissue injuryincluding liver fibrosis, heart failure, anddiabetes mellitus


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04-Intracellular Accumulations 2008