Download intracellular accumulations

Dr.Maha Arafah
To study:
 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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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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May be found:
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in the cytoplasm
within organelles (typically lysosomes)
in the nucleus
Came to the cell through:
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Synthesis by affected cells
Produced elsewhere
1.
Normal or increased rate of production of a
normal substance, but metabolic rate is
inadequate to remove it (e.g. fatty change in
liver)
2.
A normal or an abnormal endogenous
substance accumulates because of genetic or
acquired defects in its folding, packaging,
transport, or secretion.
e.g. In α-1antitrypsin deficiency,
α1at accumulates in the liver causing cirrhosis)
3. An inherited defect in an enzyme may result in
failure to degrade a metabolite.
The resulting disorders are called storage diseases.
4. An abnormal exogenous substance is deposited
and accumulates because the cell has neither
the enzymatic machinery to degrade the
substance nor the ability to transport it to
other sites.
(e.g. Accumulations of carbon or silica particles)
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Overview of intracellular accumulations
 Accumulation
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of Lipids
Accumulation of Cholesterol
Accumulation of Proteins
Accumulation of Glycogen
Accumulation of Pigments
Pathologic Calcification
(Steatosis)
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Fatty change refers to any abnormal
accumulation of triglycerides within
parenchymal cells.
Site: liver, most common site
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it may also occur in heart, skeletal muscle, kidney,
and other organs.
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Toxins (most importantly: Alcohol abuse)
diabetes mellitus
Protein malnutrition (starvation)
Obesity
Anoxia
Starvation will
increase this
Hepatotoxins (e.g. alcohol) by disrupting
mitochondria and SER ; anoxia
•Defects in any of the
steps of uptake,
catabolism, or
secretion can lead to
lipid accumulation.
CCl4 and protein malnutrition
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Depends on the cause and severity of the
accumulation.
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Mild it may have no effect on cellular function.
Severe fatty change may transiently impair cellular
function
In the severe form, fatty change may precede cell
death, and may be an early lesion in a serious liver
disease called nonalcoholic steatohepatitis
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Most common site: the liver and the heart.
With increasing accumulation, the organ
enlarges and becomes progressively yellow,
soft, and greasy.
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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)
Fatty change is reversible
except if some vital intracellular process is
irreversibly impaired (e.g., in CCl4 poisoning),
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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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
Overview of intracellular accumulations
Accumulation of Lipids
 Accumulation

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of Cholesterol
Accumulation of Proteins
Accumulation of Glycogen
Accumulation of Pigments
Pathologic Calcification
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Cellular cholesterol metabolism is tightly
regulated to ensure normal cell membrane
synthesis without significant intracellular
accumulation
Several different pathologic processes:
1. Macrophages in contact with the lipid debris of
necrotic cells or abnormal (e.g., oxidized) forms of
lipoproteins
These macrophages may
be filled with minute,
membrane-bound
vacuoles of lipid,
imparting a foamy
appearance to their
cytoplasm (foam cells).
2.
Atherosclerosis:
smooth muscle cells and macrophages are filled with
lipid vacuoles composed of cholesterol and
cholesteryl esters
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These give
atherosclerotic
plaques their
characteristic yellow
color and contribute
to the pathogenesis
of the lesion
3. In hereditary and acquired hyperlipidemic
syndromes, macrophages accumulate
intracellular cholesterol
4. Xanthomas: clusters of foamy macrophages
present in the subepithelial connective tissue of
skin or in tendons
To study:
 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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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
1.
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Nephrotic syndrome:
In the kidney trace amounts of albumin filtered
through the glomerulus are normally
reabsorbed by pinocytosis in the proximal
convoluted tubules
After heavy protein leakage, pinocytic vesicles
containing this protein fuse with lysosomes,
resulting in the histologic appearance of pink,
hyaline cytoplasmic droplets
The process is reversible; if the proteinuria abates, the protein
droplets are metabolized and disappear.
2. marked accumulation of newly synthesized
immunoglobulins that may occur in the RER of
some plasma cells, forming rounded,
eosinophilic Russell bodies.
3. Mallory body, or "alcoholic hyalin," is an
eosinophilic cytoplasmic inclusion in liver cells
that is highly characteristic of alcoholic liver
disease
These inclusions are
composed predominantly
of aggregated
intermediate filaments
4. The neurofibrillary tangle found in the brain in
Alzheimer disease is an aggregated protein
inclusion that contains microtubule-associated
proteins
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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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Associated with abnormalities in the
metabolism of either glucose or glycogen.
Examples:
1.
In poorly controlled diabetes mellitus, glycogen
accumulates in renal tubular epithelium, cardiac
myocytes, and β cells of the islets of Langerhans.
2.
Glycogen accumulates within cells in a group of
closely related genetic disorders collectively referred
to as glycogen storage diseases, or glycogenoses
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In these diseases, enzymatic defects in the
synthesis or breakdown of glycogen result in
massive stockpiling, with secondary injury and
cell death.
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Pigments are colored substances that are either:
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exogenous, coming from outside the body, or
endogenous, synthesized within the body itself.
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The most common is carbon
When inhaled, it is phagocytosed by alveolar
macrophages and transported through
lymphatic channels to the regional
tracheobronchial lymph nodes.
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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 lung
disease ( coal workers'
pneumoconiosis)
Asbestos bodies
Asbestos bodies
To study:
 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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Endogenous pigments include lipofuscin,
melanin, and certain derivatives of
hemoglobin.
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"wear-and-tear pigment" is an insoluble brownishyellow granular intracellular material that seen in a
variety of tissues (the heart, liver, and brain) as a
function of age or atrophy.
Consists of complexes of lipid and protein that derive
from the free radical-catalyzed peroxidation of
polyunsaturated 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 called
brown atrophy.
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By electron microscopy, the pigment appears
as perinuclear electron-dense granules
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is an endogenous, brown-black pigment
produced in melanocytes
Although melanocytes are the only source of
melanin, adjacent basal keratinocytes in the
skin can accumulate the pigment
(dermal macrophages)
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is a hemoglobin-derived granular pigment
that is golden yellow to brown and
accumulates in tissues when there is a local or
systemic excess of iron.
Hemosiderin pigment represents large
aggregates of ferritin micelles, can be seen by
light and electron microscopy
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Although hemosiderin accumulation is usually
pathologic, small amounts of this pigment are
normal in the mononuclear phagocytes of the
bone marrow, spleen, and liver, where there is
extensive red cell breakdown
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Local excesses of iron, and consequently of
hemosiderin, result from hemorrhage.
Bruise: The original red-blue color of
hemoglobin is transformed to varying shades
of green-blue by the local formation of
biliverdin (green bile) and bilirubin (red bile)
from the heme
The iron ions of hemoglobin accumulate as golden-yellow
hemosiderin.
The iron can be unambiguously identified by the Prussian
blue histochemical reaction
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is systemic overload of iron, hemosiderin is
deposited 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 scattered
macrophages throughout other organs.
With progressive accumulation, parenchymal
cells throughout the body (principally the
liver, pancreas, heart, and endocrine organs)
will be affected
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Hemosiderosis occurs in the setting of:
1. increased absorption of dietary iron
2. impaired utilization of iron
3. hemolytic anemias
4. transfusions (the transfused red cells
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constitute an exogenous load of iron).
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In most instances of systemic hemosiderosis,
the iron pigment does not damage the
parenchymal cells
However, more extensive accumulations of
iron are seen in hereditary hemochromatosis
with tissue injury including liver fibrosis, heart
failure, and diabetes mellitus