Intracellular Accumulations

• Various substances like proteins, lipids, pigments,

calcium etc. can accumulate in cells.
• The substance may be located in:

1. The cytoplasm
2. Within organelles (typically lysosomes)
3. The nucleus.
• Mechanisms of intracellular
accumulation.
1. Abnormal metabolism, as
in fatty change in the liver.
2. Mutations causing
alterations in protein
folding and transport, so
that defective molecules
accumulate intracellularly.
3. A deficiency of critical
enzymes responsible for
breaking down certain
compounds, causing
substrates to accumulate in
lysosomes, as in lysosomal
storage diseases.
4. An inability to degrade
phagocytosed particles, as
in carbon pigment
accumulation.
• Lipids:
• Fatty Change (Steatosis):
• Abnormal accumulation of triglycerides within cells.
• It is most often seen in:

1. The liver
2. Heart
3. Skeletal muscle
4. kidney, and other organs.
• Steatosis may be caused by:

1. Increased fatty acids entering the liver (starvation,

corticosteroids)
2. Decreased fatty acid oxidation (hypoxia)
3. Increased triglyceride formation (alcohol)
4. Decreased apoprotein synthesis (carbon tetrachloride
poisoning, starvation)
5. Impaired lipoprotein secretion from the liver (alcohol)
• Fatty change is reversible.
• It is most often seen in the liver and heart.
• Mild form have no effect on cellular function.
• In the severe form, fatty change may precede cell death,
(nonalcoholic steatohepatitis).
• Morphologically it appears as clear vacuoles within
parenchymal cells.
• Fatty liver. A, Schematic diagram of the possible mechanisms leading to
accumulation of triglycerides in fatty liver. Defects in any of the steps of
uptake, catabolism, or secretion can result in lipid accumulation. B, High-
power detail of fatty change of the liver. In most cells the well-preserved
nucleus is squeezed into the displaced rim of cytoplasm about the fat vacuole.
 Pigments
• Pigments are colored substances
• They may be:

1. Exogenous, coming from outside the body

2. Endogenous, synthesized within the body
• Exogenous pigment:
• The most common is carbon (e.g., coal dust)
• When inhaled, it is phagocytosed by alveolar
macrophages
• Aggregates of the pigment blacken the draining lymph
nodes and pulmonary parenchyma (anthracosis)
• Heavy accumulations may induce emphysema or a
fibroblastic reaction that can result in a serious lung
disease called coal workers' pneumoconiosis
Lung in anthracosis
• Endogenous pigments:
• Endogenous pigments include:

1. Lipofuscin
2. Melanin
3. Certain derivatives of hemoglobin.
 Lipofuscin
• Lipofuscin is an insoluble substance associated with
cellular and tissue atrophy (brown atrophy).
• It accumulates in a variety of tissues (particularly the
heart, liver, and brain).
• Microscopically it appears as fine, yellow-brown
intracytoplasmic granules.
• The pigment is composed of complex lipids,
phospholipids, and protein derived from cell membrane
peroxidation.
• Lipofuscin granules in a cardiac myocyte shown by:
• A. light microscopy (deposits indicated by arrows)
• B. electron microscopy
 Melanin
• Melanin is an endogenous, brown-black pigment
formed by enzymatic oxidation of tyrosine to
dihydroxyphenylalanine in melanocytes.
• It is synthesized exclusively by melanocytes located in
the epidermis and acts as a screen against harmful
ultraviolet radiation.
 Hemosiderin
• Hemosiderin is a hemoglobin-derived granular pigment,
golden yellow to brown and accumulates in tissues when
there is a local or systemic excess of iron.
• Iron is normally stored within cells in association with the
protein apoferritin, forming ferritin micelles.
• Hemosiderin pigment represents large aggregates of these
ferritin micelles.
• In systemic iron overload, hemosiderin is deposited in
many organs and tissues, a condition called hemosiderosis.
• Hemosiderosis occurs in the following settings:

1. Increased absorption of dietary iron

2. Impaired utilization of iron
3. Hemolytic anemias
4. Transfusions (the transfused red cells constitute an
exogenous load of iron).
• Extensive accumulations of iron seen in hereditary
hemochromatosis is associted with tissue injury
including liver fibrosis, heart failure, and diabetes
mellitus.
• Hemosiderin granules in liver cells.
• A, H+E stain showing golden-brown, finely granular pigment.
• B, Prussian blue stain, specific for iron (seen as blue granules).
 Bilirubin
• Is the normal major pigment found in bile.
• It is derived from hemoglobin.
• Its excesses within cells and tissues result in jaundice.
• Pathologic Calcification:
• Pathologic calcification is the abnormal tissue
deposition of calcium salts, together with smaller
amounts of iron, magnesium, and other mineral salts.
• Two forms:
• Dystrophic calcification:
• Deposition occurs locally in dying tissues with normal
serum levels of calcium.
• Metastatic calcification:
• Deposition of calcium salts in normal tissues results
from hypercalcemia
• Dystrophic Calcification:
• Encountered in areas of:

1. Necrosis (coagulative, caseous, fat, liquefactive)

2. Atherosclerosis
3. Aging or damaged heart valves
4. Tuberculous lymph node
• Dystrophic calcification is often a cause of organ
dysfunction, as in calcific valvular disease and
atherosclerosis.
• Dystrophic calcification of the aortic valve. It is markedly
narrowed (stenosis). The semilunar cusps are thickened and
fibrotic, and behind each cusp are irregular masses of piled-up
dystrophic calcification.
• Metastatic Calcification:

• Occurs in normal tissues whenever there is

hypercalcemia.
• Principal causes of hypercalcemia:

1. Hyperparathyroidism due to parathyroid tumors.

2. Vitamin D–related disorders (vitamin D intoxication,

sarcoidosis).

3. Renal failure.
4. Bone destruction secondary to (e.g., multiple myeloma,
leukemia, metastatic tumors to bone, Paget disease)
• Metastatic calcification may occur widely throughout
the body but principally affects:
1. Stomach
2. Kidneys
3. Lungs
4. Systemic arteries
5. Pulmonary veins
• Massive deposits in the kidney (nephrocalcinosis) may
in time cause renal damage.