Intracellular accumulations occur when cells abnormally store substances endogenously produced or absorbed from outside the cell. Common types of accumulations include lipids like triglycerides and cholesterol, proteins, glycogen, and pigments. Accumulations can be harmless, but often correlate with cell injury. They result from imbalances between production or absorption of the substance versus the cell's ability to metabolize or transport it out. Certain genetic disorders can also cause accumulations by impairing the breakdown of metabolites.

1. Dr. EM

2. LEARNING OBJECTIVES
 Enlist intracellular accumulations
 Describe the mechanism of intracellular
accumulations.
 Identify microscopically different types of
intracellular accumulations

3. Overview
 Under some circumstances cells may accumulate
abnormal amounts of various substances.
 They may be harmless or associated with varying
degrees of injury .

4. Overview
 Intracellular may be found:
 in the cytoplasm
 within organelles (typically lysosomes)
 in the nucleus
 Come to the cell through:
 Synthesis by affected cells (endogenous)
 Produced elsewhere (exogenous)

5. ENLIST INTRACELLULAR ACCUMULATIONS
 TRIGLYCERIDE ACCUMULATION
 Fatty change
 CHOLESTROL AND CHOLESTRYL ESTER
 Atherosclerosis
 Atheroma
 Cholesterolosis
 PROTIEN ACCUMULATION
 Amyloidosis (Protien accumalation in renal tubules in Nephrotic
syndrome )
 Hyaline change
 1- Russell bodies (multiple myeloma)
 2- Mallory bodies (alcoholic liver disease)

6.  Glycogen accumulation (Diabetes mellitus, glycogen storage
disease)
 Pigmentations
 1- Exogenous (air pollutants, silica, carbon, tattooing)
 2- Endogenous
1. Lipofuscin
2. Hemosiderin
3. Bilirubin
4. Melanin

7. MECHANISM
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)

8. MECHANISM
2. A normal or an abnormal endogenous substance
accumulates because of genetic or acquired
defects in its folding, packaging, transport, or
secretion.

9. MECHANISM
3. An inherited defect in an enzyme may result in failure
to degrade a metabolite. The resulting disorders are
called storage diseases.

10. MECHANISM
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)

14. (Steatosis)

15. Fatty Change
 Fatty change refers to abnormal accumulation of
triglycerides within parenchymal cells.
 Site: liver, most common site
 it may also occur in heart, skeletal muscle, kidney, and other
organs.
MORPHOLOGY
 Most common site: the liver and the heart.
 With increasing accumulation, the organ enlarges and
becomes progressively yellow, soft, and greasy.

20. 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)

23. Cholesterol and Cholesteryl Esters
 Cellular cholesterol metabolism is tightly regulated to
ensure normal cell membrane synthesis without
significant intracellular accumulation

24. CHOLESTEROL AND CHOLESTEROL
ESTERS
a) Atherosclerosis : In atherosclerotic plaques, smooth
muscle cells and macrophages within the intimal layer of the
aorta and large arteries are filled with lipid vacuoles, most of
which are made of cholesterol and cholesterol esters. These
cells have a foamy appearance ( foam cells)and aggregates
produce yellow cholesterol-laden atheromas.
b) Xanthomas: clusters of foamy cells are found in the sub
epithelial connective tissue of the skin and in tendons .

25. XANTHOMA

27. ATHEROSCLEROSIS:
These give atherosclerotic
plaques their characteristic
yellow color and contribute to the
pathogenesis of the lesion

28. CHOLESTEROLOSIS
There is focal accumulation of cholesterol-laden macrophages in
the lamina propria of the gall-bladder. (foam cells)

30.  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

31. AMYLOIDOSIS
 Amyloid light chain AL (Ig light chains, derived from plasma
cells) Primary amyloidosis – M Myeloma
 Amyloid associated chain AA(non-Ig protein from liver)
secondary amyloidosis – TB, R. arthritis
 Beta amyloid precurson proteins AB form (in cerebral lesions
like Alzeihemer diseases)
 Histologically: Eosinophilic hyaline extracellular
substance causes pressure atrophy in deposition area.

32. Protein accumulations
Example:
1. 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

33. The process is reversible; if the proteinuria abates, the protein
droplets are metabolized and disappear.

34. Protein accumulations
MALLORY BODY, OR "ALCOHOLIC
HYALINE," is an eosinophilic intra-cytoplasmic
inclusion in liver cells that is highly characteristic of
ALCOHOLIC LIVER DISEASE
 hepatocytes of alcoholic liver disease
 primary biliary cirrhosis
 hepatocellular carcinoma.

35. Protein accumulations
Example:
2. Multiple myeloma.
Russell bodies are eosinophilic, large, homogenous
immunoglobulin-containing inclusions usually found
in a plasma cell undergoing excessive synthesis of
immunoglobulin
 the Russell body is characteristic of the distended
endoplasmic reticulum. This is one cell variation
found in multiple myeloma.

36. Russell bodies are eosinophilic, large,
homogeneous immunoglobulin-containing
inclusions usually found in a plasma cell
undergoing excessive synthesis of immunoglobulin;
the Russell ... Multiple aggregates of Russell bodies
create what are known as Mott cells. This is one cell
variation found in multiple myeloma.

40. 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, cardiac myocytes, and β cells of
the islets of Langerhans.
Glycogen accumulates within cells in a group of closely related
genetic disorders collectively referred to as glycogen
storage diseases, or glycogenoses
In these diseases, enzymatic defects in the synthesis or
breakdown of glycogen result in massive stockpiling, with
secondary injury and cell death.

41. GLYCOGEN STORAGE DISEASES

44. Exogenous pigment
 The most common is carbon
 When inhaled, it is phagocytosed by alveolar macrophages
and transported through lymphatic channels to the regional
tracheobronchial lymph nodes.
 Tattooing is a form of localized exogenous pigmentation of
the skin.
 The pigments inoculated are phagocytosed by dermal
macrophages, in which they reside for the remainder of the
life of the bearer.
 The pigments do not usually evoke any inflammatory
response.

45. Exogenous pigment
 Aggregates of the pigment blacken the draining
lymph nodes and pulmonary parenchyma
(anthracosis).

46. CARBON IN LUNGS

48. COAL WORKERS' PNEUMOCONIOSIS
 Heavy accumulations may
induce emphysema or a
fibroblastic reaction that can
result in a serious lung disease
called coal workers'
pneumoconiosis

49. ENDOGENOUS PIGMENTS
 Endogenous pigments include:
 Endogenous pigments are characterized as hematogenous
and nonhematogenous. Hematogenous pigments originate
from blood and nonhematogenous pigments originate from
non-blood, fat or fatlike, and non-fatlike substances
 lipofuscin,
 melanin
 certain derivatives of hemoglobin
 Hemosiderin
 bilirubin

50. LIPOFUSCIN
"Wear-and-tear pigment" is an insoluble brownish-yellow
granular intracellular material that seen in a variety of tissues
(the heart, liver, kidney, retina, adrenals, nerve cells and
ganglion cells in 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 sub cellular membranes.
The brown pigment when present in large amounts, imparts an
appearance to the tissue that is called brown atrophy.

52. Lipofuscin
 By electron microscopy, the pigment appears as
perinuclear electron-dense granules

54. Melanin
 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)

55. MELANIN IN SKIN

56. Melanin

58. Hemosiderosis
 is systemic overload of iron, hemosiderin is deposited in
many organs and tissues
 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.
 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

59. Hemosiderin
 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

60. Hemosiderin
The iron ions of hemoglobin accumulate as golden-yellow
hemosiderin.
The iron can be unambiguously identified by the Prussian
blue histochemical reaction

61. Hemosiderosis
 Hemosiderosis occurs in the setting of:
1. increased absorption of dietary iron
2. impaired utilization of iron
3. hemolytic anemias
4. Repeated blood transfusions (the
transfused red cells constitute an
exogenous load of iron).
.

63. SUMMARY

64. Endogenous Accumulations
 Bilirubin Kernicterus: fat-soluble unconjugated bilirubin derived
from Rh hemolytic disease of newborn; bilirubin enters basal
ganglia nuclei of brain, causing permanent damage
 Cholesterol Xanthelasma: yellow plaque on eyelid; cholesterol in
macrophages
 Atherosclerosis: cholesterol-laden smooth muscle cells and
macrophages (i.e., foam cells); components of fibrofatty plaques
 Glycogen Diabetes mellitus: increased glycogen in proximal renal
tubule cells (cells are insensitive to insulin and become
overloaded with glycogen
 Von Gierke's glycogenosis: deficiency of glucose-6-phosphatase;
glycogen excess in hepatocytes and renal tubular cells

65.  Hemosiderin and ferritin Iron overload disorders (e.g.,
hemochromatosis): excess hemosiderin deposition in
parenchymal cells, leading to free radical damage and
organ dysfunction (e.g., cirrhosis); increase in serum
ferritin
 Melanin; Addison's disease: destruction of the adrenal
cortex; hypocortisolism leads to an increase in ACTH
causing excess synthesis of melanin and diffuse
pigmentation of the skin and mucosal membranes
 Triglyceride Fatty liver: triglyceride in hepatocytes
pushes the nucleus to the periphery

66.  Exogenous Accumulations
 Lead poisoning: lead deposits in nuclei of proximal
renal tubular cells (acid-fast inclusion) contribute to
nephrotoxic changes in the proximal tubule