Basic principles of pathology

INTRACELLULAR
ACCUMULATIONS
Dr. Mohamed Zakaria, PhD.,
Assistant Prof. of Pathology
Clinical Pharmacy Dept.
Definition:
Accumulation of abnormal amounts of various
substances due to manifestations of metabolic
derangements in the cell.

Categories:
1. Normal cellular constituents
e.g., Water, lipids, proteins, and CHO

2. Abnormal substances
a) Exogenous
e.g., Mineral or products of infectious agents

b) Endogenous
e.g., Products of abnormal synthesis or
metabolism
2
Site of IC accumulation:
a) Cytoplasm (phagolysosomes)
b) Nucleus

Sources of IC accumulation:
- Produced by the affected cell
- Produced elsewhere in the body, but stored in the cell

3
2. Accumulation of an abnormal endogenous substance
(product of mutated gene) due to defects in protein folding,
transport & inability to degrade abnormal proteins
efficiently.
e.g., accumulation of mutated proteins in liver cells

3. Accumulation of normal endogenous substance due to

inherited defect in enzymes required for metabolism of the
substance.
e.g., Lipid & Glycogen storage diseases

4. Accumulation of abnormal exogenous substance due to

unavailability of enzymatic & transport mechanisms to
degrade & transport it to other sites.
e.g., Silicosis & Anthracosis

4
ACCUMULATION OF LIPIDS
- Triglycerides, cholesterol/cholesterol esters,
phospholipids

STEATOSIS ( FATTY CHANGE)

- Abnormal accumulations of TGs within
parenchymal cells.

SITES:
- Liver (most common site)
- May also occurs in heart, skeletal muscle,
kidney, and other organs
5
CAUSES:

- Toxins (most importantly: Alcohol abuse)

- Diabetes mellitus

- Protein malnutrition (starvation)

- Obesity

- Anoxia

6
MECHANISMS OF FATTY CHANGE

7
MORPHOLOGY OF FATTY CHANGE
Most common site:
• Liver
• Heart.
• With increasing accumulation, the organ enlarges
and becomes progressively yellow, soft & greasy.

8
LIGHT MICROSCOPY OF FATTY CHANGE
Early stages:
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)

9
ACCUMULATION OF CHOLESTEROL AND
CHOLESTEROL ESTERS

1. ATHEROSCLEROSIS:
. In atherosclerotic plaques, SMCs and macrophages within
intimal layer of aorta & large arteries are filled with lipid
vacuoles, most of which are made up of cholesterol &
cholesterol esters.
. Have foamy appearance (foamy cells)
. produce yellow cholesterol-laden
atheromas

Foam cells
2. XANTHOMAS:
formed by clusters of foamy cells found in the subepithelial connective tissue of the skin and in tendons

3.CHOLESTEROLOSIS:
focal accumulations of cholesterol-laden macrophages in the lamina propria of gallbladder

4. NIEMANN-PICK DISEASE, TYPE C:

Lysosomal storage disease caused by mutations affecting an enzyme involved in cholesterol trafficking, resulting in cholesterol accumulation in multiple organs

11
ACCUMULATION OF PROTEINS

Appear as rounded, eosinophilic droplets, vacuoles or

aggregates in cytoplasm.

On Electron Microscopy they can be amorphous, fibrillar, or

crystalline in appearance.

12
MODES OF PROTEIN ACCUMULATION

1. Reabsorption droplets in proximal renal tubules are seen

in renal diseases associated with protein loss in urine
(proteinuria).
- in disorders with heavy protein leakage across the gromerular
filter there is increased reabsorption of protein into vesicles and
the protein appears as pink hyaline droplets within the
cytoplasm of the tubular cell

2. Proteins accumulated may be normal secreted proteins

that are produced in excessive amounts as occurs in certain
plasma cells engaged in active synthesis of immunoglobulin's.

ER becomes hugely distended producing large, homogenous

eosinophilic inclusions called Russell Bodies.
13
3. Defective intracellular transport and secretion of
critical proteins
e.g., α1-antitrypsin deficiency (Liver lipid deposition)

4. Accumulation of cytoskeleton proteins

e.g.,
. Microtubules
. Actin filaments
. Myosin filaments
. Intermediate filaments keratin filaments,
neurofilaments, desmin filaments, vimentin filaments & glial
filaments

5. Aggregation of abnormal proteins

e.g., Amyloidosis (proteinopathies or protein –
aggregation diseases)
14
HYALINE CHANGE
Refers to alteration within cells or in the extracellular space
that gives a homogeneous, glassy, pink appearance in routine
histologic sections stained with H&E.

Examples:
. Reabsorption droplets
. Russell bodies
. Alcoholic hyaline
. Hyalinization of walls of renal arterioles in
long standing HTN & DM

ACCUMULATION OF GLYCOGEN

Excessive intracellular deposits of glycogen are seen in patients

with an abnormality in either glucose or glycogen metabolism.
e.g. Diabetes Mellitus & Glycogen storage diseases 15
PIGMENTS
Colored substances, some of which are normal constituents of
cells (e.g., melanin), whereas others are abnormal and
accumulate in cells only under special circumstances.

EXOGENOUS PIGMENTS:
Carbon (coal dust) most common examples:
. Anthracosis (Accumulation of carbon in the lungs from
inhaled smoke or coal dust. Also called miner's lung )
. Pneumoconios (Occupational lung disease and a restrictive
lung disease caused by the inhalation of dust, often in mines).
. Tattooing (Is a form of body modification, made by
inserting indelible ink into the dermis layer of the skin to
change the pigment.
. Silicosis (Occupational lung disease caused by inhalation of
crystalline silica dust)
16
 ENDOGENOUS PIGMENTS

Examples:
- Lipofuscin: Granular yellow-brown pigment granules
found in the liver, kidney, heart muscle, retina,
adrenals, nerve cells, and ganglion cells.

- Melanin: Pigment is produced in a specialized group

of cells known as melanocytes

- Hemosiderin Hemosiderosis

17
Lipofuscin in liver cells Melanin in pigmented melanoma