ABNORMAL INTRACELLULAR ACCUMULATIONS
Under some circumstances cells may accumulate abnormal amounts of various substances, which may be harmless or associated with varying degrees of injury.
•The substance may be located
•in the cytoplasm, within organelles (typically lysosomes),
•or in the nucleus,
It may be synthesized by the affected cells or
•may be produced elsewhere.

PATHWAYS OF ABNORMAL INTRACELLULAR ACCUMULATIONS
1. ABNORMAL METABOLISM
There are 3 main pathways of abnormal intracellular accumulations
A normal substance is produced at a normal or an increased rate, but the metabolic rate is inadequate to remove it.
Example of this type of process is fatty change in the liver.
Abnormal metabolism, as in fatty change in the liver

2. GENETIC OR ACQUIRED DEFECTS
A normal or an abnormal endogenous substance accumulates because of genetic or acquired defects in its folding, packaging, transport, or secretion.
Example: Mutations that cause defective folding and transport may lead to accumulation of proteins (e.g.,
α1-antitrypsin deficiency
).
An inherited defect in an enzyme may result in failure to degrade a metabolite. The resulting disorders are called storage diseases.
Mutations causing alterations in protein folding and transport, so that defective molecules accumulate intracellularly.

3. DEFICIENCY OF CRITICAL ENZYMES
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.
Example: Accumulations of carbon or silica particles are examples of this type of alteration.
An inability to degrade phagocytized particles, as in carbon pigment accumulation.
A deficiency of critical enzymes responsible for breaking down certain compounds, causing substrates to accumulate in lysosomes, as in lysosomal storage diseases.

Fatty Change (Steatosis)
Fatty change refers to any abnormal accumulation of triglycerides within parenchymal cells.
It is most often seen in the liver, since this is the major organ involved in fat metabolism, but it may also occur in heart, skeletal muscle, kidney, and other organs.
Steatosis may be caused by toxins, protein malnutrition , diabetes mellitus, obesity, and anoxia.
Alcohol abuse and diabetes associated with obesity are the most common causes of fatty change in the liver (fatty liver) in industrialized nations.

Other Lipids Accumulation
• Cholesterol and cholesterol esters
• In atherosclerosis, cholesterol accumulates in smooth muscle cells and macrophages (A type of white blood ) in the intima of arteries

Other Lipids Accumulation
• In hereditary hyperlipemia, cholesterol accumulates in macrophages, usually under the skin, forming tumor-like structures known as xanthomas
(accumulation of lipids in large foam cells within the skin)

Intracellular Accumulations of Proteins
1. Normal constituent –
Proteins -Mostly intracellular ( exception- Amyloid protein);
Folding is important for transport and function;
Chaperones - help in the protein folding & transport ;
Defects in Protein folding - lead to neurodegenerative diseases
(Alzheimer's; Huntington's, Parkinson's diseases) and Type II DM;

Intracellular Accumulations of Protiens
Disorders due to defects in protein folding
 1. α1-antitrypsin deficiencySlow folding of protein
(↑accumulation in ER -liver) ;
 2. Cystic fibrosis Cystic fibrosis (CF) is a genetic disorder that particularly affects the lungs and digestive system
 3. Familial Hypercholesterolemia is a genetic disorder characterized by high cholesterol levels , specifically very high levels of low-density lipoprotein (LDL, "bad cholesterol"), in the blood and early cardiovascular disease .

Intracellular Accumulation of Glycogen
Glucose derived from glycogen breakdown is an important source of energy for the body.
It provides energy for muscle contraction, and serves as the primary source of energy for the brain.
Defective metabolism in Normal constituent of Glycogen leads to glycogen storage/accumulation
Glycogen storage disease (GSD,) is the result of defects in the processing of glycogen synthesis or breakdown within muscles , liver , and other cell types

Extracellular Accumulations
1) Calcification
2) Hyaline change
3) Amyloid and amyloidosis
4) Gout
5) Fibrinoid

• “Deposition of calcium salts in vital or dying/dead tissues”
•
A- Dystrophic and
•
B- Metastatic
•
Dystrophic calcification is the deposition of calcium in dead tissues while metastatic calcification is deposition of calcium in normal tissues.

A- Dystrophic Calcification
• “Deposition of calcium salts in dead or dying tissues ”
•
Principally in areas of coagulative, liquefactive, caseous and/or fat necrosis that persist for rather long periods of time.
•
Represents evidence of previous cell injury
•
Normal levels of serum calcium ( around 10 mg/100 ml) and in the absence of derangement in calcium metabolism
•
Can cause organ dysfunction (heart valves,
Atherosclerosis)

B- Metastatic Calcification
Deposition of calcium salts in vital tissues in association with a defect in calcium metabolism that is characterized by hypercalcemia
Usual causes:
(1) Hyperparathyroidism, either primary or secondary
(2) Vitamin-D intoxication
(3) Deficiency of magnesium
(4) Hypercalcemia of malignancy
•
Principally in interstitial tissue of blood vessels, kidneys, lungs and gastric mucosa
•
Fundamental abnormality: Pathologic entry of large amounts of ionic calcium into cell organelles, chiefly the mitochondria

2) Hyaline Change
• “A homogeneous, glassy, pink appearance in tissues or cells stained with H&E”
•
Widely used descriptive histologic term rather than a specific marker for cell injury
•
Connective tissue hyaline
•
Epithelial hyaline
•
Kerato-hyaline

3) Amyloid and Amyloidosis
•
Deposition of amyloid protein fibrils in tissue
•
Immune system dysfunction
•
Abnormal processing of components of immunoglobulins, insulin, growth hormone and an acute-phase reactant of inflammation called the serum amyloid associated protein (SAA)

• “Deposition of uric acid and urate crystals in tissues subsequent to defective purine metabolism”
•
The condition occurs primarily in humans and in birds.
•
In birds, articular and visceral forms of gout are recognized

Articular Gout
•
Uric acid and urate crystals are deposited in joint spaces
•
Affected joints are enlarged, and white, chalky masses (“tophil”) may be observed when opened. The condition may result in severe pain

•
Uric and urate crystals are deposited over the serous surfaces within the body cavity (pleural, pericardium, etc.)
•
Serous membranes line and enclose several body cavities, known as serous cavities
•
Deposits are also found in the renal tubules
•
Grossly, serous membranes are encrusted by a thin grayish layer having a metallic sheen.

•
Fibrinoid : There is accumulation of proteinaceous material) in the tissue matrix resembles fibrin
•
It is typically seen in a focus of tissue injury
(especially in vessel walls or in connective tissue)
•
It is most often located in the intima and media of vessel walls

Intracellular Accumulations
• Colored substances;
• can be


• can be



Exogenous Pigments
•Carbon particles enter our bodies in smoke and soot
Carbon: causes coal worker’s pneumoconiosis (CWP)
•Heavy deposits could be associated with lung fibrosis and emphysema
•
Tattoo

Pigmentation of the skin (dermal pigment laden macrophages without inflammatory response)

• 1.
Melanin : (normal black pigment)
• 2. Hemosiderin : Hemoglobin - derived, golden yellow-to-brown pigment; Complications Liver

Fibrosis, Cirrhosis; Heart

Failure
(Cardiomyopathy), Pancreas- Diabetes mellitus
• 3.
Bilirubin : Major pigment of bile; Non iron hemoglobin derived pigment in patients with
Jaundice

Lipofuscin (lipochrome)
•Composed of polymers of lipids, phospholipids and protein
•Lipofuscin is normally present in:
– Interstitial cells of the testis,
–Epithelial cells of the epididymis and seminal vesicles
–Cardiac nuclei
•Lipofuscin becomes more abundant during –normal aging – severe malnutrition –cancer cachexia
•By age 90, the heart may contain
30% lipofuscin by weight.