INTRACELLULAR ACCUMULATIONS

DR. USMAN NASIR

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, CHO

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

b) Endogenous e.g., products of abnormal synthesis or metabolism

SITES: a) Cytoplasm (phagolysosomes) b) Nucleus

SOURCE: . Produced by the affected cell . Produced elsewhere in the body, but stored in the cell

PROCESSES OF ACCUMULATIONSFOUR PROCESSES1. Production of a normal endogenous substance at normal or increased rate, but the rate of metabolism is inadequate to remove it.e.g., fatty liver, reabsorption protein droplets in tubules of kidney

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

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 occur in heart, skeletal muscle, kidney, and other organs

CAUSES:

.Toxins (most importantly: Alcohol abuse)

.diabetes mellitus

.Protein malnutrition (starvation)

.Obesity

.Anoxia

MECHANISMS OF FATTY CHANGE

MORPHOLOGY OF FATTY CHANGEMOST COMMON SITE:• liver •heart.

• with increasing accumulation, the organ enlarges and becomes progressively yellow, soft & greasy.

LIGHT MICROSCOPY OF 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)

ACCUMULATION OF CHOLESTEROL AND CHOLESTEROL ESTERSCONDITIONS: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

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

Foam cells

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.

Protein reabsorption droplets in renal tubular epithelium

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 immunoglobulins.ER becomes hugely distended producing large, homogenous eosinophilic inclusions called Russell Bodies.

3. Defective intracellular transport and secretion of critical proteinse.g., α1- antitrypsin deficiency

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)

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.

EXAMPLES OF DISORDERS OF GLYCOGEN METABOLISM: . Diabetes Mellitus . Glycogen storage diseases

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 commonExamples: . Anthracosis . Pneumoconiosis . Tattooing . Silicosis

ENDOGENOUS PIGMENTS:

Examples: . Lipofuscin . Melanin . Hemosiderin----Hemosiderosis