Intracellular Accumulation and Extracellular Deposition

I. Intracellular Accumulation

1. Definition:

Intracellular accumulation refers to the buildup of normal or abnormal metabolic byproducts within the cytoplasm of cells. These byproducts can include carbohydrates, lipids, proteins, water, pigments, and more. This accumulation disrupts cellular function, negatively affecting cell activity and potentially leading to cell death.

2. Causes:

– Hypoxia (Lack of Oxygen): Reduced oxygen supply results in insufficient ATP production, disrupting cellular processes and leading to water accumulation within the cell.

– Ischemia (Reduced Blood Flow): Similar to hypoxia, ischemia limits oxygen and nutrient delivery, impairing cellular function and causing water retention.

– Nutritional Deficiencies: Lack of essential nutrients can disrupt metabolic pathways, leading to the accumulation of specific byproducts.

– Genetic Defects: Inherited metabolic disorders can cause the accumulation of specific substances due to missing or dysfunctional enzymes.

– Toxic Exposure: Chemicals and toxins can disrupt cellular processes and lead to the buildup of various byproducts.

– Infections: Viruses and bacteria can damage cells, impairing their normal metabolic functions and causing accumulation.

3. Gross Appearance:

– Organs affected by water accumulation often appear enlarged, heavier, tense, and pale in color.

4. Microscopic Appearance:

– Cellular Swelling (Hydropic Degeneration):

– Mild water accumulation causes cells to swell and appear granular, staining poorly. The nucleus remains centrally located.

– This condition is often reversible.

– Vacuolization (Vacuolar Degeneration):

– Severe water accumulation results in cell swelling, with multiple clear vacuoles forming within the cytoplasm, pushing the nucleus to the periphery.

– Cells can rupture and die.

5. Types of Intracellular Accumulation:

a) Lipid Accumulation:

– Commonly seen in the liver, heart, kidneys, and muscles.

– Types of lipid accumulation:

– Triglyceride accumulation (Fatty Change)

– Cholesterol and Cholesteryl Ester (CE) accumulation

– Complex lipid accumulation

i. Triglyceride Accumulation:

– Causes:

– Alcohol abuse, malnutrition (liver)

– Chronic hypoxia, bacterial toxins (heart)

– Gross Appearance: Organs with triglyceride accumulation often appear enlarged and yellow.

– Microscopic Appearance: The cytoplasm is filled with small, clear, vacuoles or a single large vacuole that pushes the nucleus to the periphery.

– Severe accumulation can lead to cell death.

ii. Cholesterol and CE Accumulation:

– Causes: Atherosclerosis, familial hypercholesterolemia…

– Gross Appearance: Xanthomas – soft, yellow nodules caused by the accumulation of foam cells in the connective tissue of the skin.

– Microscopic Appearance: Cholesterol and CE accumulate within cells as small, clear vacuoles, creating foam cells.

iii. Complex Lipid Accumulation:

– Causes: Lysosomal storage diseases (due to a deficiency of specific hydrolytic enzymes).

– Gross Appearance:

– Gaucher’s disease: A deficiency in the enzyme glucocerebrosidase, leading to the accumulation of glucocerebroside within cells, creating Gaucher cells.

– Niemann-Pick disease: Deficiency in the enzyme sphingomyelinase, resulting in the accumulation of sphingomyelin within cells.

b) Carbohydrate Accumulation:

– Types:

– Glycogen accumulation

– Mucopolysaccharide accumulation

i. Glycogen Accumulation:

– Causes:

– Diabetes mellitus: Renal tubular cells attempt to reabsorb glucose, leading to glycogen accumulation within the cytoplasm, appearing as small, clear vacuoles that are difficult to visualize (requiring PAS staining).

– Glycogen storage diseases: Deficiencies in enzymes involved in glycogen breakdown, causing glycogen accumulation in the liver, heart, and kidneys.

ii. Mucopolysaccharide Accumulation:

– Causes:

– Mucopolysaccharidoses: Inherited genetic disorders caused by a deficiency of enzymes that break down mucopolysaccharides. These substances accumulate within lysosomes of endothelial cells, smooth muscle cells, and fibroblasts throughout the body.

c) Protein Accumulation:

– Characterized by the presence of hyaline inclusions.

– Mechanisms:

– Excessive uptake: For example, glomerulonephritis leads to protein loss in the filtrate, causing hyaline inclusions to accumulate within renal tubular cells.

– Slowed excretion: For example, in multiple myeloma, hyaline inclusions appear within the cytoplasm of cells, representing undigested immunoglobulin.

– Cellular cytoskeletal damage: For example, alcohol abuse can cause the appearance of Mallory hyaline inclusions in hepatocytes.

d) Pigment Accumulation:

– Source:

– Endogenous (Internal): Lipofuscin, melanin, hemosiderin, bilirubin

– Exogenous (External): Tattoo ink, coal dust

i. Exogenous Pigment Accumulation:

– Accumulation of exogenous pigments usually does not cause inflammation.

ii. Endogenous Pigment Accumulation:

– Lipofuscin:

– Found in hepatocytes and cardiac muscle cells in the elderly or those who have experienced prolonged starvation.

– Microscopic Appearance: Lipofuscin granules represent the remnants of autophagic vacuoles.

– Staining: Black with Fontana stain; Red with PAS stain.

– Melanin:

– Origin: From melanocytes in the basal layer of the epidermis.

– Found in benign and malignant tumors originating from melanocytes.

– Staining: Black with Fontana stain.

– Hemosiderin:

– Commonly found within macrophages in the spleen.

– Also found in endothelial cells of peripheral blood vessels in individuals with heart failure and in parenchyma of the liver, kidneys, and heart in individuals with iron overload.

– Staining: Blue with Perls stain.

– Bilirubin:

– Found in hepatocytes in cholestatic liver disease.

– Staining: Green with Fouchet stain.

Note:

– All four endogenous pigments appear brown when stained with routine hematoxylin and eosin staining.

II. Extracellular Deposition

1. Definition:

Extracellular deposition refers to the buildup of abnormal substances outside of cells, within blood vessels, connective tissue, body cavities, and other locations.

2. Types of Extracellular Deposition:

– Cholesterol Deposition:

– Commonly found in atherosclerosis.

– Deposited as crystals or needle-shaped crystals.

– CE is phagocytized by macrophages, forming foam cells.

– Hyaline Deposition:

– Amorphous, glassy material that stains with acid dyes.

– Origin: From plasma proteins leaking from blood vessels: fibrin, IgG, IgM, lipoproteins, complement.

– Does not trigger inflammation.

– Found in the walls of arteries in the elderly, old scars, chronic inflammatory lesions…

– Fibrinoid Deposition:

– Similar to hyaline but contains more fibrin.

– Fibrillar, stains with acid dyes.

– Induces inflammation.

– Found in the walls of small arteries in individuals with malignant hypertension, connective tissue in individuals with collagen vascular diseases.

– Amyloid Deposition:

– Primarily composed of immunoglobulin and hormones.

– Appears as a hyaline, acellular, eosinophilic substance that stains with Congo red.

– Found in the walls of small arteries, sinusoidal walls in the liver and spleen in individuals with chronic hepatitis, myeloma.

– Calcium Deposition (Calcification):

– Dystrophic calcification:

– Deposition in dead tissue: caseous necrosis, hematomas, atherosclerotic plaques, papillary thyroid carcinoma.

– Microscopic Appearance: Amorphous basophilic deposits or granular structures resembling sand.

– Metastatic calcification:

– Deposition in living tissue: walls of blood vessels, parenchyma of the liver, kidneys, gastric mucosa.

– Microscopic Appearance: Similar to dystrophic calcification.

– Seen in hypercalcemia conditions: hyperparathyroidism, bone tumors with bone resorption…

– Urate Deposition:

– Commonly found in gout due to a disturbance in purine metabolism, leading to hyperuricemia (uric acid levels above 7mg%).

– Urate often deposits in joints (causing chronic arthritis), kidneys (causing nephritis), and triggers strong inflammatory responses.

– Gross Appearance: Tophi in periarticular tissue.

– Microscopic Appearance: Consists of needle-shaped crystals surrounded by inflammatory cells: endothelial cells, macrophages, lymphocytes.

Note:

– Amyloid and hyaline materials appear similar with routine staining. To differentiate, Congo red staining is used: Amyloid stains orange but turns yellow-green under polarized light microscopy.

III. Conclusion

– Intracellular accumulation and extracellular deposition are common pathological manifestations reflecting metabolic disturbances, cellular, and tissue damage.

– Understanding the mechanisms, causes, and microscopic appearances of these various accumulations aids in accurate diagnosis and effective treatment of diseases.