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Characteristics of Intracellular Accumulations:
- origin - endogenous or exogenous
- substance- normal or abnormal
- synthesis by cell or produced elsewhere
- accumulate in organelles, cytosol or nucleus
- significance - completely harmless and indicators of pathology or the primary cause of disease
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The nature of accumulated intracellular substances
- normal cellular constituent in excess - Water, proteins, lipids, carbohydrates, or complexes
- abnormal substance: faulty synthesis or metabolism (endogenous) or Foreign and originates from outside the body (exogenous)
- Pigments: endogenous (lipofuscin and hemosiderin) or exogenous
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Pathways of intracellular accumulations
- Normal or increased rate of production of a normal substance, inadequate metabolic rate to remove it (e.g. fatty change in liver)
- normal or abnormal endogenous substance accumulates because of genetic or acquired defects in its folding, packaging, transport, or secretion (e.g. α-1-antitrypsin deficiency)
- Inherited defect in enzyme -> failure to degrade a metabolite; storage diseases
- abnormal exogenous substance is deposited and accumulates, w/o enzymatic machinery to degrade or transport ability
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Fatty Change (Steatosis)
- any abnormal accumulation of triglycerides within parenchymal cells.
- Sites: liver, heart, kidney, skeletal muscle, and other organs.
- Causes: Toxins (alcohol), diabetes mellitus, protein malnutrition (starvation), obesity, anoxia.
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Defects in any step of lipid metabolism can lead to lipid accumulation
- Uptake, catabolism, secretion
- Starvation -> increased free fatty acid uptake
- CCl4 , protein malnutrition -> affect apoprotein which combines w/ triglyceride to form lipoprotein
- Hepatotoxins (eg alcohol), anoxia -> affect oxidation of fatty acid to ketone bodies and CO2.
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Morphology of fatty change
With increasing accumulation, the organ enlarges and becomes progressively yellow, soft, and greasy.
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Fatty change is reversible except if
some vital intracellular process is irreversibly impaired (e.g., in CCl4 poisoning).
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Alcoholic liver disease
- alcoholic steatosis - fatty change, periventricular fibrosis
- alcoholic hepatitis - mallory bodies, inflammation, fatty change, necrosis
- alcoholic cirrhosis (irreversible) - fibrosis, hyperplastic nodules
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Cellular cholesterol metabolism is tightly regulated to ensure ________ synthesis without significant intracellular accumulation.
normal cell membrane
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Foam cells:
Lipid-laden macrophages
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Atherosclerosis:
- Intimal layer of aorta & large arteries
- deposition of cholesterol, phagocytosed by macrophage cells to form different kinds of foam cells
- triggers inflammatory process
- enlarges the deposition
- Causes narrowing of the vessels
- High incidence of myocardial and cerebral infarction
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Xanthomas:
- Fats build up under the surface of the skin.
- foam cells
- subepithelial connective tissue of skin or in tendons
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Cholesterolosis:
Abnormal deposits of cholesterol esters (foam cells) in Gallbladder
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protein accumulations
- much less common than lipid accumulations
- excesses are presented to the cells or the cells synthesize excessive amounts
- Reabsorption droplets in proximal renal tubules – proteinuria
- Immunoglobulin in plasma cells - Marked accumulation of newly synthesized immunoglobulins in the RER of some plasma cells, forming rounded,
- eosinophilic Russell bodies
- Defective protein folding - Alpha-1 Antitrypsin deficiency; Neurodegenerative diseases
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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
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Mallory body
- "alcoholic hyalin"
- eosinophilic cytoplasmic inclusion in liver cells highly characteristic of alcoholic liver disease
- composed predominantly of aggregated intermediate filament proteins
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alpha-1 antitrypsin deficieny (A1AT)
- made in liver, released into blood, ultimately protects the lungs from attack by antibacterial elastase made by neutrophil
- When mutated, A1AT is stuck in liver, the lungs are attacked by neutrophil elastase w/o the protection, and the accumulation of A1AT can damage the liver.
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Pathogenesis of emphysema
- Oxidative stress, increased apoptosis and senescence
- Inflammatory cells and mediators
- Protease-antiprotease imbalance (can be induced by A1AT deficiency)
- All lead to alveolar wall destruction
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Glycogen accumulations
- abnormalities in the metabolism of 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. high glucose inhibits metabolism of glycogen.
- 2. Glycogen accumulates within cells in a group of closely related genetic disorders - glycogen storage diseases, or glycogenoses
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Pompe disease (glycogen storage disease type II)
- shows myocardial fibers full of glycogen seen as clear spaces.
- alpha-1,4-glucosidase deficiency which breaks down the glycogen that accumulates in autophagosomes
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Pigments
- colored substances
- exogenous or endogenous
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Exogenous pigment - Carbon or coal dust
- inhaled, phagocytosed by alveolar macrophages, and transported through lymphatic channels to the
- regional tracheobronchial lymph nodes
- anthracosis (blackening of lung)
- also asbestosis, silicosis, and pneumoconiosis.
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Exogenous pigment - Tattooing
- Pigments inoculated
- phagocytosed by dermal macrophages
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Endogenous pigments
- lipofuscin
- melanin
- certain derivatives of hemoglobin (hemosiderin)
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Lipofuscin
- "wear-and-tear pigment"
- insoluble brownish-yellow granular intracellular material
- seen in a variety of tissues (heart, liver, and brain) as a function of age or atrophy
- Mechanism of formation: product of lipid peroxidation, accumulates in lysosomes as the cell ages.
- Not injurious
- important marker of past free-radical injury.
- when present in large amounts, imparts an appearance to the tissue that is called brown atrophy.
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Melanin
- endogenous, brown-black pigment
- the pigment primarily responsible for skin color
- only produced in melanocytes
- accumulates in adjacent basal keratinocytes in the skin (dermal macrophages)
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Hemosiderin
- hemoglobin-derived granular pigment
- golden yellow to brown
- accumulates when there is a local or systemic excess of iron, result from hemorrhage
- represents large aggregates of ferritin (Ferrin plus iron) micelles, can be seen by light and electron microscopy
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Bruise:
- Extravasated red cells at the site of injury are phagocytosed over several days by macrophages, which break down the hemoglobin and recover the iron.
- The original red-blue color of hemoglobin is transformed to varying shades of green-blue by the local formation of biliverdin (green bile) and then bilirubin (red bile) from the heme, after removal of iron
- iron released from heme is incorporated into ferritin and eventually hemosiderin, the iron can be unambiguously identified by the Prussian blue histochemical reaction
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