Intracellular Accumulations
The accumulated substances fall into three categories:(1) a normal cellular constituent accumulated in excess, such as water, lipids, proteins, and carbohydrates;
(2) an abnormal substance, either exogenous, such as a mineral or products of infectious agents, or endogenous, such as a product of abnormal synthesis or metabolism; and
(3) a pigment.
These substances may accumulate either transiently or permanently, and they may be harmless to the cells, but on occasion they are severely toxic. The substance may be located in either the cytoplasm or the nucleus.
Mechanisms:
Most accumulations are attributable to three types of abnormalities .
1. A normal endogenous substance is produced at a normal or increased rate, but the rate of metabolism is inadequate to remove it. An example of this type of process is fatty change in the liver because of intracellular accumulation of triglycerides .
2. A normal or abnormal endogenous substance accumulates because of genetic or acquired defects in the metabolism, packaging, transport, or secretion of these substances. One example is the group of conditions caused by genetic defects of specific enzymes involved in the metabolism of lipid &carbohydrates resulting in intracellular deposition of these substances. These so-called storage diseases. Another is alpha1-antitrypsin deficiency, in which a single amino acid substitution in the enzyme results in defects in protein folding and accumulation of the enzyme in the endoplasmic reticulum of the liver .
3. 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. Accumulations of carbon particles and such nonmetabolizable chemicals as silica particles are examples of this type of alteration.
LIPIDS ۞
1- Fatty changes2-Cholesterol and Cholesterol Esters
The cellular metabolism of cholesterol is tightly regulated such that most cells use cholesterol for the synthesis of cell membranes without intracellular accumulation of cholesterol. Accumulations are seen in several pathologic processes.
a- Atherosclerosis. In atherosclerotic plaques, smooth muscle cells and macrophages within the intimal layer of the aorta and large arteries are filled with lipid vacuoles. Such cells have a foamy appearance (foam cells), and aggregates of them in the intima produce the yellow atheromas characteristic of this serious disorder.
b- Xanthomas. Clusters of foamy cells are found in the skin and in tendons, producing tumorous masses known as xanthomas.
c- Cholesterolosis. This refers to the focal accumulations of cholesterol-laden macrophages in the lamina propria of the gallbladder.
PROTEINS۞
Intracellular accumulations of proteins usually appear as rounded, eosinophilic aggregates in the cytoplasm. In some disorders, such as amyloidosis, abnormal proteins deposit primarily in the extracellular space .
Excesses of proteins within the cells have diverse causes.
a- Reabsorption droplets in proximal renal tubules are seen in renal diseases associated with proteinuria. In disorders with heavy protein leakage, there is increased reabsorption of the protein. which appear as pink hyaline droplets within the cytoplasm of the tubular cell. The process is reversible; if the proteinuria diminishes, the protein droplets are metabolized and disappear.
b- synthesis of excessive amounts of normal secretory protein, as occurs (Russell bodies)
c- Defects in protein folding
In the process of protein folding, partially folded intermediates arise, and these may form intracellular aggregates. Under normal conditions, however, these intermediates are stabilized by a number of molecular chaperones. If the folding process is not successful, the chaperones facilitate degradation of the damaged protein.
♦Defective intracellular transport and secretion of critical proteins. In alpha1-antitrypsin deficiency, mutations in the protein significantly slow folding, resulting in the build-up of partially folded intermediates, which aggregate in the ER of the liver and are not secreted. The resultant deficiency of the circulating enzyme causes emphysema . In cystic fibrosis, mutation delays dissociation of a chloride channel protein from one of its chaperones, resulting in abnormal folding and loss of function. In familial hypercholesterolemia, mutations in low-density lipoprotein receptors interfere with proper folding of receptor proteins .
♦ Aggregation of abnormal proteins.
Abnormal or misfolded proteins may deposit in tissues and interfere with normal functions. The deposits can be intracellular, extracellular, or both, and there is accumulating evidence that the aggregates may either directly or indirectly cause the pathologic changes, as in amyloidosis
HYALINE CHANGE ۞
The term hyaline usually refers to an alteration within cells or in the extracellular space, which gives a homogeneous, glassy, pink appearance . Intracellular accumulations of protein, reabsorption droplets, Russell bodies, are examples of intracellular hyaline deposits.Extracellular hyaline. Collagenous fibrous tissue in old scars may appear hyalinized. In long-standing hypertension and diabetes mellitus, the walls of arterioles, especially in the kidney, become hyalinized, owing to extravasated plasma protein and deposition of basement membrane material.
GLYCOGEN۞
Excessive intracellular deposits of glycogen are seen in patients with an abnormality in either glucose or glycogen metabolism. Diabetes mellitus is the prime example of a disorder of glucose metabolism. Glycogen also accumulates within the cells in a group of closely related disorders, all genetic, collectively referred to as the glycogen storage diseases, or glycogenoses . In these diseases, enzymatic defects in the synthesis or breakdown of glycogen result in massive accumulation, with secondary injury and cell death.PIGMENTS ۞
Pigments are colored substances, some of which are normal constituents of cells (e.g., melanin), whereas others are abnormal or exogenous.Exogenous Pigments.
carbon or coal dust. When inhaled, it is picked up by macrophages within the alveoli and is then transported through lymphatic channels to the regional lymph nodes in the tracheobronchial region. Accumulations of this pigment blacken the tissues of the lungs (anthracosis). In coal miners, the aggregates of carbon dust may cause a serious lung disease known as coal workers pneumoconiosis. Tattooing is a form of localized, exogenous pigmentation of the skin. The pigments inoculated are phagocytosed by dermal macrophages, in which they reside for the remainder of the life . The pigments do not usually evoke any inflammatory response.
Endogenous Pigments.
Lipofuscin is an insoluble pigment, also known wear-and-tear or aging pigment. Lipofuscin is not injurious to the cell or its functions. Its importance lies in its being the telltale sign of free radical injury and lipid peroxidation. In tissue sections, it appears as a yellow-brown, finely granular intracytoplasmic, often perinuclear pigment. It is seen in cells of the liver and heart of aging patients or patients with severe malnutrition and cancer cachexia.
2- Melanin
is an endogenous, non-hemoglobin-derived, brown-black pigment formed when the enzyme tyrosinase convert tyrosine to dihydroxyphenylalanine in melanocytes.
3- Hemosiderin is a hemoglobin-derived, golden yellow-to brown, granular pigment in which iron is stored in cells. Under normal conditions, small amounts of hemosiderin can be seen in the mononuclear phagocytes of the bone marrow, spleen, and liver, all actively engaged in red cell breakdown. Excesses of iron cause hemosiderin to accumulate within cells, either as a localized process or as a systemic derangement.
Local excesses of iron,
The best example of localized hemosiderosis is the common bruise. The original red-blue color of hemoglobin is transformed to varying shades of green-blue, comprising the local formation of biliverdin (green bile), then bilirubin (red bile), and thereafter the iron of hemoglobin is deposited as golden yellow hemosiderin.
Systemic overload of iron,
hemosiderin is deposited in many organs and tissues, a condition called hemosiderosis. It is seen with: (1) increased absorption of dietary iron, (2) impaired use of iron, (3) hemolytic anemias, and (4) transfusions.
Morphology. Iron pigment appears as a coarse, golden, granular pigment lying within the cells cytoplasm. Iron can be visualized in tissues by the Prussian blue histochemical reaction. In most instances of systemic hemosiderosis, the pigment does not damage the parenchymal cells or impair organ function. The more extreme accumulation of iron, however, in a disease called hemochromatosis, is associated with liver, heart, and pancreatic damage, resulting in liver fibrosis, heart failure, and diabetes mellitus.
4- Bilirubin
is the normal major pigment found in bile. It is derived from hemoglobin but contains no iron. Jaundice is a common clinical disorder caused by excesses of this pigment within cells and tissues.PATHOLOGIC CALCIFICATION
Pathologic calcification is the abnormal tissue deposition of calcium salts. It is a common process occurring in a variety of pathologic conditions. There are two forms of pathologic calcification. When the deposition occurs locally in dying tissues, it is known as dystrophic calcification; it occurs despite normal serum levels of calcium and in the absence of derangements in calcium metabolism. In contrast, the deposition of calcium salts in otherwise normal tissues is known as metastatic calcification, and it almost always results from hypercalcemia secondary to disturbance in calcium metabolism.DYSTROPHIC CALCIFICATION
Dystrophic calcification is encountered in areas of necrosis, whether they are of coagulative, caseous, or liquefactive type, and in foci of enzymatic necrosis of fat. Calcification is almost inevitable in the atheromas of advanced atherosclerosis. It also commonly develops in aging or damaged heart valves. Whatever the site of deposition, the calcium salts appear macroscopically as fine, white granules or clumps, often felt as gritty deposits.Morphology. Histologically, with the usual hematoxylin and eosin stain, the calcium salts have a basophilic, amorphous granular, sometimes clumped, appearance. They can be intracellular, extracellular, or in both locations.
METASTATIC CALCIFICATION
Metastatic calcification may occur in normal tissues whenever there is hypercalcemia.. There are four principal causes of hypercalcemia:
(1) hyperparathyroidism due to parathyroid tumors, and ectopic secretion of PTH-related protein by malignant tumors
(2) destruction of bone tissue, occurring with primary tumors of bone marrow (e.g., multiple myeloma, leukemia) or diffuse skeletal metastasis (e.g., breast cancer), or immobilization;
(3) vitamin Drelated disorders, including vitamin D intoxication, sarcoidosis (in which macrophages activate a vitamin D precursor), and
(4) renal failure, which causes retention of phosphate, leading to secondary hyperparathyroidism.
Metastatic calcification may occur widely throughout the body but principally affects the interstitial tissues of the gastric mucosa, kidneys, lungs, systemic arteries, and pulmonary veins.
Cellular Aging
Cellular aging represent the progressive accumulation over the years of sublethal injury that may lead to cell death or at least to the diminished capacity of the cell to respond to injury. Aging in individuals is affected to a great extent by genetic & environmental factors( diet, social conditions, and occurrence of age-related diseases, such as atherosclerosis, diabetes, and osteoarthritis)..Structural and Biochemical changes with cellular Aging.
A number of cell functions decline progressively with age. Oxidative phosphorylation by mitochondria is reduced, as is synthesis of nucleic acids and proteins, cell receptors, and transcription factors. Senescent cells have a decreased capacity for uptake of nutrients and for repair of chromosomal damage. There is a steady accumulation of the pigment lipofuscin, which represent an evidence of oxidative damage;
THEORIES OF CELLULAR AGING
I- Genome-Based Theories◘Replicative Senescence.
Cells from children undergo more rounds of replication than cells from older people. In contrast, cells from patients with Werner syndrome, a rare disease characterized by premature aging, have a markedly reduced in vitro life span. After a fixed number of divisions, all cells become arrested in a terminally nondividing state, known as cellular senescence. How dividing cells can count their divisions is under intensive investigation. One likely mechanism is that with each cell division, there is incomplete replication of chromosome ends (telomere shortening), which ultimately results in cell cycle arrest. When somatic cells replicate, a small section of the telomere is not duplicated, and telomeres become progressively shortened. As the telomeres become shorter, the ends of chromosomes cannot be protected and are seen as broken DNA, which signals cell cycle arrest. The lengths of the telomeres are normally maintained by an enzyme called telomerase. Telomerase activity is expressed in germ cells and is present at low levels in stem cells, but it is usually absent in most somatic tissues. Therefore, as cells age, their telomeres become shorter, and they exit the cell cycle, resulting in an inability to generate new cells to replace damaged ones. Conversely, in immortal cancer cells, telomerase is reactivated, and telomeres are not shortened, suggesting that telomere elongation might be an important—possibly essential—step in tumor formation.
◘Genes That Influence the Aging Process.
Analyses of humans with premature aging are establishing the fundamental concept that aging is not a random process but is regulated by specific genes (Clock genes), receptors, and signals.
II- Wear and Tear Theories
◘Accumulation of Metabolic and Genetic Damage.cellular life span may also be determined by the balance between cellular damage resulting from metabolic events occurring within the cell and counteracting molecular responses that can repair the damage. Smaller animals have generally shorter life spans and faster metabolic rates.
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