Mechanisms of cellular accumulations

Acquired or hereditary enzymatic defects,

Deposition and accumulation of an abnormal exogenous substance when the cell has neither the enzymatic machinery to degrade the substance nor the ability to transport it to other sites. Accumulation of carbon or silica particles is an example of this type of alteration.

Decreased metabolism of substances, which then accumulate.

 

Pathways of abnormal intracellular accumulations

In general these occurs when there is

damage to the cell, or

there is an intrinsic abnormality in metabolic function (e.g., genetic disease).

The accumulation of substances in a cell may or may not cause damage to the cell. Substances that commonly accumulate are lipofuscin (also referred to as wear-and-tear pigment), calcium, protein, iron, fat, cholesterol, glycogen, and pigments.

 

 

The substance may be located in the cytoplasm, within organelles (typically lysosomes), or in the nucleus. The substance may be synthesized by the affected cells or may be produced elsewhere. The accumulation of substances in a cell may or may not cause damage to the cell.

The accumulation of substances in a cell may or may not cause damage to the cell. Substances that commonly accumulate are lipofuscin (also referred to as wear-and-tear pigment), calcium, protein, iron, fat, cholesterol, glycogen, and pigments.

Substances that commonly accumulate are iron, fat, cholesterol,

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, or anoxia. Alcohol abuse and diabetes associated with obesity are the most common causes of fatty change in the liver (fatty liver).

 

Wear-and-tear pigment.

Mechanism of formation: Lipofuscin is a product of lipid peroxidation, which accumulates in lysosomes as the cell ages. The cell cannot rid itself of these lipofuscin-laden lysosomes.

Organs with lipofuscin accumulation: The most common organs where lipofuscin accumulates are the heart and liver.

Gross morphology of lipofuscin accumulation: Lipofuscin accumulation can impart brown discoloration to organ. Such organs may also be atrophic, giving rise to the term “brown atrophy.”

Microscopic morphology of lipofuscin accumulation (Figure 1-8): Finely granular, yellow-brown pigment, which often surrounds the nucleus.

Reference

See: Lipofuscin

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Cellular cholesterol metabolism is tightly regulated to ensure normal cell membrane synthesis without significant intracellular accumulation. However, phagocytic cells may become overloaded with lipid (triglycerides, cholesterol, and cholesteryl esters) in several different pathologic processes. Of these, atherosclerosis is the most important.

 

Morphologically visible protein accumulations are much less common than lipid accumulations; they may occur when excesses are presented to the cells or if the cells synthesize excessive amounts. In the kidney, for example, trace amounts of albumin filtered through the glomerulus are normally reabsorbed by pinocytosis in the proximal convoluted tubules. However, in disorders with heavy protein leakage across the glomerular filter (e.g., nephrotic syndrome), there is a much larger reabsorption of the protein, and vesicles containing this protein accumulate, giving the histologic appearance of pink, hyaline cytoplasmic droplets. The process is reversible: If the proteinuria abates, the protein droplets are metabolized and disappear. Another example is the marked accumulation of newly synthesized immunoglobulins that may occur in the RER of some plasma cells, forming rounded, eosinophilic Russell bodies. Other examples of protein aggregation are “alcoholic hyaline” in the live and neurofibrillary tangles in neurons.

 

 

Excessive intracellular deposits of glycogen are associated with abnormalities in the metabolism of either glucose or glycogen. In poorly controlled diabetes mellitus, the prime example of abnormal glucose metabolism, glycogen accumulates in renal tubular epithelium, cardiac myocytes, and β cells of the islets of Langerhans. Glycogen also accumulates within cells in a group of closely related genetic disorders collectively referred to as glycogen storage diseases, or glycogenoses.

 

 

Pigments are colored substances that are either exogenous, coming from outside the body, such as carbon, or endogenous, synthesized within the body itself, such as lipofuscin, melanin, and certain derivatives of hemoglobin.

 

  • The most common exogenous pigment is carbon (an example is coal dust), a ubiquitous air pollutant of urban life. When inhaled, it is phagocytosed by alveolar macrophages and transported through lymphatic channels to the regional tracheobronchial lymph nodes. Aggregates of the pigment blacken the draining lymph nodes and pulmonary parenchyma (anthracosis).
  • Lipofuscin, or “wear-and-tear pigment,” is an insoluble brownish-yellow granular intracellular material that accumulates in a variety of tissues (particularly the heart, liver, and brain) as a function of age or atrophy. Lipofuscin represents complexes of lipid and protein that derive from the free radical–catalyzed peroxidation of polyunsaturated lipids of subcellular membranes. It is not injurious to the cell but is a marker of past free radical injury. The brown pigment , when present in large amounts, imparts an appearance to the tissue that is called brown atrophy. By electron microscopy, the pigment appears as perinuclear electron-dense granules.

     

     

     

    Lipofuscin

    Lipofuscin pigment in macrophages in the liver. Almost all the cells in the photomicrograph contain finely granular, yellow-brown pigment, often surrounds the nucleus, which is lipofuscin. Lipofuscin is the product of lipid peroxidation and free radical injury (wear-and-tear pigment) and, therefore, accumulates as the cell ages. This patient had centrilobular necrosis of the liver (normal hepatocytes are not visible in this section). Centrilobular hepatocytes normally contain lipofuscin, and the death of the hepatocytes releases the pigment for engulfment by macrophages. Hematoxylin and eosin, 400×.

     

    Mechanism of formation: Lipofuscin is a product of lipid peroxidation, which accumulates in lysosomes as the cell ages. The cell cannot rid itself of these lipofuscin-laden lysosomes.

    Organs with lipofuscin accumulation: The most common organs where lipofuscin accumulates are the heart and liver.

    Gross morphology of lipofuscin accumulation: Lipofuscin accumulation can impart brown discoloration to organ. Such organs may also be atrophic, giving rise to the term “brown atrophy.”

     

     

  • Melanin is an endogenous, brown-black pigment that is synthesized by melanocytes located in the epidermis and acts as a screen against harmful ultraviolet radiation. Although melanocytes are the only source of melanin, adjacent basal keratinocytes in the skin can accumulate the pigment (e.g., in freckles), as can dermal macrophages.
  • Hemosiderin is a hemoglobin-derived granular pigment that is golden yellow to brown and accumulates in tissues when there is a local or systemic excess of iron. Iron is normally stored within cells in association with the protein apoferritin, forming ferritin micelles. Hemosiderin pigment represents large aggregates of these ferritin micelles, readily visualized by light and electron microscopy; the iron can be unambiguously identified by the Prussian blue histochemical reaction. Although hemosiderin accumulation is usually pathologic, small amounts of this pigment are normal in the mononuclear phagocytes of the bone marrow, spleen, and liver, where aging red cells are normally degraded. Excessive deposition of hemosiderin, called hemosiderosis, and more extensive accumulations of iron seen in hereditary hemochromatosis.

 

 

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