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In this section, those abnormal substances that accumulate extracellularly in tissues are considered. The extracellular accumulations are not necessarily related to each other and they are discussed in the section as isolated examples of specific abnormalities that occur in tissues.
At the conclusion of this section, each student should be able to perform the following tasks.
The student should attempt to define and/or describe the following terms prior to and after embarking on a study of this section.
The term calcification refers to the deposition of calcium salts in vital or dying/dead tissues. The two classical types of calcification are dystrophic and metastatic.
Dystrophic calcification refers to the deposition of calcium salts in dead or dying tissues. It occurs principally in areas of coagulative, liquefactive, caseous and/or fat necrosis that persist for rather long periods of time. Dystrophic calcification occurs in the presence of normal levels of serum calcium (around 10 mg/100 ml) and in the absence of derangement in calcium metabolism. Even though dystrophic calcification is prominent in chronic destructive lesions, it can develop in degenerating cells and tissues very rapidly (considerable calcium salt deposits may be prominent in acute heart and skeletal muscle lesions). The exact form that the calcium accumulates in is hydroxyapatite.
Metastatic calcification refers to the deposition of calcium salts in vital tissues in association with a defect in calcium metabolism that is characterized by hypercalcemia. The usual causes of the hypercalcemia include
Primary hyperparathyroidism is usually caused by functional parathyroid neoplasms. Secondary hyperparathyroidism usually occurs due to hyperphosphatemia and there are two basic types: nutritional and renal.
Nutritional secondary hyperparathyroidism occurs when animals are fed diets that are too rich in proteins. This excessive protein contains considerable phosphorus and high protein diets cause hyperphosphatemia.
Renal secondary hyperparathyroidism occurs when the renal tubules loose their ability to eliminate phosphorus. Because of this, phosphorus concentrations in the blood tend to increase, leading to hyperphosphatemia.
In either nutritional or renal secondary hyperparthyroidism, the excessive phosphorus binds with calcium, thus reducing the concentration of ionized calcium. Since ionized calcium is the form involved in the feedback control mechanism for the parathyroid gland, the low concentrations of this mineral result in release of excessive amounts of parathormone. This occurs in spite of the fact that total serum calcium concentrations are elevated.
Whatever the cause, excessive parathormone production causes hypercalcemia by increasing calcium absorption from the intestines and increasing calcium reabsorption from bone.
Vitamin D intoxication can occur by simply administering toxic doses of vitamin D. Also, there are several toxic plant whose toxic principle is a vitamin D-like substance. Ingestion of excessive amounts of these plants mimics vitamin D toxicosis. These plants include Cestrum diurnum (day-blooming jasmine, wild jasmine, day cestrum, Chinese inkberry), Solanum malacoxyon (nightshade) and Trisetum flavescens (golden oats, yellow oat grass). In addition, there is a rodenticide that contains vitamin D as its main active ingredient. Animals that ingest excessive amounts of this rodenticide will develop vitamin D toxicosis.
The exact mechanism responsible for the development of hypercalcemia due to a dietary deficiency of magnesium is uncertain. It was a finding in an experiment studying nutritional deficiency of magnesium in calves.
Hypercalcemia of malignancy develops by two basic mechanisms. Some neoplasms secrete a parathormone-like substance that mimics parathormone. This results in hypercalcemia in much the same manner as does hyperparathyroidism. Also, highly invasive neoplasms in bone tend to liberate large amounts of calcium from osteoid as the neoplasm grows.
Metastatic calcification may occur widely throughout the body, but it is found principally in interstitial tissue of blood vessels, kidneys, lungs and gastric mucosa. The explanation for this selective localization has not been clearly elucidated. The fundamental abnormality is the pathologic entry of large amounts of ionic calcium into cell organelles, chiefly the mitochondria (it is suggested that mitochondria are the organelles first involved in the pathogenesis of metastatic calcification). In general, the deposited calcium salts do not cause clinical dysfunction unless massive.
Calcinosis is a term sometimes used to describe extensive metastatic calcification.
Calciphylaxis is the process whereby calcium precipitates in tissues in response to a challenging agent such as iron. The term was coined during studies of an experimental model utilizing a sensitizing calcifier such as vitamin D or parathyroid hormone, a critical waiting period of 24 hours and challenge with mineral salts such as ferric chloride. Calciphylaxis is considered an experimental condition, but may well occur naturally in circumstances related to overfeeding of minerals and vitamins.
The term hyaline refers to a homogeneous, glassy, pink appearance in tissues or cells stained with H & E. It is a widely used descriptive histologic term rather than a specific marker for cell injury. Pathologically, the tinctorial change known as hyaline is produced by a variety of alterations and does no represent a specific pattern of accumulation. Some intracellular accumulations (e.g., Russell bodies and the hyaline granules in renal tubular epithelial cells due to pinocytosis of proteins from the glomerular filtrate) have hyaline appearances and these were discussed previously in that section. For convenience, extracellular hyaline change is divided into connective tissue hyaline, epithelial hyaline and kerato-hyaline. These alterations are quite unrelated to each other and have different causative mechanisms. Amyloid is also classified under extracellular hyaline and will be discussed in this section.
Connective tissue hyaline refers to an alteration in connective tissue which gives it the typical appearance of hyaline in H & E sections (hyaline connective tissue). The condition is represented by old scars, the corpus albicans, wall of arteriosclerotic blood vessels and places where connective tissue has been chronically injured or deprived of nutrition. On light microscopy, connective tissue hyaline is structureless, homogeneous and acidophilic and there may be an absence of nuclei and fibrils. Grossly, connective tissue hyaline is white, shiny, semi-translucent, glassy and dense.
Epithelial hyaline is usually limited to corpora amylacea which are circular laminated concretions found in glandular tissue or free in secretions. They are common in apparently normal mammary glands; occasionally, they occur in the brain, lungs and seminal vesicles. Corporal amylacea are usually incidental findings and they form from a nidus of debris with successive layers of debris forming strata. Microscopically, they are rounded, homogeneous or concentrically laminated bodies which stain pink to blue with H & E. Grossly, corpora amylacea are not observed.
Kerato-hyaline is actually a form of epithelial hyaline, since it is formed from epithelial cells. Keratin may be normal or it may be pathological. It is formed by stratified squamous epithelial cells (it is normal as the cornified layer of stratum corneum of the epidermis). Abnormal keratinization is associated with corns, calluses, warts, certain specific diseases, certain neoplasms (squamous cell carcinomas), etc. Keratinization is basically a protective reaction, but when excessive, it can interfere with secretion, absorption, etc.
Amyloidosis is the disease resulting from the deposition of amyloid protein fibrils in tissue. Early observations of its association with chronic antigenic stimulation and plasmacytosis implicated reticuloendothelial and immune system dysfunctions in its pathogenesis. Amyloid fibrils can be formed by abnormal processing of components of such diverse proteins as immunoglobulins, insulin, growth hormone and an acute-phase reactant of inflammation called the serum amyloid associated protein (SAA).
In all cases, there is an underlying abnormality of protein processing and typical reticular cells are present in deposits of amyloid. These cells are most likely macrophages and they probably process the amyloid in the immediate vicinity of where it is deposited.
Grossly, small amounts of amyloid are virtually undetectable. Large amounts cause organ enlargement and a yellowish to greyish discoloration. Also it tends to cause the organs to have a rubbery consistency. Amyloid may be recognized by painting the cut surface organs with an iodine solution. This imparts to sufficiently large deposits of amyloid, a brownish to yellow-red color. This is transformed into blue or violet after the application of dilute sulfuric acid.
Histologically, amyloid has been described as a homogeneous, eosinophilic material that stains reddish pink with the Congo red stain. Under polarized light, the Congo red-stained amyloid has a green birefringence. It tends to compress adjacent cells and tissues as it accumulates and compression atrophy is usually evident. It has been shown that AA proteins lose their affinity for Congo red stains after treatment with potassium permanganate but AL and other types do not. Based on this, it is possible to distinguish between these types of amyloid deposits.
Ultrastructurally, amyloid fibrils are 7.5-10 nm in diameter. They are rigid, nonbranching, hollow-cored tubules of indeterminate length. When examined by X-ray diffraction, fibrils have a characteristic B-pleated sheet configuration and it is this feature that is responsible for the previously described birefringence. It is probably also responsible for its resistance to proteolytic digestion. Thus, the implacable deposition of these inert fibrils in tissue leads to pressure atrophy and interference with tissue function.
Amyloid is composed primarily (approximately 90%) of amyloid fibrils. The remaining 10% is a doughnut shaped pentamer called the "P" component. Two basic types of amyloid fibrils have been identified. The amyloid light (AL) chain fibers are formed from immunoglobulin light chains and this type of fiber is found in the immunocyte derived forms of amyloidosis. The amyloid associated (AA) fibers are formed from a serum amyloid associated (SAA) protein which is probably produced by the liver. This type of amyloid fiber is found in reactive systemic amyloidosis.
Amyloidosis is classified, based on its distribution, into systemic and localized forms. It is further classified, based on its pathogenesis, into reactive, immunocyte derived, and endocrine forms. The resulting classifications are
Reactive systemic amyloidosis is a form of amyloidosis that develops secondarily to a prolonged inflammatory problem. It is characterized by systemic deposition of AA amyloid fibers with the liver, kidney, spleen, and adrenals glands being the more significant sites of involvement. The pathogenesis involves the production of a SAA protein by the liver in response to the inflammatory process. This SAA protein is then processed to form amyloid in the various organs of involvement. This is the most common form of systemic amyloidosis in animals. It is usually associated with chronic infectious processes. It is encountered in osteomyelitis, metritis, arthritis, and disseminated infectious processes such as tuberculosis and other granulomatous diseases.
Heredofamilial amyloidosis probably represents a variant of reactive systemic amyloidosis that is characterized by an inherited problem that results in recurrent or persistent inflammatory bouts. It too is characterized by systemic deposition of AA amyloid fibrils.
Immunocyte-derived systemic amyloidosis, is a form of amyloidosis that develops secondarily to dyscrasias involving immunocytes, mainly B cells or plasma cells. It is characterized by systemic deposition of AL amyloid fibrils, again, with hepatic, renal, and splenic involvement being most significant. In this type, the pathogenesis involves production of excessive amounts of immunoglobulins by neoplastic immunocytes and abnormal processing of this immunoglobulin to form amyloid.
What is known as primary amyloidosis is probably a variant of immunocyte-derived systemic amyloidosis in which the immunocyte dyscrasia goes undiagnosed. It is characterized by systemic deposition of AL amyloid fibers and usually there is a plasmacytosis, but no plasma cell or B cell neoplasm is identified. When no underlying condition is found, primary amyloidosis is the term used.
Immunocyte-derived local amyloidosis is a form of amyloidosis that occurs in small localized foci and is characterized by deposition of AL amyloid fibrils. Usually, there are infiltrates of lymphocytes and plasma cells in the immediate vicinity of the deposit, prompting the suggestion that this represents a localized version of the immunocyte-derived amyloidosis. These localized accumulations occur in many locations and they may or may not be visible grossly.
Endocrine-derived local amyloidosis is a form of amyloidosis that is characterized by the development of amyloid by enzymatic conversion of polypeptide hormones. With this form of amyloidosis, the amyloid deposits occur in the immediate vicinity of the source of the hormone involved. Examples include microscopic deposits of amyloid in such locations as the islets of Langerhans and in several neoplasms of amine precursor uptake and decarboxylation (APUD) cells.
In the brain of aged dogs, amyloid occurs in neurotic plaques of senile atrophy and in cortical and leptomeningeal blood vessels. Similar amyloid deposits in human presenile atrophy brains (Alzheimer's disease) have been shown to contain prealbumin.
To a certain extent, the pathogenesis of the various forms of amyloidosis has been discussed. The common denominator in these syndromes is the conversion of some precursor protein into amyloid by reticuloendothelial cells, most likely macrophages. The amyloid is then deposited, either locally or systemically, and the clinical problems ensue.
Clinically, the most devastating forms of amyloidosis are the systemic forms, and renal amyloidosis is usually the most life threatening with hepatic amyloidosis being a close second.
Generally, amyloid deposits in the kidney occur in the walls of glomerular capillary tufts. This lessens the ability of the glomerulus to retain larger molecules in the blood, and therefore proteins, mainly albumin, begin to filter into the glomerular filtrate. The significance of this occurrence is two-fold. One significant result is that albumin is lost in large amounts from the blood. This results in a dramatic drop in the blood osmotic pressure and generalized edema ensues. The other result is that the proteinaceous filtrate often forms casts that plug up renal tubules, thus leading to renal tubular damage. This tubular damage will become progressively worse and eventually destroy the kidneys.
Amyloid deposition in the liver usually reflects a systemic form of the disease. The deposits usually occur in the walls of sinusoids. Typically, this results in compression of the hepatocytes causing pressure atrophy and necrosis and eventually leading to liver failure.
The spleen is the chief site of amyloid deposition in most animals. In the spleen, it is formed in three sites:
The greatest amount is deposited at the marginal zone at the periphery of the periarterial lymphoid sheath, resulting in the term "perifollicular amyloid."
Amyloidosis is progressive and amyloid is inefficiently removed by the RES. Amyloid fibrils are curiously resistant to phagocytosis and proteolysis and are not remarkably immunogenic. These characteristics probably result from the large size of the amyloid molecules. When amyloid is incubated with neutrophils and monocytes experimentally, very little is phagocytized. However, if the molecules are slightly altered or distorted by the addition of heterologous antibody, phagocytosis readily occurs. Neutrophils will rapidly take up degraded amyloid and further hydrolytic destruction occurs within phagolysosomes. Even though some phagocytosis and elimination occur in vivo, the persistence of the underlying defect usually causes amyloid production to dominate its resorption. If the cause of the diseases is removed, amyloid disappears from organs with active macrophages such as spleen but may not do so from the renal glomerulus. There has been recent evidence that dimethyl sulfoxide (DMSO) will facilitate the removal of amyloid from tissues, even the glomeruli.
Gout is the disease that occurs when uric acid and urate crystals are deposited in tissues subsequent to defective purine metabolism. The condition occurs primarily in humans and in birds. In birds, articular and visceral forms of gout are recognized.
In articular gout, uric acid and urate crystals are deposited in joint spaces over the serous membranes. Grossly, affected joints are enlarged, and white, chalky masses ("tophil") may be observed when opened. Microscopically, inflammatory cells (including macrophages and giant cells) along with sharp crystals (or spaces left after the crystals dissolve out) are found over articular surfaces and/or joint capsules. The condition may result in severe pain.
In visceral gout, uric and urate crystals are deposited over the serous surfaces within the body cavity (pleural, pericardium, etc.). Also, deposits are found in the renal tubules. Microscopically, various serous membranes are covered with finely crystalline or nearly amorphous material which does not stain. Grossly, serous membranes are encrusted by a thin grayish layer having a metallic sheen.
Gout in birds is believed to be caused by incomplete metabolism of purine derivatives (uric acid and urates are decomposition products of nucleic acid). Also, active uric acid excretion as urates is interfered with in the kidneys by peritubular lesions, such as chronic renal inflammation (birds eliminate semisolid urates instead of urine and uric acid).
Fibrinoid is an amorphous, eosinophilic, sometimes granular deposit that resembles fibrin. It is typically seen in a focus of tissue injury (especially in vessel walls or in connective tissue).
With H & E stains, fibrinoid appears as a deeply eosinophilic, amorphous material which sometimes entraps leukocytes or other necrotic cells. It is most often located in the intima and media of vessel walls. Many substances have been identified in fibrinoid including
However, the precise composition of fibrinoid varies with the underlying disorder. Regardless, there is general agreement that fibrinoid develops as a result of an Arthus reaction, and represents an antigen-antibody reaction going on locally in connective tissue.
After completing this section, each student should be in a position to provide appropriate answers for the following questions.
