Fatty Metamorphosis

In science under biology, microbiology and pathology, as observed under the various microscopes such as electron microscopes, forensic microscopes or light microscopes, there is another common form of retrograde cellular change, which is characterized by an abnormal accumulation of lipid in parenchymal cells of an organ in which lipid normally is not demonstrable histologically. This disturbance has been designated by various terms, such as fatty metamorphosis or fatty change, fatty degeneration, steatosis, and parenchymal fatty infiltration or deposition. The most widely used term however, is fatty metamorphosis or fatty change. In pathology, this process is to be differentiated from interstitial fatty infiltration, or adiposity, a condition characterized by the abnormal accumulation of adipose tissue in the stroma of parenchymatous organs as between parenchymal cells as seen under the microscopes. Fatty metamorphosis is defined in pathology or in microbiology as a disturbance of fat metabolism, but is often preceded by cellular swelling or hydropic degeneration. Fatty change, although a more serious disturbance than the latter degenerative lesions, is generally reversible, but, when severe, it may result in death of cells or necrosis as viewed using the microscope. Functional impairment of affected organs sometimes occurs when the process is extensive. In preparations of ordinary paraffin sections using a microscope, the intracellular lipid is dissolved out, so that it appears as small or large vacuoles in the cytoplasm. Special staining procedures are available for demonstration of the lipid such as scarlet red or Sudan III used on frozen sections, or osmic acid stain.

Through microscopy, fatty metamorphosis is seen most frequently in the liver, kidneys, and heart. The gross appearance of the affected organ depends upon the amount of fatty change. Little or no alteration is observed when there is only a slight degree of involvement.

The severely involved liver as seen through specialized microscope is enlarged, yellow, and decreased in consistency, the margins are rounded, the cut surface is greasy and bulgy, and the lobular markings are obscured when the change is diffuse but may be accentuated if the lipid is limited to a particular zone of the hepatic lobules such as centrilobular regions. As seen in a microscope, the vacuoles in the cytoplasm of the hepatic cells may be tiny and numerous or may be large, sometimes replacing the cell and pushing aside the nucleus. In some areas there may be rupture of the membranes of adjacent cells with confluence of large vacuoles, producing so called lipid cysts. In pathology, it is said that these lipid cysts may rupture into sinusoids and release the lipid into the venous circulation as fat emboli.

The fatty kidney may be normal in size or slightly enlarged, and the cut surfaces are pale grayish brown or yellowish brown and soft or friable. Under the microscope, small vacuoles are found mainly in the epithelial cells of the convoluted tubules, particularly the proximal.

In the heart, as observed by means of microscopes specially designed for such, fatty change affects the myocardium and may be patchy or diffuse. In patchy involvement, such as occurs in severe anemias, the change is best seen through microscopy in the subendocardial region of the ventricles as irregular yellow streaks or lines alternating with lines of unaffected muscle, producing the so called tigroid, tabby cat, or thrush breast appearance. In diffuse fatty change, usually caused by severe infections or toxic states, the entire myocardium is pale yellow or yellowish brown, soft, and flabby when the condition is severe, but lesser degrees are detected only upon histologic examination. With the use of a microscope, it can be seen that a fine vacuolization is observed within the sarcoplasm of myocardial fibers in ordinary paraffin sections. The minute droplets are often less distinct than the small or large, vacuoles usually seen in liver or renal tubular cells with the help of the microscopes.

The causes of fatty metamorphosis in both clinical and experimental situations include a variety of noxious agents, such as toxins of infectious diseases, phosphorus, carbon tetrachloride, chloroform, ethionine, puromycin, orotic acid, and ethanol, and also anoxia resulting from circulatory insufficiency or severe anemias. A deficiency of lipotropic substances such as choline and methionine also can induce fatty change, particularly in the liver. This state may be brought about by an inadequate diet, as in starvation or chronic alcoholism. In fatty livers said to be caused by excessive amounts of lipids brought to the cells as in overfeeding, a relative deficiency of lipotropic substances may play a role. Certain studies suggest that alcohol or ethanol itself may cause fatty change in the liver, probably by an increased uptake of plasma fat by the liver and a decreased hepatic oxidation of fatty acids. That alcohol also directly interferes with release of lipids from hepatic cells has not been proved. A deficiency of intracellular carbohydrate, as in diabetes mellitus or starvation, is another cause of fatty change in the liver. Apparently, decreased liver glycogen leads to an increased oxidation of fat in hepatic cells, with a resultant increase of mobilization of lipid from the fat depots as observed through microscopy.

In the various instances of fatty metamorphosis, the predominant lipid that accumulates intracellularly is triglyceride. Thus, the factors in the pathogenesis of fatty change are those mechanisms that produce an excess of triglyceride within cells. Using the microscopes, most of the information concerning these mechanisms has been derived mainly from investigations of fatty change in the liver rather than in the heart, kidneys, or other organs. These studies as supported by findings gathered by means of the microscopes have shown that the various causative agents or conditions previously mentioned may bring about triglyceride accumulation in a cell singly or in combination by the mechanisms. There may be an increased synthesis of triglyceride. Since triglyceride normally is formed from fatty acids, some of which are utilized also in phospholipid and cholesterol ester synthesis, an increased triglyceride synthesis would be related to an elevated concentration of fatty acids in the liver as observed in microscopy. The rise in hepatic fatty acids may occur as a result of increased uptake of plasma fat by liver cells or increased mobilization from fat depots or excess dietary fats, increased hepatic synthesis of fatty acids or from acetate, decreased hepatic oxidation of fatty acids, or impairment in the esterification of fatty acids to esters other than triglyceride as seen under the microscopes. There may be a decrease in the release or secretion of triglyceride from the cell. Normally, after synthesis in the endoplasmic reticulum of the liver cell, triglyceride is coupled with protein, cholesterol, cholesterol ester, and phospholipid to become lipoprotein, the form in which it is secreted from the cell as observed using the microscopes. Interference with protein synthesis may occur following administration of carbon tetrachloride, phosphorus, ethionine, or puromycin, blocks lipoprotein synthesis and thus prevents release of hepatic triglyceride. Under the microscope, the impairment may be in the phospholipid moiety of the lipoprotein, as may happen in fatty livers caused by choline deficiency. In orotic acid induced fatty livers, the defect appears not to involve the synthesis of the protein or the lipid moieties but a later event in the metabolism of lipoprotein, either the coupling of lipid with protein or the release of the formed lipoprotein from the liver cell. Ultrastructural changes by means of the microscopes have been identified in the endoplasmic reticulum to support some of the foregoing concepts.