The present report on experimental hepatic injury is based on observations amassed during the last 9 years, comprising 1922 rats.
It has been shown that there are several dietary factors which may intervene, singly or in combination, in the development of massive or zonal hepatic necrosis. Deficiency of sulfur-containing amino acids is only one of them. From the present studies, tocopherol emerges as an additional protective dietary factor. With regard to the development of massive hepatic necrosis tocopherol may compensate for the absence of sulfur-containing amino acids (cystine, methionine) and vice versa. As a further factor, the quality of dietary fat should be taken into consideration. Fats, like lard and cod liver oil, with a high content of unsaturated fatty acids enhance, whereas fats low in unsaturated fatty acids, such as crisco and butter, retard or prevent the development of massive hepatic necrosis.
It is questionable whether with all these dietary factors the etiology of massive hepatic necrosis is completely defined.
The interchangeability of sulfur-containing amino acids (cystine, methionine) and vitamin E as leading etiologic factors makes it difficult to accept pure deficiency as the basis of massive hepatic necrosis. The rôle of possible endogenous hepatotoxic substances and their neutralization by cystine (methionine) or tocopherol are discussed.
Diffuse hepatic fibrosis is a regular occurrence in rats kept for 100 to 150 days on a diet low in lipotropic factors. Cystine, and, among the fats, lard and especially cod liver oil, have an enhancing effect on the production of hepatic cirrhosis. In rats fed rations free from cod liver oil, and with vegetable shortening such as crisco as source of fat, the incidence and severity of cirrhosis are reduced.
Ceroid deposit accompanies cirrhosis only in rats which have been kept on a cirrhosis-producing diet containing fats with a high content of unsaturated fatty acids (cod liver oil, lard). Tocopherol, even when given in excessively large doses (30 mg. daily) will not prevent the formation of ceroid, and will reduce only slightly its total quantity. Under the same treatment the incidence and intensity of cirrhosis remain uninfluenced.
Cellular injury in the form of degenerated or necrotic hepatic parenchymal cells, found singly or in small groups in and around the fibrous bands in the cirrhotic liver of rats, is a common occurrence. The fibrotic changes seem to begin, not in the portal spaces, but close to the central vein, although they are not as distinctly and exclusively pericentral as, for instance, in cardiac cirrhosis. Thus, experimental dietary cirrhosis is non-portal.
The role of fat infiltration is discussed with special reference to the other microscopic changes found in hepatic cirrhosis.
Acute necrotizing nephrosis or various stages of healing of this process are often found with great frequency in rats kept on a cirrhosis-producing diet.
Metabolism of Sulfur-Containing Amino Acids in the Liver: A Link between Hepatic Injury and Recovery