The Spectrum of Hepatotoxicity

THE SPECTRUM OF HEPATOTOX1C1TY HYMANf ZIMMERMAN, M.D.* I appreciate keenly the honor ofdelivering the George Kober Lecture for 1968 and theprivilege ofjoining the list ofthe truly more distinguished speakers who have preceded me. Dr. Kober was a pioneer in the field of public health and occupational medicine and a great physician intensely interested in clinical problems. He was also devoted to the importance of experimental medicine and made this devotion clear by emphasizing, in his endowment of this lecture, the importance of studies with experimental animals. In reading his modest autobiography [1] made available through the kindness of Dr. William Herbst, I became aware of Dr. Kober's humanitarianism and anthropologic interests. I was pleased to recognize that the topic of hepatotoxicity seems relevant to all of these interests. Hepatotoxicity has been medically recorded for a little more than one hundred years [2]. It has lived in the Annals of Treachery for at least 2,000 years. History records that Agrippina, the third wife of Claudius, poisoned her husband to gain the throne for her wretched son, Nero [3, p. 781]. Allegedly, she used the poisonous mushroom, Amanita phallo ïdes [4, 5]. This hepatotoxic fungus is known to all ofyou as a villainous plant that is mistaken by the unwary to be an edible mushroom. Ingestion usually leads to fatal necrosis [6]. The toxins responsible are of incredible potency many thousandfold greater than that of CCl4, which is a very potent hepatotoxin [7]. A glance at the variety ofthe chemical agents that can induce hepatic * Chief, Medical Service, Boston Veterans Administration Hospital, Boston, Massachusetts 02130, and professor of medicine, Boston University School of Medicine. This paper was presented as the annual George Kober Lecture at Georgetown University, Washington, D.C., April, 1968, and appears here with the permission ofthe Georgetown Medical Bulletin. The speech was prepared while I was chiefofliver and metabolic research, Veterans Administration Hospital, and professor ofmedicine, Georgetown University School^ofMedicine. I35 injury [7-11] permits the inference that man finds himself in a chemical jungle. Some hepatotoxins have been provided by a generous nature in the form of a variety of botanical substances able to produce hepatic necrosis, cirrhosis, or hepatoma [5, 7, 8], or simply jaundice, without injuring the hepatic parenchyma [12]. The ingenuity of man, however, has provided many more chemical agents that can produce hepatic injury [7-11]. Some toxins, like A. phalloides, are encountered as environmental hazards that are ingested in ignorance of their toxicity. Others, like the mycotoxins, are encountered because climatic conditions in some parts ofthe world favor their presence as contaminants offood [13]. In various parts ofthe world, decoctions ofSenecio plants are prepared for medicinal purposes [7]. "Bush tea" is a decoction of Senecio alkaloids used in Jamaica [14]. Intended to provide health and vigor, it provides instead a concentrated potion ofhepatotoxic alkaloids that can produce acute and chronic hepatic disease, and perhaps even lead to hepatic carcinoma [7]. Inhabitants of the island öf Guam eat the cycad nut which has been shown to contain methylazoxymethanol, closely related to the potent hepatotoxin dimethylnitrosamine [7, 15]. Recent attention has focused on hepatotoxic fungi [5, 7, 13], particularly Aspergillus filavus [i6] and Pénicillium islandicum [17]. A. filavus, a common contaminant of moldy peanut meal and of ground nuts, was first described in England in i960 as a cause of the severe hepatic injury in turkeys given a diet of ground nut meal [18-22]. The cause ofthe hepatic injury was found to be a family of toxins, one of which, Anatoxin B1, is of enormous hepatotoxic potency [7, 16]. Tiny amounts are able to produce hepatic necrosis, cirrhosis, or hepatoma in experimental animals. Epidemiologic studies have provided strong evidence for the importance of this mycotoxin in the production of human hepatic disease [13, 23]. There is a high incidence of cirrhosis and of primary carcinoma in parts of Africa and Asia, where the climate provides conditions of temperature and moisture that foster growth and toxin production by molds [13]. Nevertheless, the relevance to disease in humans ofthese and other botanical hepatotoxins is inferred from circumstantial evidence and remains to be proved. Varieties ofhepatotoxic chemical agents have been encountered in the...