Electron Microscopy as Related to Hepatotoxicity*

Abstract

On the basis of light microscopic studies, drug reactions involving the liver have been classified as hepatitic, cholestatic, and toxic. 1 The last is the result of administration of poisons affecting all species and all indi viduals in a clear dose related fashion and with a distinctive morphologic picture. These chemicals, usually organic solvents best exemplified by carbon tetrachloride, have been widely used in experimental models of hepatic injury. However, most drug reactions in the liver occur infre quently, are not clearly dose related, and mimic other diseases of the liver and biliary tract, particularly viral hepatitis and extrahepatic biliary obstruction, as far as clinical, laboratory, and morphologic features are concerned. In an effort to effect a separation of drug-induced hepatic injury from other diseases, liver biopsy specimens were examined electronmicroscopically. Cholestasis following drug administration was found to be associated with changes of bile canaliculi, whereas hepatitis-like reactions seemed to primarily alter endoplasmic reticulum. 2 · 3 Many drug reactions with cholestasis were accompanied by bile canalicular dilatation and microvillar loss and shortening. 2 · 4 · 5 However, similar changes were also found in extrahepatic biliary obstruction, 69 in viral hepatitis, 2 and in liver disease in alcoholic persons. 10 Therefore, the canalicular changes failed to provide a means of differential diagnosis of the causes of cholestasis, particularly hepatic disease versus biliary tract obstruction. The electronmicroscopic studies did indicate that short term administration of drugs such as norethandrolone, known to produce cholestasis in some persons, and retention of Bromsulphalein in most persons 11 · 12 caused canalicular dilatation even in the absence of jaundice, and the same find ings were noted in rats given the drug. 6 In rats, however, the light micro scopic hallmark of cholestasis, namely bile thrombi, are not seen. In addition to electronmicroscopic changes in bile canaliculi, the enzyme histochemical reactions of the bile canaliculi were altered.

Structural Alterations of Liver Parenchyma Induced by Anabolic Steroids*

“…The signs of this functionally retrograde bile secretion, the so-called paracholia (20), are shown in Fig. 6 and have already previously been described (14)(15)(16). The acidophilic transformation and occurrence of "feathery degeneration" of large areas of liver cells are supposed to be the characteristic consequence of cholestasis (20).…”

“…After a morphologically inconspicuous stage, intrahepatic cholestasis occurs, which is termed "drug icterus" (1,13,15). During this process, the hepatocytes are unable to excrete esterified bilirubin and organic anions into the bile ducts, which leads to the accumulation of bilirubin within the liver cells and to the excretion of bilirubin and bile acids into the sinusoids.…”

“…Conversely, C-17 alkylated steroids, which are most frequently employed, are known to cause secondary effects that primarily affect the liver structure and function (8,(21)(22)(23). Three different liver diseases are supposed to occur after application of anabolics: (1) general liver damage occurring as cholestatic icterus (13,15), (2) peliosis hepatis (6,17), and (3) formation of liver tumors (18). Whereas the induction of cholestasis by all kinds of steroids has been confirmed, a positive correlation between peliosis hepatis and tumor genesis is controversial.…”

Mechanisms of Intrahepatic Cholestasis in Drug‐induced Hepatic Injury*

“…In this sense the term cholestasis might be applied to rats as damage of the bile secretory mechanism, and this is also regularly produced by anabolic steroids in a dose-related fashion. The same holds true for chlorpromazine which produces regularly similar changes of the microvilli in rats, 24 and alterations of dye clearance in such animals have been reported by two groups in Europe. 25 · 2e Survey of the literature suggests that administration of chlorpromazine to healthy persons causes at least transient Bromsulfalein retention.…”

Effects of chlorpromazine hydrochloride on bile salt synthesis, bile formation and biliary lipid secretion in the Rhesus monkey: a model for chlorpromazine‐induced cholestasis

“…In prospective studies, abnormal liver function tests, increased bromosulphthalein retention [2, 51 and morphological abnormalities in liver biopsies [2] have been observed in nearly 50% of patients taking CPZ.HC1 for prolonged periods of time, all of which suggest a direct hepatotoxic effect of the drug. Furthermore there is experimental evidence indicating a direct impairment of the bile secretory apparatus of the liver; thus, altered bile canaliculi and reduction of bromosulphthalein excretion have been observed in CPZ.HC1 treated rats [6,71, and the drug inhibits bile flow both in dogs [8] and in isolated perfused rat liver preparations 191. Others, however, have found no effect of CPZ.HC1 on the plasma clearance of bromosulphthalein in mice [lo], or on the rate of bile flow in rats [I 1,121. Nonetheless, based on circumstantial evidence, hypersensitivity to the drug has generally been implicated as a mechanism for CPZ.HC1 associated cholestatic jaundice [ l , 13,141.…”