Biomedical subjects
Publications and source records attributed to B H Ruebner.
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The effect of chronic ethanol feeding on hepatic mitochondrial morphology and histochemically measured succinic dehydrogenase activity was assessed. Five monkeys of the species Macaca radiata received a nutritionally adequate diet containing 50% of the calories as ethanol, while five others were pair-fed the same diet except that ethanol was isocalorically substituted by carbohydrate. Liver morphology was assessed at 12 and 24 months and at sacrifice after 40 to 48 months of ethanol feeding. The ethanol-fed animals developed mild to moderate fatty liver as did some of the controls. No necrosis or fibrosis developed. All ethanol-fed animals developed centrilobolar megamitochondria and centrilobular "shift" in histochemically assayed succinic dehydrogenase activity characteristic of animals fed ethanol for prolonged periods. These mitochondrial changes persisted throughout the 48-month test period without progressive increase in severity or accompanying pathology. It is concluded that the morphologic and histochemically assessed mitochondrial changes do not necessarily represent a progressive destructive effect of ethanol.
Mallory bodies (MBs) were induced in hepatic tumors by administration for up to 85 weeks of a diet containing 10 ppm dieldrin to 50 C3H/He and 62 C57BL/6J x C3H/He B6C3F1 male mice. MBs were seen in 15 of 28 (54%) mice which developed benign hepatic tumors and 33 of 45 (73%) mice with hepatocellular carcinoma, but in only 3 of 39 (8%) mice without hepatic tumors. In mice with tumors, the MBs were predominantly confined to tumor tissue and persisted in a carcinoma transplanted into a nude mouse. MBs were not observed, however, in hepatic tumors of 67 C57BL/6J, 49 C3H/He, or 81 B6C3F1 mice given 12 micrograms diethylnitrosamine i.p. on Days 0, 3, 9, and 15. Thirty-one of 195 control mice of all three strains had hepatic tumors. Only one of the controls had a tumor with an MB, and no MBs were seen in nontumor-bearing livers of controls animals. These observations, coupled with the results of a previous study in which MBs were observed in hepatocytes of dieldrin-treated C57BL/6J mice, indicate that mice treated with dieldrin are a reliable animal model for the study of MBs.
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To assess the reliability of technetium-99m disofenin scanning in evaluating neonatal cholestasis, 33 neonates (less than 3 months of age) with direct hyperbilirubinemia were evaluated prospectively by cholescintigraphy. Results of this test were compared to those of standard serum tests of liver function, ultrasonography, and liver biopsy. The diagnosis of biliary atresia was suggested by a serum gamma-glutamyl transpeptidase (gamma-GTP) greater than 300 units/L, absence of the gallbladder on ultrasonography, and a lack of detectable radioisotope in the gastrointestinal and/or extrahepatic biliary tract on cholescintigraphy. Each of these tests lacked sensitivity and/or specificity when compared to liver biopsy. Of the nine neonates with biliary atresia, three had gallbladders identified by ultrasonography and two had gamma-GTP less than 300 units/L. Of the 24 neonates without biliary atresia, eight had cholescintigraphy without detectable radioisotope excretion, four had ultrasonography that failed to visualize the gallbladder, and nine had gamma-GTP greater than 300 units/L. Cholescintigraphy excluded the diagnosis of biliary atresia when gut and/or extrahepatic biliary excretion of isotope was seen. However, cholescintigraphy required more time, 6-8 days, and was less specific than ultrasonography and liver biopsy. We recommend that cholescintigraphy should not be routinely used in evaluating neonatal cholestasis, especially if it delays surgical intervention.
Reports of an increase in a serum epoxide hydrolase (sEH), immunochemically related to microsomal EH in humans and rats with hepatocellular carcinoma (HCC), suggested its use as a serum marker for this disease. We have now measured sEH levels (as either immunochemically determined content or enzyme activity) in a number of human and experimental models of liver disease. sEH was elevated above the normal range in at least 50% of individuals with HCC, including: 3 of 6 northern Californians; 4 of 7 Koreans with hepatitis B-associated HCC; hepatitis B-associated HCC in woodchucks; and male rats receiving chronic treatment with aflatoxin B1 or ciprofibrate. sEH was rarely elevated in other forms of chronic liver disease. Only 2 of 9 Koreans with hepatitis B-associated cirrhosis, 1 of 8 carriers, but none with chronic active hepatitis or infection with no apparent liver disease had elevated sEH. In addition, no elevations were found in woodchucks with noncancerous viral hepatitis. In aflatoxin B1- and M1-treated rats sEH was not elevated in those with only hyperplastic foci or hepatocellular adenomas, and in two rat initiation-promotion protocols sEH was elevated only in those rats which received the entire set of treatments. sEH was also increased during acute hepatotoxicity in rats treated with CCl4 or 1,2-dibromo-3-chloropropane. The mechanism of increase in sEH during hepatocarcinogenesis appears to be different from that of other markers of HCC, for in the Korean patients, there was no correlation between sEH concentrations and those of alpha-fetoprotein or ferritin, nor was there a correlation with alpha-fetoprotein concentrations in the aflatoxin-treated rats. Furthermore, the increase in sEH does not correlate with induction of microsomal EH in the liver of experimental animals. Studies to date indicate that sEH is selective for HCC and severe hepatonecrotic injury, and may be of some use in the diagnosis of HCC, particularly as a complement to other serum markers.