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Serological markers for hepatitis A (HAV), B (HBV) and C (HCV) were documented in 315 inhabitants (27%) of a central Manitoba First Nations community. Serologic evidence of HAV infection (anti-HAV positive) was almost universal (92%) by the age of 20 years. HBV infection (antibody to hepatitis B core antigen positive) had occurred in only 2.3% of the study population and no chronic carriers were identified. Serological evidence of HCV infection (anti-HCV positive) was documented in 2.2% of the population but ongoing viremia (HCV-RNA positive by polymerase chain reaction) was absent. The results of this study highlight the importance of universal HAV vaccination; likely reflect the efficacy of existing prenatal screening and immunoprophylaxis programs for HBV; and raise the possibility that First Nations peoples have an enhanced ability to spontaneously clear HCV.

Increasing hepatocyte membrane potentials by augmenting GABAergic activity inhibits nonmalignant hepatocyte proliferative activity. The objectives of this study were to document 1) potential differences (PDs) of four malignant hepatocyte cell lines, 2) GABAA receptor mRNA expression in the same cell lines, and 3) effects of restoring malignant hepatocyte PDs to levels approximating those of resting, nonmalignant hepatocytes. Hepatocyte PDs were documented in nonmalignant and malignant (Chang, HepG2, HuH-7, and PLC/PRF/5) hepatocytes with a fluorescent voltage-sensitive dye and GABAA receptor expression by RT-PCR and Western blot analyses. Compared with nonmalignant human hepatocytes, all four malignant cell lines were significantly depolarized (P < 0.0001, respectively). Only PLC/PRF/5 cells had detectable GABAA-beta3 receptor mRNA expression and all cell lines were negative for GABAA-beta3 receptor protein by Western blot analysis. Stable transfection of Chang cells with GABAA-beta3 receptor cDNA resulted in significant increases in PD and decreases in proliferative activity as manifest by decreased [3H]thymidine and bromodeoxyurieine incorporation rates, 4-[3-(4-lodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate activity, a lower mitotic index, prolongation of cell-doubling times, and attenuated growth patterns compared with cells transfected with vector alone. Colony formation in soft agar and the number of abnormal mitoses were also significantly decreased in GABAA-beta3 receptor transfected cells. The results of this study indicate 1) relative to healthy hepatocytes, malignant hepatocytes are significantly depolarized, 2) GABAA-beta3 receptor expression is absent in malignant hepatocyte cell lines, and 3) increasing the PD of malignant hepatocytes is associated with less proliferative activity and a loss of malignant features.

The inhibitory effects of alcohol on hepatic growth in adults raises the possibility that the liver may be involved in fetal alcohol syndrome (FAS) in infants. To test this hypothesis, pregnant Sprague-Dawley rats were fed liquid diets containing either ethanol as 36% of the total calories, or were allowed ad libitum feeding of a control liquid diet (controls) throughout pregnancy. Other dams were exposed to the ethanol diet only during the first or last half of pregnancy. Pups delivered of dams exposed to the various diets (N = 40-45/group) were killed at 1, 3, 7, and 14 days of age. In addition to brain weights, crown-rump lengths, and facial features, the following parameters of liver development were documented; liver weight, liver/body weight ratio, liver histology, hepatic ornithine decarboxylase activity (ODC), hepatic protein content, and rate of hepatic DNA synthesis (as determined by [3H]thymidine incorporation). The results revealed that pups exposed to ethanol throughout pregnancy but not ad libitum control diet pups had brain weights, crown-rump lengths, and facial features in keeping with FAS. With respect to liver development, the livers in FAS pups were consistently smaller than in the control group. However, total body weights were decreased to a greater extent, such that when corrected for body weights, the smaller livers in FAS pups only became significant on day 14 of life. Liver histology was similar in the two groups with no signs of active inflammation or fibrosis. Hepatic ODC activity was also similar, indicating no impairment in polyamine synthesis. Hepatic DNA synthesis rates were decreased in FAS pups at all time intervals. Pups delivered of dams exposed to ethanol during either the first or last half of pregnancy had results comparable to those of controls. To identify the mechanism(s) responsible for these findings, a second series of experiments was performed wherein the hepatic expression of the following factors associated with liver development were documented by northern-blot analyses; growth hormone receptor (GHr), insulin-like growth factor-I (IGF-I) and -II (IGF-II) and IGF binding proteins (IGFBPs) 1, 2, 3, and 4 mRNA on gestational days 16 and 20 and postpartum days 1 and 7. In this series, a third group of pups derived from dams in whom caloric consumption was matched to that of the ethanol-fed dams (isocaloric controls) were also studied. The results revealed no consistent differences in GHr, IGF, or IGFBP mRNA expression in the three groups. In conclusion, liver development and hepatic DNA synthesis were significantly impaired in this animal model of FAS. That impairment, however, was not associated with decreases in either polyamine synthesis or disturbances in the hepatic component of the GH/IGF/IGFBP axis.

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