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OBJECTIVE: To assess whether prolonged neonatal cholestasis, described in congenital hypopituitarism and septo-optic dysplasia (SOD), is associated with altered expression of selected canalicular ectoenzymes and canalicular transport proteins. STUDY DESIGN: Children with congenital hypopituitarism (n = 21), SOD (n = 18), and cholestasis seen in our center over 26 years were reviewed. Histopathologic findings in archival liver biopsy specimens were assessed (n = 10) and in those with low/normal levels of serum γ-glutamyltransferase (GGT) activity despite conjugated hyperbilirubinemia, expression of canalicular ectoenzymes and canalicular transport proteins was evaluated immunohistochemically. RESULTS: Patients presented at a median age of 8 weeks (range 3-20 weeks) with median total bilirubin 116 µmol/L (45-287 µmol/L), GGT 95 IU/L (25-707 UI/L), and serum cortisol 51 nmol/L (17-240 nmol/L). All but 3 had low free thyroxin (median 9.6 pmol/L [6.8-26.9]) with increased thyroid-stimulating hormone levels (median 5.95 mU/L [<0.1-9.24]). Liver histologic features included moderate-to-severe intralobular cholestasis with nonspecific hepatitis, giant-cell transformation of hepatocytes, and fibrosis. In all, immunohistochemical staining for canalicular ectoenzymes and canalicular transport proteins revealed a degree of reduced expression, associated with normal serum GGT values in 6 of the 10 patients, and another 6 nonbiopsied infants with cholestasis also had low/normal serum GGT activity. Sequencing of ABCB11 and ATP8B1 performed in 6 of the biopsied patients did not identify pathogenic mutations. Following replacement therapy, biochemical evidence of hepatobiliary injury resolved in all children within a median period of 6 months. CONCLUSION: Hepatobiliary involvement in congenital hypopituitarism associated with SOD has a good prognosis, but its etiology remains uncertain. Immunohistochemical expression of canalicular transport proteins was reduced in available liver samples.

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Hepatocellular carcinoma (HCC) has very poor prognosis. Astemizole has gained great interest as a potential anticancer drug because it targets several proteins involved in cancer including the Eag1 (ether à-go-go-1) potassium channel that is overexpressed in human HCC. Eag1 channels are regulated by cancer etiological factors and have been proposed as early tumor markers. Here, we found that HepG2 and HuH-7 HCC cells displayed Eag1 messenger RNA (mRNA) and protein expression, determined by real-time RT-PCR and immunochemistry, respectively. Astemizole inhibited human HCC cell proliferation (assessed by metabolic activity assay) and induced apoptosis (studied with flow cytometry) in both cell lines. The subcellular Eag1 protein localization was modified by astemizole in the HepG2 cells. The treatment with astemizole prevented diethylnitrosamine (DEN)-induced rat HCC development in vivo (followed by studying γ-glutamyl transpeptidase (GGT) activity). The Eag1 mRNA and protein levels were increased in most DEN-treated groups but decreased after astemizole treatment. GGT activity was decreased by astemizole. The Eag1 protein was detected in cirrhotic and dysplastic rat livers. Astemizole might have clinical utility for HCC prevention and treatment, and Eag1 channels may be potential early HCC biomarkers. These data provide significant basis to include astemizole in HCC clinical trials.

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Se determinaron los niveles séricos de gammaglutamil transpoptidasa (GGT) en ganado ovino infectado experimentalmente con Fasciola hepatica, con el objetivo de valorar el tiempo en que se normalizan después del tratamiento con triclabendazol. Se empleó un lote de corderos adultos y se conformaron 3 lotes de 5 animales cada uno. Los lotes 1 y 2 fueron infectados con 60 metacarcarias de Fasciola hepatica, los días 1, 30 y 75 del experimento. A los 90 días de la infección, se trató el lote 1 con triclabendazol a una dosis de 10 mg/kg; el lote 3 no fue infectado ni tratado, fue el testigo negativo. Los niveles séricos de GGT fueron cuantificados 8 días antes de la infección y posteriormente cada 30 días durante 165. Se encontró un incremento significativo (P< 0.05) de GGT en los lotes 1 y 2 en relación con el 3 posinfección, con una x de 35.4 y de 44.7 UY, y un pico a los 90 días con una x de 71.7 y 57.3 unidades internacionales, respectivamante. Los niveles séricos de GGT se normalizaron en los ovinos a los 75 días de haber sido tratados con triclabendazol

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gamma-Glutamyl transpeptidase (GGT) activity may be a sensitive index of hepatobiliary dysfunction. GGT activity, however, has been shown to be affected by several factors in different clinical situations. The present study was designed to determine the effect of heparin on serum and plasma GGT activity. Blood samples were collected from 15 normal male Wistar rats weighing 200-250 g for the determination of GGT activity in plasma prepared with heparin (group P(H), N = 10), in serum (group S, N = 15) and in serum with heparin added (group S + H, N = 10). GGT activity was 45.1 +/- 9.5 U/l (mean +/- SD) for serum compared with 161.2 +/- 46.1 U/l for serum plus heparin and 93.3 +/- 30.9 U/l for plasma prepared with heparin. The mean for each group was significantly different from the means for the other groups. These data demonstrate that GGT activity measurements should be made on serum in the absence of heparin, which produces elevated results.

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Sixty-three children with seizure disorders receiving phenobarbital and/or diphenylhydantoin for more than 12 months had liver function tests evaluated. All 56 whose serum anticonvulsant concentrations were in the therapeutic range had elevations of their serum gamma glutamyl transpeptidase activity. Of the 11 who had elevated SGOT and SGPT concentrations initially, six had persistent transaminase abnormalities for more than 20 weeks. Liver tissue from these six patients revealed by light microscopy uniform swelling of the hepatocytes without cell necrosis, inflammation, fibrosis, or disturbance of hepatic architecture. Electron microscopy demonstrated proliferation of the smooth endoplasmic reticulum without other ultrastructural alterations. All six patients were maintained on the same dosages of PB and/or DPH, and their transaminase activities returned to normal within eight to 14 months. The clinical well being of these patients, the transient nature of their SGOT and SGPT elevations, and the absence of specific histopathology suggest that chronic treatment with PB and/or DPH does not result in hepatotoxicity but rather in enzyme induction. The data indicate that liver biopsies are not warranted in such children and that PB and DPH may be continued despite mild elevations of SGOT and SGPT, without concern for hepatic damage.

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