bluuebunny/crossref_metadata_2025 huggingface dataset:
Anti—pre-S responses and viral clearance in chronic hepatitis B virus infection
Authors: Budkowska Agata , Dubreuil Pascal , Poynard Thierry , Marcellin Patrick , Loriot Marie-Anne , Maillard Patrick , Pillot Jacques
Published: March 2007

Serial sera were collected prospectively during the clinical course of 13 HBsAg carriers with chronic liver disease and analyzed for ALT levels, pre-S1 and pre-S2 antigens and corresponding antibodies and other serological hepatitis B virus markers. In five patients, anti—pre-S1 and anti—pre-S2 antibodies became detectable in multiple serum samples, whereas in eight patients anti—pre-S was never detected or only appeared transiently during the follow-up. The first pattern was associated with normalization of ALT levels and undetectable pre-S antigens and viral DNA by the polymerase chain reaction assay at final follow-up. HBsAg clearance occurred in two of the five patients. The second pattern was one of persistence of HBsAg and pre-S antigens, associated with the presence of serum HBV DNA detectable by spot hybridization or polymerase chain reaction regardless of clinical outcome. These findings demonstrate the occurrence of anti—pre-S antibodies in chronic hepatitis B virus—induced liver disease and associate anti—pre-S appearance with the clearance of hepatitis B virus from serum. (Hepatology 1992;15:26-31).
Demonstration of hepatitis B virus DNA by polymerase chain reaction in the serum and the liver after spontaneous or therapeutically induced HBeAg to anti-HBe or HBsAg to Anti-HBs seroconversion in patients with chronic hepatitis B
Authors: Loriot Marie-Anne , Marcellin Patrick , Bismuth Eric , Martinot-Peignoux Michèle , Boyer Nathalie , Degott Claude , Erlinger Serge , Benhamou Jean-Pierre
Published: March 2007

The objective was to determine the proportion of patients with chronic hepatitis B in whom hepatitis B virus DNA is demonstrated by polymerase chain reaction after HBeAg to anti-HBe or HBsAg to anti-HBs spontaneous or therapeutically induced seroconversion.

Polymerase chain reaction was performed on serum 6 and 12 mo after HBeAg to anti-HBe seroconversion in 12 patients and 2, 6 and 12 mo after HBsAg to anti-HBs seroconversion in 13 patients. Polymerase chain reaction was performed on liver tissue after HBeAg to anti-HBe seroconversion in five patients and after HBsAg to anti-HBs seroconversion in one patient.

Serum HBV DNA was demonstrated by polymerase chain reaction in 83% of patients 6 or 12 mo after HBeAg to anti-HBe seroconversion and in 58%, 31% and 15% of patients at 2, 6 and 12 mo, respectively, after HEsAg to anti-HBs seroconversion. Liver HBV DNA was demonstrated by polymerase chain reaction in all patients tested.

Our results show that (a) a reduced level of hepatitis B virus replication persists in most of the patients after HBeAg to anti-HBe seroconversion and might be predictive of reactivation, and (b) in contrast, hepatitis B virus replication progressively disappears in most of the patients after HBsAg to anti-HBs seroconversion. (Hepatology 1992;15:32-36).
Detection of hepatitis C virus RNA in serum of patients with chronic hepatitis C treated with interferon-α
Authors: Hagiwara Hideki , Hayashi Norio , Mita Eiji , Ueda Keiji , Takehara Tetsuo , Kasahara Akinori , Fusamoto Hideyuki , Kamada Takenobu
Published: March 2007

We tested serial serum samples for hepatitis C virus RNA from patients undergoing treatment for chronic hepatitis C with interferon-α using an assay that combined reverse transcription and polymerase chain reaction. The subjects studied were 20 patients with chronic hepatitis who had serum antibody to hepatitis C virus (anti-C100-3). Before therapy, hepatitis C virus RNA was detected in 18 (90%) and 20 (100%) patients using primer sets derived from the NS3 region or the 5′-noncoding region of hepatitis C virus, respectively. Hepatitis C virus RNA became undetectable in all patients whose ALT level fell into the normal range during therapy. However, hepatitis C virus RNA reappeared in all patients whose ALT levels rose again after therapy, usually before the relapse. In patients whose ALT levels did not become normal, hepatitis C virus RNA did not disappear during therapy. Thus therapy with interferon-α appears to be beneficial in chronic hepatitis C because of its suppressive effects on hepatitis C virus replication. Detection of hepatitis C virus RNA in serum is useful for evaluating the antiviral effect of interferon (Hepatology 1992;15:37-41).
Plasma catecholamine concentrations are a reliable index of sympathetic vascular tone in patients with cirrhosis
Authors: Braillon Alain , Gaudin Christophe , Poo Jorge L. , Moreau Richard , Debaene Bertrand , Lebrec Didier
Published: March 2007

In patients with cirrhosis, the significance of elevated plasma catecholamine concentrations is unclear. Thus we investigated the relationship between plasma catecholamine concentrations and the hemodynamic effect of pindolol (an index of sympathetic vascular tone) in 10 patients with cirrhosis. Systemic and splanchnic hemodynamics and plasma catecholamine concentrations in the pulmonary artery and the splanchnic veins (hepatic and azygos veins) were studied before and after the oral administration of pindolol (20 mg). In basal conditions patients exhibited a hyperkinetic circulatory syndrome and elevated plasma catecholamine concentrations. Alterations in basal hemodynamics were correlated with plasma epinephrine concentrations but not with norepinephrine. Pindolol administration significantly decreased heart rate and increased right atrial pressure. After pindolol administration, individual hemodynamic changes (cardiac index, systemic vascular resistance, wedged hepatic venous pressure) were significantly correlated with plasma catecholamine concentrations. In conclusion, this study shows that in cirrhotic patients epinephrine may play a role in hemodynamic alterations, and plasma catecholamine concentrations are an index of sympathetic vascular tone. (Hepatology 1992;15:58-62).
Endoscopic injection sclerotherapy for 1,000 patients with esophageal varices: A nine-year prospective study
Authors: Hashizume Makoto , Kitano Seigo , Koyanagi Nobuhiro , Tanoue Kazuo , Ohta Masayuki , Wada Hiroya , Yamaga Hirohiko , Higashi Hidefumi , Iso Yasunori , Iwanaga Tetsuya , Sugimachi Keizo
Published: March 2007

We report here the results of endoscopic injection sclerotherapy performed in 1,000 consecutively treated Japanese patients with esophageal varices. This prospective study covered the period from 1982 to 1990. Variceal bleeding was controlled in 215 (97.7%) of 220 patients. Esophageal varices were completely eradicated in 778 patients (77.8%); the mean number of sessions was 4.2. In only 3 of the 778 patients did esophageal varices of the same size recur. Small, dilated, venous vessels that required additional sclerotherapy in follow-up endoscopy at 3-mo intervals appeared in 171 (22.2%) of 778 patients. The cumulative nonbleeding rate at 5 yr was 94.5% in patients in whom the varices had been eradicated. Deaths caused by upper gastrointestinal bleeding accounted for 2.6% of cases, whereas the rates of liver failure and hepatoma were 4.6% and 47.3%, respectively. The 5-yr cumulative survival rate was 54.1% in patients without concomitant hepatoma; it was 12.0% in patients with hepatomas. Multivariate analysis showed that hepatoma, Child classification, indication (acute, elective or prophylactic) and eradication were independent factors that significantly influenced survival time. This study clearly shows that close follow-up with endoscopy and complete eradication lead to significant reduction in bleeding from esophageal varices and reduction of mortality related to this bleeding. (Hepatology 1992;15:69-75).
The role of transcription and messenger RNA stability in the regulation of epidermal growth factor receptor gene expression in regenerating mouse liver
Authors: Noguchi Shinzaburo , Ohba Yoshito , Oka Takami
Published: March 2007

The influence of partial hepatectomy on epidermal growth factor receptor gene expression was studied in mouse liver. Epidermal growth factor receptor binding and epidermal growth factor receptor messenger RNA levels in the liver showed a rapid peak 8 hr after partial hepatectomy, whereas the sham operation had no effects on these levels. The peak epidermal growth factor receptor messenger RNA level was approximately threefold higher than preoperative values. The increase in epidermal growth factor receptor messenger RNA levels occurred primarily as a consequence of an increase in the rate of transcription. Partial hepatectomy slightly increased the half-life of epidermal growth factor receptor messenger RNA in the liver from 2.8 to 3.6 hr. Treatment of partially hepatectomized mice with cycloheximide increased hepatic epidermal growth factor receptor messenger RNA levels about fivefold by prolonging the half-life of the messenger RNA to 11.2 hr, although this treatment inhibited the increase in transcription induced by partial hepatectomy. Cycloheximide also increased epidermal growth factor receptor messenger RNA levels in the liver or kidney of sham-operated mice about threefold, primarily through stabilizing epidermal growth factor receptor messenger RNA. In contrast, cycloheximide had no effects on β-actin messenger RNA levels in the liver and kidney. These results suggest that transcription induced by partial hepatectomy requires protein synthesis and that labile proteins are involved in the regulation of the stability of epidermal growth factor receptor messenger RNA. (Hepatology 1992;15:88-96).
Viability and primary culture of rat hepatocytes after hypothermic preservation: The superiority of the leibovitz medium over the university of wisconsin solution for cold storage
Authors: Poullain Marie-gwenaëlle , Fautrel Alain , Guyomard Claire , Chesne Christophe , Grislain Luc , Guillouzo André
Published: March 2007

Hepatocytes isolated from adult rat livers were hypothermically preserved for 24 or 48 hr before being plated under conventional culture conditions. They were stored either in the Leibovitz medium, a cell culture medium with and without polyethylene glycol (PEG), a compound known to suppress ischemia-induced cell swelling, or in the University of Wisconsin solution, the most effective solution for cold organ preservation. After 24 or 48 hr of storage at 4.5° C in Leibovitz medium, cell viability and adherence efficiency to plastic dish, were only slightly reduced, whereas University of Wisconsin hepatocytes had a decreased viability and (especially after 48-hr storage) lost their adhesion ability; they did not survive in vitro. The metabolic competence of hepatocytes maintained in Leibovitz medium was retained over the 3 days of culture, as shown by low extracellular levels of the membrane-bound and cytosolic hepatic enzymes, as well as by intracellular glutathione content, albumin secretion rate and several phase I and phase II drug metabolic reactions very close to those found with fresh hepatocytes maintained under similar culture conditions. Addition of polyethylene glycol to the Leibovitz medium resulted in slightly higher viability and function of hepatocytes after cold storage.

These results clearly demonstrate that viability of a transplanted liver does not correlate with long-term in vitro viability of isolated hepatocytes after hypothermic preservation in University of Wisconsin solution. They also suggest that nutritional and energy substrates as found in the Leibovitz medium are probably required to define a suitable solution for cold preservation of isolated parenchymal cells. The findings with Leibovitz medium favor the conclusion that hypothermically preserved hepatocytes could be used for various metabolic studies and for the treatment of liver insufficiency. (Hepatology 1992;15:97-106).
Circulatory changes induced by portal venous diversion and mesenteric hypertension in rats
Authors: Lee Samuel S. , Johansen Kaj , Lebrec Didier
Published: March 2007

We studied the hemodynamics in four groups of rats with combinations of mesenteric hypertension and portal diversion. Operations created three groups with mesenteric hypertension and different degrees of portal venous diversion: mesenteric vein stenosis, portal vein stenosis and end-to-side portacaval anastomosis with mesenteric vein stenosis, the fourth group had only portacaval anastomosis. A control group had sham operations. Cardiac output, splanchnic blood flows and portosystemic shunt indices were measured with radioactive microspheres. Mesenteric venous pressures in the mesenteric-stenosed, portal-stenosed, portacaval-shunted and end-to-side portacaval anastomosis with mesenteric vein stenosis rats were, respectively, 13.5 ± 0.6, 15.3 ± 0.7, 4.3 ± 0.5 and 13.0 ± 0.9 mm Hg, which were all significantly different from controls: 8.3 ± 0.3 mm Hg. Portosystemic shunt indices were also significantly different from each other: controls, 0.4% ± 0.02%; mesenteric-stenosed, 5.9% ± 2.3%; and portal-stenosed, 52.1% ± 4.9%. Cardiac output and splanchnic visceral blood flows were significantly increased in the portal-stenosed rats and the two groups with portacaval anastomoses, with the latter two groups having the highest values. The addition of mesenteric stenosis did not change the blood flows because mesenteric-stenosed rats did not differ from controls and end-to-side portacaval anastomosis with mesenteric vein stenosis rats did not differ from rats with portacaval anastomosis alone. These results suggest that mesenteric venous hypertension per se does not affect hemodynamics but that diversion of portal venous blood from the liver is a critical factor in the development of hyperkinetic circulation in portal hypertension. (Hepatology 1992;15:117-121).
Hepatocyte growth factor
Authors: Michalopoulos George K. , Zarnegar Reza
Published: March 2007

The two papers in this issue of Hepatology (1, 2) dealing with hepatocyte growth factor (HGF) underscore the increasing importance of this novel growth factor in relation to hepatic growth biology. The emerging literature has already established HGF as a growth factor with potential importance not only for the liver but for other tissues such as the kidney, placenta, brain, lung, pancreas and hemopoietic tissues. This editorial will attempt to correlate the findings of the two HGF papers presented in this issue of Hepatology, summarize the existing literature on HGF and provide a synthetic overview for its role in the liver and other tissues. Several specific features already described set HGF aside in comparison with other growth factors in terms of structure and function.
Yet another role for the “good” matrix protein: Laminin in regenerating liver
Authors: Maher Jacquelyn J.
Published: March 2007

After partial hepatectomy, the liver is capable of complete regeneration, restoring normal hepatic size, architecture, and function. To study the role of the extracellular matrix in regeneration, the temporal and spatial sequence of deposition of several of its components, including collagen types I, III, and IV, laminin, and fibronectin, in rat liver, after an 80% hepatectomy, was characterized by light microscopy immunohistochemistry. A minimum of five animals were studied for each date. In agreement with previous reports, subsequent to 80% hepatectomy, there was a brisk mitosis of hepatocytes. The mitotic activity was maximal at 48 hours, primarily in the periportal and centrilobular zones, and resulted in the formation of hepatocyte clusters and widening of the hepatic plates. Of the extracellular matrix components studied, laminin was the one demonstrating the most dramatic changes. By 24 hours, laminin appeared in the hepatic sinusoids reaching a maximum staining intensity at 48 hours. Intracellular laminin was prominent in numerous nonparenchymal cells, with many having the morphology, location, and desmin content characteristic of Ito cells. Laminin staining decreased in the sinusoids at 4 days; however, some intracellular staining of Ito cells was present even at 8 days after hepatectomy. At the completion of regeneration, there was no evidence of any substantial change in the ratio: extracellular matrix/cell mass. The results indicate that: (a) hepatocytes can divide without prior removal of the subsinusoidal extracellular matrix; (b) during regeneration, hepatocyte division precedes sinusoidal formation; (c) during hepatic regeneration, and in spite of the presence of laminin in Ito cells, no basement membranes are formed; (d) the prominent expression of laminin and its proposed functions in morphogenesis suggest a critical role for this matrix component in the formation and reorganization of the regenerating liver.
Seroprevalence of hepatitis C virus nucleocapsid antibodies in patients with cryptogenic chronic liver disease
Authors: Brown Jonathan , Dourakis Spyros , Karayiannis Peter , Goldin Robert , Chiba Joe , Ohba Hiroyoshi , Miyamura Tatsuo , Thomas Howard C.
Published: March 2007

The serological responses to two different hepatitis C virus antigens were studied by enzyme-linked immunosorbent assay in a variety of chronic liver diseases and in healthy blood donors. The study population comprised 97 cases of cryptogenic chronic liver disease (40% with a history suggestive of parenterally transmitted non-A, non-B hepatitis and 60% without such a history), 87 cases of other well-characterized chronic liver diseases and 96 voluntary blood donors. The commercially available C100-3 assay and a new assay utilizing a 22 kD recombinant protein (c22) from the nucleocapsid region of the virus were used for antibody detection. Overall in the non-A, non-B hepatitis group, 77% were positive for anti-c22, 55% were positive for anti-C100-3 and 24% were negative by both tests. In the parenterally transmitted chronic liver disease group, 82% were positive for anti-C100-3 and 90% were positive for anti-c22 (not significant). In the cryptogenic chronic liver disease cases 36% were positive for anti-C100-3 and 67% were positive for anti-c22 (p < 0.001). Only in one case (a patient with hepatitis B virus infection) was anti-C100-3 detected without concomitant anti-c22. None of the voluntary blood donors had detectable hepatitis C virus antibodies. The new enzyme-linked immunosorbent assay test for anti-c22 would appear to be a more sensitive indicator of chronic hepatitis C virus infection than the existing commercial test, suggesting a useful diagnostic role in both cases of cryptogenic chronic non-A, non-B hepatitis liver disease and for the screening of blood products for prevention of hepatitis after transfusion. (Hepatology 1992;15:175-179).
Antibodies against synthetic oligopeptides deduced from the putative core gene for the diagnosis of hepatitis C virus infection
Authors: Okamoto Hiroaki , Tsuda Fumio , Machida Atsuhiko , Munekata Eisuke , Akahane Yoshihiro , Sugai Yoshiki , Mashiko Kazuo , Mitsui Takehiro , Tanaka Takeshi , Miyakawa Yuzo , Mayumi Makoto
Published: March 2007

Immunoassays were developed to detect antibodies against oligopeptides deduced from the putative core gene of hepatitis C virus, and their performances were compared with that of the commercial immunoassay for antibodies against the product of nonstructural regions of hepatitis C virus (anti-C100-3). A 19-mer oligopeptide (CP10) and a 36-mer oligopeptide (CP9) were chemically synthesized, which represented hydrophilic regions of the product of the hepatitis C virus core gene. They were used to capture corresponding antibodies, anti-CP10 and anti-CP9, by enzyme-linked immunosorbent assay in sera from patients with acute or chronic non-A, non-B liver disease and in blood donations. At the onset of acute non-A, non-B hepatitis, anti-CP10 was detected in 15 of 20 patients (75%), and anti-CP9 was detected in 14 patients (70%). This was more frequent than anti-C100-3, which was found in only 9 patients (45%). In 186 patients with chronic non-A, non-B liver disease, anti-CP9, anti-CP10 or both were detected in 170 patients (91%). This was more frequent than anti-C100-3, which was found in 138 patients (74%). Blood with anti-CP10 as the single serological marker for hepatitis C virus infection transmitted non-A, non-B hepatitis by needlestick exposure. In sera from 558 apparently healthy blood donors, anti-CP10 was detected in 55 donors (9.9%), anti-CP9 was detected in 26 donors (4.7%) and anti-C100-3 was detected in 7 donors (1.3%). Among sera positive by at least one test, 14 were found to contain hepatitis C virus RNA; 7 of them were negative for anti-C100-3 but positive for anti-CP10 and/or anti-CP9 in high titers. These results indicate that antibodies against antigenic determinants of the hepatitis C virus core would complement anti-C100-3 for the diagnosis of non-A, non-B liver disease and contribute toward further decreasing the incidence of posttransfusion non-A, non-B hepatitis. (Hepatology 1992;15:180-186).
Prevalence of antibodies to hepatitis C virus among patients with cryptogenic chronic hepatitis and cirrhosis
Authors: Jeffers Lennox J. , Hasan Fuad , de Medina Maria , Reddy Rajender , Parker Talley , Silva Marcelo , Mendez Leonardo , Schiff Eugene R. , Manns Michael , Houghton Michael , Choo Qui-Lim , Kuo George
Published: March 2007

Many cases of chronic hepatitis and cirrhosis cannot be attributed to a known cause and are collectively referred to as cryptogenic chronic liver disease. We have evaluated the role of the hepatitis C virus in the pathogenesis of this condition in a retrospective serum analysis for antibody to hepatitis C virus in 129 patients with cryptogenic liver disease. Other causes of chronic hepatitis and cirrhosis were ruled out by clinical, serum biochemical and serological techniques. All 129 patients were HBsAg negative, but 28 (22%) had antibody to HBcAg. Sera were tested by radioimmunoassays using recombinant peptides for antibodies to nonstructural (C 100-3 and C33c) and structural regions (C22) of HCV. Among the 129 patients, 61 (47%) had antibody to C100-3, 76 (59%) had antibody to C33c and 74 (57%) had antibody to C22. Seventy-nine (61%) were reactive with at least one and 76 (59%) were reactive with at least two HCV peptides (this is the criterion used for hepatitis C virus antibody reactivity). A proportion of patients with chronic hepatitis and cirrhosis (55 of 91; 60%) similar to that of patients without cirrhosis (21 of 38; 55%) had hepatitis C virus antibody. No significant clinical, serum biochemical or histological differences were noted between the group of patients with hepatitis C virus antibody and those without this antibody reactivity. Thus more than half the patients with cryptogenic chronic liver disease had hepatitis C virus antibody, suggesting that chronic HCV infection plays a major role in the origin of cryptogenic chronic hepatitis and cirrhosis. (Hepatology 1992;15: 187-190).
Fibroproliferation in liver disease: Role of monocyte factors
Authors: Peterson Theresa C. , Isbrucker Richard A.
Published: March 2007

Fibroproliferation was measured as the uptake of [3H]thymidine into fibroblasts. Human fibroblasts were incubated with 200 μl monocyte-conditioned medium, the 0.22 μm filtrate from cultured monocytes, in Dulbecco’s modified Eagle medium supplemented with controlled process serum replacement 2, a fetal calf serum substitute with low mitogenic activity. Increasing the numbers of fibroblasts resulted in a parallel increase in thymidine uptake to a maximal level. Fibroblasts (2 × 103) were plated into microwell plates and incubated with monocyte-conditioned medium for 72 hr. At 16 hr before harvest, 1 μCi [3H]thymidine was added. Cells were harvested with phosphate-buffered saline and washed, and the filters were counted. Fibroblasts incubated with Dulbecco’s modified Eagle medium and controlled process serum replacement 2 showed minimal thymidine uptake. Fibroblasts incubated with Dulbecco’s modified Eagle medium plus monocyte-conditioned medium from monocytes stimulated with 10 μg/ml lipopolysaccharides showed a sixfold increase in thymidine uptake over fibroblasts in Dulbecco’s modified Eagle medium and controlled process serum replacement 2 alone. Fibroblasts incubated with Dulbecco’s modified Eagle medium plus monocyte-conditioned medium from monocytes of patients with liver disease (n = 20) showed a 10-fold elevation in thymidine uptake compared with Dulbecco’s modified Eagle medium and controlled process serum replacement 2. Results indicated that preincubation of monocyte-conditioned medium with either anti-interleukin-1β (12.5 halfmaximal units, 4° C, 16 hr) or catalase (1,870 IU, 25° C, 1 hr) did not alter the fibroproliferative activity of the monocyte-conditioned medium, suggesting that neither interleukin-1β nor activated oxygen intermediates were involved in fibroproliferation. Fibroblasts were incubated with platelet-derived growth factor in increasing concentrations to produce a dose-response relationship. Platelet-derived growth factor was found to significantly enhance fibroproliferation. The addition of antibody to platelet-derived growth factor reduced the fibroproliferation activity of plateletderived growth factor. Samples of monocyteconditioned medium were then preincubated with anti—platelet-derived growth factor to determine whether platelet-derived growth factor in the monocyte-conditioned medium was mediating fibroproliferation. Anti—platelet-derived growth factor reduced the fibroproliferative activity of the monocyteconditioned medium, suggesting that platelet-derived growth factor probably plays a role in the fibroproliferation observed with monocyte-conditioned medium obtained from patients with liver disease. (Hepatology 1992;15:191-197).
Oral bile acid treatment and the patient with zellweger syndrome
Authors: Setchell Kenneth D. R. , Bragetti Patrizia , Zimmer-Nechemias Linda , Daugherty Cynthia , Pelli Maria Antonietta , Vaccaro Renato , Gentili Giorgio , Distrutti Eleonora , Dozzini Giuliano , Morelli Antonio , Clerici Carlo
Published: March 2007

The cerebrohepatorenal syndrome of Zellweger is a congenital syndrome of multiple manifestations, including hepatomegaly and liver dysfunction. Treatment is generally of a supportive nature, aimed at improving nutrition and growth, controlling the central nervous system symptoms and limiting progression of liver disease. Because the liver disease in Zellweger syndrome may be attributed to an overproduction and accumulation of cholestanoic acids, exacerbated by diminished primary bile acid synthesis, we hypothesized that primary bile acid administration would be beneficial in improving liver function by a mechanism involving down-regulation in the synthesis of these atypical bile acids. We report here the clinical and biochemical responses to primary bile acid administration in a 2-mo-old boy who was seen with the typical signs of Zellweger syndrome. Liver disease was evident from hepatomegaly and elevated serum liver enzymes and bilirubin. The diagnosis was supported by markedly elevated serum very long chain fatty acids and the bile acids dihydroxycholestanoic acid and trihydroxycholestanoic acid. Confirmation of the lack of peroxisomes was established by electron microscopy. When the patient was 6 mo old, the primary bile acids cholic acid and chenodeoxycholic acid, (100 mg each/day) were administered orally. A significant improvement in biochemical indices of liver function occurred with a normalization of the serum bilirubin and liver enzymes and a histological improvement in the extent of inflammation and bile duct proliferation and disappearance of cannalicular plugs. Serum and urinary cholestanoic acids showed a significant decrease within a few days. A striking and sustained increase in growth was observed after therapy, and an improvement in neurological symptoms was noted. In conclusion, this study indicates that primary bile acid therapy improves liver function and growth in the patient with peroxisomal dysfunction and should be considered in the supportive therapies for this condition. (Hepatology 1992;15:198-207).
Lactitol or lactulose in the treatment of chronic hepatic encephalopathy: Results of a meta-analysis
Authors: Blanc Pierre , Daures Jean-Pierre , Rouillon Jean-Michel , Peray Pascale , Pierrugues Robert , Larrey Dominique , Gremy François , Michel Henri
Published: March 2007

Lactitol (β-galactosido-sorbitol) has been recently compared with lactulose for the treatment of chronic hepatic encephalopathy in a few studies, each comprising a small number of patients. The results are controversial. We studied the efficiency and tolerance of both compounds by using a meta-analysis on the basis of published controlled trials. Our study only included controlled or randomized trials comprising cirrhotic patients with chronic hepatic encephalopathy. Analyzed parameters were the portosystemic encephalopathy index of Conn after treatment, the percentage of improved patients and the percentage of patients who had ill effects related to the treatment (flatulence, diarrhea). Bibliographical screening revealed five studies comparing the effects of lactitol and lactulose in chronic hepatic encephalopathy. Four crossover studies were done that included 48 patients and one parallel study that included 29 patients. The duration of the treatment ranged from 3 to 6 mo. All studies found a similar efficiency with both drugs. However, they exhibited some discrepancies in the relative frequency of adverse reactions (flatulence). Meta-analysis showed no statistical differences in the portosystemic encephalopathy index after lactitol or lactulose treatment. The percentage of improved patients after lactitol or lactulose was similar. In contrast, the analysis revealed a higher frequency (p < 0.01) of flatulence in patients treated with lactulose compared with those treated with lactitol. Inconclusion, this meta-analysis shows no statistical difference between therapeutic effects of lactitol and lactulose, but it does show a higher frequency of flatulence with lactulose. This suggests that lactitol should be preferred to lactulose for the treatment of chronic hepatic encephalopathy. (Hepatology 1992;15:222-228).
Portal-vein obstruction in children leads to growth retardation
Authors: Sarin Shiv K. , Bansal Anupam , Sasan Shailja , Nigam Aruna
Published: March 2007

The portal vein is the main source of blood and hepatotrophic factors to the liver. Partial portal-vein ligation in rats results in reduced growth compared with that in control rats. To investigate whether extrahepatic portal vein obstruction occurring in early childhood influences growth in humans, anthropometric and nutritional assessments were prospectively carried out in 61 patients with extrahepatic portal vein obstruction. Comparisons were made with 183 matched healthy controls using National Center of Health Statistics reference. Fifty-one percent of children with extrahepatic portal vein obstruction had stunted growth (height for age <90% of normal), compared with 16% of controls (p < 0.01). Growth retardation was severe in patients with longer (>5 yr) than with shorter (<2.5 yr) duration of clinical portal hypertension (height for age, 88.0 ± 3.2 vs. 95.1 ± 3.0; p < 0.01). Little difference was seen in the energy intake (1,302 ± 463 kcal/day vs. 1,335 ± 449 kcal/day; p = not significant) and weight for height index (83.6 ± 9.3 vs. 88.0 ± 7.9; p = not significant) between extrahepatic portal vein obstruction patients and controls. This suggested that despite comparable nutrition, marked growth retardation occurred in extrahepatic portal vein obstruction patients. Incremental growth velocity was studied in 31 patients; in 24 (73%) the baseline Z score (-2.1 ± 0.2) had decreased further (-2.4 ± 0.2) at the end of follow-up (15.5 ± 1.6 mo). Although the incremental height velocity was only 56% of the expected height, incremental weight gain was 98% of the expected weight for the attained height. This indicates linear growth failure despite optimal nutrition. In conclusion, our results demonstrate that most children with extrahepatic portal vein obstruction have marked growth retardation and diminished growth velocity. The roles of hemodynamic and hormonal factors in modulation of growth in young extrahepatic portal vein obstruction patients must be studied. (Hepatology 1992;15:229-233).
Drug-induced prolonged cholestasis in adults: A histological semiquantitative study demonstrating progressive ductopenia
Authors: Degott Claude , Feldmann Gérard , Larrey Dominique , Durand-Schneider Anne-Marie , Grange Didier , Machayekhi Jean-Pierre , Moreau Alain , Potet François , Benhamou Jean-Pierre
Published: March 2007

Drug-induced acute hepatitis may be followed by prolonged cholestasis despite the withdrawal of the drug. Eight patients suffering from prolonged cholestasis caused by several drugs were investigated with sequential liver biopsies. At the early stage, lesions of acute cholangitis were observed in most patients; at the chronic phase, ductopenia, defined by the absence of interlobular bile ducts in at least 50% of small portal tracts, was demonstrated in all patients. Ductopenia might be the consequence of acute cholangitis; the degree of ductopenia and the chronicity of the disease might be directly related to the severity of the early acute damage of bile ducts. Consequently, in patients with severe cholestasis related to drugs, research of early morphological signs of acute cholangitis and then of ductopenia seems to be important.
High cardiac output of advanced liver disease persists after orthotopic liver transplantation
Authors: Henderson Michael J. , Mackay Gregory J. , Hooks Michael , Chezmar Judith L. , Galloway John R. , Dodson Thomas F. , Kutner Michael H.
Published: March 2007

This study measured cardiac output before and 1 or 2 yr after orthotopic liver transplantation in 23 patients. Cardiac output was measured by thermodilution before transplantation and by first-pass radionuclide angiocardiography at follow-up. Study patients were selected as those doing well clinically and by standard laboratory tests at 1-yr and 2-yr reevaluations with no evidence of rejection: six had mild recurrent hepatitis shown on biopsy samples. Hepatocyte function was normal at the time of the study as shown by galactose elimination capacity of 442 ± 90 mg/min. Medications were cyclosporine and prednisone in all patients, azathioprine in 10 patients and a combination of antihypertensive therapy to maintain diastolic blood pressure less than 90 mm Hg in 20 patients. Mean (± S.D.) pretransplantation cardiac output was 9.1 ± 3.1 L/min and remained elevated at 8.3 ± 2.1 L/min 1 yr, and 9.6 ± 2.6 L/min (n = 13) 2 yr after transplantation. A significant (p < 0.001) correlation was found between pretransplant and follow-up cardiac output. End diastolic, end systolic and stroke volumes are all increased in a pattern similar to that seen in end-stage cirrhosis. These data show that the high cardiac output of the hyperdynamic state of advanced liver disease persists after liver transplantation. The mechanisms and consequences of this require further study.
Human leukocyte antigen typing of siblings in hereditary hemochromatosis: A cost approach
Authors: Adams Paul C. , Kertesz Ann E.
Published: March 2007

To assess the clinical value of human leukocyte antigen typing in the diagnosis and management of hereditary hemochromatosis, 105 siblings of 35 proband cases of hemochromatosis were retrospectively analyzed to study whether the exclusion of human leukocyte antigen typing would have adversely affected management. All siblings and probands had already been tested for human leukocyte antigen-A and human leukocyte antigen-B typing, serum ferritin and transferrin saturation. The median age of siblings was 55 yr (range = 11 to 82). Siblings were categorized according to putative genotype (homozygote, heterozygote and normal) using human leukocyte antigen typing. Phenotypic expression of hemochromatosis was considered to be iron overload as indicated by an elevated ferritin (male = > 350 μ/L, female = > 200 μg/L) and/or transferrin saturation (>55%). Six of 37 homozygotes had a normal ferritin and transferrin saturation, with five of these patients under 32 yr old. No putative heterozygotes with both an abnormal ferritin and transferrin saturation were seen, although 12 of 48 (25%) heterozygotes had either an elevated ferritin or transferrin saturation. Twenty of 20 normal siblings had a normal ferritin and transferrin saturation. To assess the cost of screening with and without human leukocyte antigen typing, a cost model simulation was used that compared the costs of both methods in a hypothetical family (proband, homozygote, heterozygote and normal sibling). The use of human leukocyte antigen typing reduced the costs of unnecessary follow-up of normal and heterozygote siblings, but because of the high cost of human leukocyte antigen typing ($220) compared with ferritin and transferrin saturation ($90) screening of a sibship of four with serum ferritin, transferrin saturation and human leukocyte antigen typing was approximately 1.6 times as expensive as screening with ferritin and transferrin saturation. This study suggests that although HLA typing of siblings of patients with hemochromatosis is a useful test for the identification of affected siblings, screening of siblings with ferritin and transferrin saturation may be adequate in many families. (Hepatology 1992;15:263-268).
Effect of α-tocopherol on hepatic mixed function oxidases in hepatic ischemia/reperfusion
Authors: Lee Sun-Mee , Clemens Mark G.
Published: March 2007

This study was done to determine the relationship between microsomal lipid peroxidation during hepatic ischemia/reperfusion and alteration in cytochrome P-450-dependent drug metabolism. Rats were pretreated with α-tocopherol to inhibit lipid peroxidation or with vehicle (soybean oil) and then subjected to 60 min no-flow hepatic ischemia in vivo. Control animals were time-matched sham-ischemic animals. After 1, 5 or 24 hr of reperfusion, liver microsomes were isolated and cytochrome P-450 and mixed function oxidases were studied. In vehicle-treated ischemic rats, serum ALT levels peaked at 5 hr (5,242 ± 682 U/L) and were significantly reduced by α-tocopherol pretreatment (1,854 ± 229 U/L, p < 0.01). Similarly, microsomal lipid peroxidation was elevated in the vehicle-treated ischemic group, but this elevation was prevented by α-tocopherol pretreatment. Microsomal cytochrome P-450 content and aminopyrine-N-demethylase activity were both decreased in vehicle-treated ischemic rats to 60% and 70% of sham-ischemic control levels, respectively. Although α-tocopherol restored cytochrome P-450 content to the level of sham-ischemic control rats, aminopyrine-N-demethylase activity remained at 76% of control with α-tocopherol treatment (p < 0.01 compared with sham-ischemic control). In contrast to what was seen with cytochrome P-450 and aminopyrine-N-demethylase, aniline p-hydroxylase activity was elevated in the vehicle-treated ischemic rats compared with sham-ischemic control rats. These increases were prevented by α-tocopherol pretreatment. Our findings suggest that pretreatment with α-tocopherol reduces hepatocellular damage as indicated by abnormalities in microsomal drug-metabolizing function during ischemia/reperfusion and that this protection is, in major part, caused by decreased lipid peroxidation. (Hepatology 1992;15:276-281).
S -adenosylmethionine protects against acetaminophen hepatotoxicity in two mouse models
Authors: Bray Gary P. , Tredger Michael J. , Williams Roger
Published: March 2007

Because S-adenosylmethionine promotes synthesis of hepatic glutathione in chronic liver disease and is well tolerated in man, we investigated its use as an antidote to acetaminophen hepatotoxicity in two mouse models.

In C57B16 mice, deaths were abolished by S-adenosylmethionine given within 1 hr of 3.3 mmol/kg body wt acetaminophen (0 of 32 vs. 13 of 49, p < 0.005) and reduced if given 2 to 5 hours after acetaminophen administration (4 of 42 vs. 13 of 49, p < 0.01). Mixed disulfate/tosylate salt of S-adenosylmethionine abolished mortality in C3H mice given 2 mmol/kg body wt acetaminophen (0 of 24 vs. 4 of 18; p < 0.05). In both mouse models, S-adenosylmethionine reduced depletion of plasma (median = 20.8 μmol/L vs. 14.6 μmol/L) and liver glutathione (198% vs. 100%; p < 0.05), liver damage and release of AST after acetaminophen administration. Pretreatment with buthionine sulfoximine, which inhibits glutathione synthesis, abolished the beneficial effect of S-adenosylmethionine on survival and plasma glutathione level.

S-adenosylmethionine reduces acetaminophen hepatotoxicity by metabolism of the active moiety to glutathione. This benefit may last as long as 5 hr after acetaminophen ingestion. (Hepatology 1992;15:297-301).
Influence of albumin on the net sinusoidal efflux of the organic anion dibromosulfophthalein from rat liver
Authors: Nijssen Henricus M. J. , Pijning Tjaard , Meijer Dirk K. F. , Groothuis Geny M. M.
Published: March 2007

Besides being excreted into bile, several anionic drugs and anionic drug conjugates are excreted from liver into plasma by a carrier-mediated process (sinusoidal efflux). In the study presented here, we investigated the influence of albumin on the net sinusoidal efflux of an organic anion from isolated perfused liver, with net sinusoidal efflux defined as the resultant of efflux and reuptake. We tested the hypothesis that albumin exerts its effect on net sinusoidal efflux through inhibition of repeat uptake rather than on the sinusoidal efflux process itself. We also studied possible acinar heterogeneity in net sinusoidal efflux rate of the organic anion. Isolated rat livers were preloaded with the nonmetabolizable anionic model compound dibromosulfophthalein in the absence (type I) or presence (type II) of bovine serum albumin. Fluorescence microscopy of dibromosulfophthalein in liver sections showed selective zone 1 loading after type I loading and homogeneous acinar distribution after type II loading. The rate of net sinusoidal efflux and biliary excretion was then studied in single-pass perfusions with various concentrations of bovine serum albumin in the medium. Net sinusoidal efflux of dibromosulfophthalein showed a marked dependence on albumin concentration in both type I and type II experiments. Net efflux rate reached a maximal value at a medium concentration of 300 μmol/L bovine serum albumin and was not increased further at 600 μmol/L. The initial uptake rate of dibromosulfophthalein was not significantly different in the 300 μmol/L and 600 μmol/L bovine serum albumin experiments. We conclude that the net sinusoidal efflux rate of the organic anion from the hepatocyte as measured in perfusion outflow medium is the resultant of an albumin-independent sinusoidal efflux process combined with albumindependent inhibition of reuptake of this material. The relationship between unbound concentration of dibromosulfophthalein in perfusion outflow medium and initial net efflux rate is nonlinear, probably because nonequilibrium conditions exist in the sinusoid, and effluxed dibromosulfophthalein is recaptured by the cells before extracellular binding to albumin can occur. Because no difference was found between efflux in type I and type II perfusions, it was concluded that no acinar heterogeneity exists in transport of dibromosulfophthalein. Surprisingly, the rapid efflux from the cells induced by albumin had virtually no effect on the biliary excretion rate of dibromosulfophthalein. Therefore we conclude that the sinusoidal efflux process is operating from an intracellular pool different from that for biilary excretion.
An improved model of acetaminophen-induced fulminant hepatic failure in dogs
Authors: Kelly James H. , Koussayer Tarek , He Da-Er , Chong Maria G. , Shang Thomas A. , Whisennand Hartwell H. , Sussman Norman L.
Published: March 2007

We have established an improved model of fulminant hepatic failure in dogs. Buthionine sulfoximine is used to inactivate glutathione synthesis, and small increments of acetaminophen are given intravenously to maintain the plasma level at approximately 200 μg/ml for 20 hr. This regimen produces severe liver injury along with many of the features seen in humans with acetaminophen poisoning. The first sign of impending liver failure is hypoglycemia. This occurs about 15 hr into the experiment and requires treatment with a continuous infusion of glucose. Between 15 and 20 hr, serum ALT activity begins to rise, indicating the onset of liver necrosis. Over the following 15 to 20 hr ALT activity continues to rise and is accompanied by an increase in bilirubin, a prolongation of the prothrombin time and the development of fetor hepaticus. Thirty to 48 hr after the initial acetaminophen dose, the animals begin to exhibit symptoms of encephalopathy and progress from lethargy to the inability to maintain posture and then coma, seizures and death. Liver biopsy specimens obtained at several stages throughout the study showed progressive necrosis, ultimately resulting in the complete destruction of zones 2 and 3. (Hepatology 1992;15329-335).
Ito cell expression of a nuclear retinoic acid receptor
Authors: Weiner Francis R. , Blaner William S. , Czaja Mark J. , Shah Anish , Geerts Albert
Published: March 2007

Although it has been suggested that retinoids regulate Ito cell proliferation and collagen synthesis, little is known about the ability of Ito cells to respond to retinoids in vivo. Because retinoids may mediate their molecular effects through nuclear receptors, Ito cells were examined for the presence of one of these receptors, nuclear retinoic acid receptor-β. The modulation of nuclear retinoic acid receptor-β expression was also studied during cell culture and hepatic fibrogenesis. Northern hybridization analysis revealed that Ito cells freshly isolated from normal rat liver contained nuclear retinoic acid receptor-β messenger RNA at levels significantly higher than those found in other hepatic cell types. Ito cells also contained messenger RNA for two other nuclear retinoic acid receptors, nuclear retinoic acid receptor-α and nuclear retinoic acid receptor-γ. Using an antibody to human nuclear retinoic acid receptor-β, the nuclear presence of this receptor was demonstrated in normal Ito cells. In contrast, Ito cells cultured for at least 7 days had no detectable messenger RNA or nuclear staining for nuclear retinoic acid receptor-β despite a 20 ± 5-fold increase in the messenger RNA level of another retinoid binding protein, cellular retinol binding protein. Analysis of Ito cells isolated from rats with carbon tetrachloride—induced hepatic fibrosis revealed an 81% ± 3% decrease in nuclear retinoic acid receptor-β messenger RNA levels in these cells when compared with normal Ito cells. No difference in the messenger RNA levels of cellular retinol binding protein was found in Ito cells isolated from either normal or fibrotic liver. The effect of retinoid treatment on Ito cell nuclear retinoic acid receptor-β messenger RNA level was also studied because retinoic acid treatment of other cells has been shown to induce nuclear retinoic acid receptor-β gene expression. Treatment for 48 hr with either 10−6 mol/L retinoic acid or 10−5 mol/L retinyl acetate induced the expression of nuclear retinoic acid receptor-β messenger RNA in primary cultured Ito cells. These data demonstrate that Ito cells possess a nuclear retinoic acid receptor allowing them to respond to retinoic acid in vivo. Increased Ito cell proliferation and collagen synthesis during cell culture or hepatic fibrosis may result in part from decreased Ito cell retinoid responsiveness as reflected by the loss or decrease in nuclear retinoic acid receptor-β gene expression observed under these two conditions. Furthermore, the ability of retinoids to induce Ito cell nuclear retinoic acid receptor-β messenger RNA expression suggests that Ito cell retinoid unresponsiveness during cell culture and hepatic fibrogenesis is reversible. (Hepatology) 1992;15:336-342.