bluuebunny/crossref_metadata_2025 huggingface dataset:
Adoptive transfer of immunity to hepatitis B virus in mice by bone marrow transplantation from immune donors
Authors: Shouval Daniel , Adler Ruth , Ilan Yaron
Published: March 2007

Recipients of allogeneic bone marrow transplantation are immunosuppressed as a result of their primary disease and by myeloablative therapy. Such patients are dependent on multiple blood products and are at risk for hepatitis B virus infection. Active immunization against hepatitis B in the immediate pre- and post-transplant periods is ineffective, pre- sumably because of decreased T cell-dependent B-cell responses. This study was designed to evaluate, in a mouse model system, the transfer of immunity against hepatitis B to bone marrow transplant recipients through immunization of bone marrow donors against hepatitis B before transplantation. Bone marrow donor BALB/c mice were immunized with a recombinant hepatitis B vaccine. Seroconversion to HBs antibody occurred within 4 wk of primary immunization, and antibody levels in treated donor mice rose above 300 mIU/ml after a single booster injection. Bone marrow recipient mice, conditioned by sublethal irradiation, were injected intravenously with bone marrow cells obtained from syngeneic HBs antibody-positive immune donors. Antibody was detected in 10% of bone marrow recipients within 30 days of transplantation and in 56% 1 mo after a booster injection that led to a secondary rise in HBs antibody. Adoptive transfer of immunity to hepatitis B also occurred after transplantation of T cell-depleted bone marrow cells from hepatitis B-immune donors, albeit at a lower HBs antibody level. These results indicate that immunity to hepatitis B can be transferred in mice by bone marrow transplantation from hepatitis B-immune donors to immunosuppressed recipients. Furthermore, such bone marrow transplant recipients were able to respond to a booster immunization, suggesting secondary immune response in bone marrow recipients after primary response in donors. These data support the rationale for active vaccination of potential human bone marrow donors against hepatitis B, followed by booster vaccination to bone marrow recipients. (Hepatology 1993;17:955-959.)
Risk of hepatitis C virus infections through household contact with chronic carriers: Analysis of nucleotide sequences
Authors: Honda Masao , Kaneko Shuichi , Unoura Masashi , Kobayashi Kenichi , Murakami Seishi
Published: March 2007

We evaluated the risk of hepatitis C virus transmission through household contact with chronic carriers using nucleotide sequence analysis. Chronic hepatitis C patients (76 patients) were divided into two groups: familial transmission of hepatitis C virus was studied in group A (53 patients); group B (23 patients) served as nonfamilial controls for group A. Of 88 family members of group A patients, 18 (20%) had elevated serum ALT levels, 20 (23%) had antibodies against hepatitis C virus and 16 (18%) had hepatitis C virus RNA in serum. Nucleotide sequences of the region of the hepatitis C virus genome spanning the core and envelope genes were compared among the three groups. In group B, the average nucleotide sequence homology was 91.0% ± 2.29% (a pairwise comparison was made for each of the patients; n = 253). Isolates from two family members were significantly more homologous to isolates from corresponding patients in group A than to isolates from group B patients. Of the two isolates from family members, one was from a child whose mother was a patient (97.7% homology) and one was from a spouse (98.1% homology). These results strongly suggest familial transmission of the same hepatitis C virus strain. Further studies are necessary to elucidate the route of intrafamilial transmission. (Hepatology 1993;17:971-976.)
Differential depletion of carotenoids and tocopherol in liver disease
Authors: Leo Maria A. , Rosman Alan S. , Lieber Charles S.
Published: March 2007

Carotenoids and tocopherols are major natural protective agents against free radical-mediated liver damage, but their levels in diseased liver are largely uncharted. Therefore we carried out measurements with high-pressure liquid chromatography of α- and β-carotene, lycopene, cryptoxanthin, lutein and zeaxanthin, total retinoids and α- and γ-tocopherol. Liver tissue was obtained from percutaneous needle biopsies, livers of transplant recipients or a donor bank. Compared with controls (transplant donors; n = 13), levels of all carotenoids and retinoids were extremely low at all stages of liver disease. Patients with alcoholic cirrhosis (n = 11) had 20- and 25-fold decreases of levels of lycopene (p <0.001) and α- and β-carotene (p <0.005), respectively. Even in subjects with less severe alcoholic liver disease (steatosis, perivenular fibrosis, portal fibrosis; n = 14) and in patients with nonalcoholic liver disease (n = 13), levels were four to six times lower than those in normal subjects. By contrast, levels of α-tocopherol were decreased significantly only in patients with cirrhosis, who displayed a threefold reduction. In the serum of most patients, lycopene and tocopherol concentrations were not depressed, whereas one third of α- and β-carotene levels were low, probably reflecting poor dietary intake. A significant correlation was observed between serum and liver α- and β-carotene levels (p <0.0001; r = 0.715). However, of the patients with extremely low liver α- and β-carotene concentrations, more than half had blood levels in the normal range, suggesting that liver disease interferes with the uptake, excretion or, perhaps, metabolism of α- and β-carotene. In the cirrhotic livers of eight candidates for liver transplantation, the ratios of α- and β-carotene to total retinoids and of β-carotene to retinoids were much higher than those in normal livers, suggesting some impairment in the conversion of α- and β-carotene to retinoids. In most cases, even with high ratios, absolute levels of heptic α- and β-carotene and retionids were severely depressed. We concluded that, even in the presence of normal serum levels α- and β-carotene, tocopherol and lycopene, patients with cirrhosis have extremely low hepatic levels. (Hepatology 1993;17:977-986.)
Magnetic resonance imaging and different levels of Iron overload in chronic liver disease
Authors: Rocchi Emilio , Cassanelli Marco , Borghi Athos , Paolillo Franco , Pradelli Marcello , Casalgrandi Giovanna , Burani Aldo , Gallo Ennio
Published: March 2007

The need for accurate and noninvasive evaluation of liver iron stores prompted us to evaluate the reliability of high-field magnetic resonance imaging equipment in liver patients with low or moderate siderosis, given the poor results obtained using systems operating at low field strength in such cases. Twenty patients with sporadic porphyria cutanea tarda and 28 with comparable chronic liver diseases (chronic hepatitis or cirrhosis) and moderate siderosis were compared with 10 patients with idiopathic or secondary hemochromatosis and 10 healthy controls. Plasma iron profile, ferritin concentration and liver iron concentration, determined with atomic absorption spectroscopy, were matched with the magnetic resonance parameters - namely, transverse relaxation time and the signal intensity for a given proton amount, obtained with equipment operating at a field strength of 1.5 T. Hemochromatosis patients with mean liver iron concentrations of 550 μmol/gm dry wt (vs. 10 μmol of controls) exhibited an impressive reduction in the signal intensity with respect to the other three groups, and this reduction prevented any further comparison with the same porphyria cutanea tarda and chronic liver disease groups, whose liver iron level was twice that of the controls. The signal intensity remained almost unchanged in the latter groups, whereas the transverse relaxation time was significantly reduced. Moreover, correlation with liver iron was significantly inverse in the case of the transverse relaxation time (n = 17, r = 0.62, p = 0.008) and direct in the case of the transverse relaxation rate. The transverse relaxation time values returned to normal in five patients who had completed an iron-depletion program. No significant relationships between porphyrinuria (in porphyria cutanea tarda patients) or associated histological lesions (steatosis or inflammation) and the signal intensity or the transverse relaxation time were observed. We conclude that a magnetic resonance imaging system operating at higher field strength (with respect to previous studies) represents a useful, non-invasive diagnostic tool for the evaluation of even modest liver iron overload. Under these conditions, the decrease in the transverse relaxation time is proportional to the decrease in iron. Hemochromatosis cannot be investigated under the same conditions. (Hepatology 1993; 17:997-1002.)
Diagnosis and follow-up of small hepatocellular carcinoma with selective intraarterial digital subtraction angiography
Authors: Ikeda Kenji , Saitoh Satoshi , Koida Isao , Tsubota Akihito , Arase Yasuji , Chayama Kazuaki , Kumada Hiromitsu
Published: March 2007

To clarify the angiographic features of small hepatocellular carcinoma, we performed digital subtraction angiography in 91 patients with hepatocellular carcinomas of 2 cm or less. Repeated digital subtraction angiography studies were performed in 25 patients whose first angiograms showed no tumor staining. Digital subtraction angiography showed hypervascular tumor staining in only 51 patients (56.0%). We found that the smaller a tumor nodule was, the lower the detection rate of tumor stain on digital subtraction angiography. The detection rate of hypervascularity was closely correlated with the grading of histological differentiation of the tumors: well-differentiated hepatocellular carcinomas more often showed negative tumor staining. Repeated digital subtraction angiography studies showed alteration of tumor staining from isovascular to hypervascular in 6 of 6 patients with tumors that became larger than 2 cm and in 12 of 19 patients with tumors that remained 2 cm or smaller. Conversion of vascularity is commonly found in the early stage of small hepatocellular carcinoma, and the process is usually slow, taking approximately 1 yr. (Hepatology 1993;17:1003-1007.)
Influence of human leukocyte antigen matching on liver allograft survival and rejection: “The dualistic effect”
Authors: Donaldson Peter , Underhill James , Doherty Derek , Hayllar Karen , Calne Roy , Tan Kai-Chah , O'Grady John , Wight Derek , Portmann Bernard , Williams Roger
Published: March 2007

To date only one published large series of human leukocyte antigen matching and liver allograft survival exists, and considerable confusion has arisen about the advantage or disadvantage of human leukocyte antigen matching. In the present study we have reinvestigated the relationship between human leukocyte antigen mismatch and graft survival in 466 first liver allografts, seeking to clarify the relationship between human leukocyte antigen and both acute rejection and the vanishing bile duct syndrome. In view of current criticism regarding the accuracy of serological tissue typing for human leukocyte antigen-DR, we have used both classic serology and restriction fragment length polymorphism analysis to ensure the accurate assignment of recipient DR types. In addition, we have used polymerase chain reaction amplification and allele-specific and sequence-specific oligonucleotide probes to retest the hypothesis that human leukocyte antigen class II matching may increase susceptibility to the vanishing bile duct syndrome. One-year graft survival was significantly lower in patients with zero or two human leukocyte antigen-A mismatches (52% and 63%, respectively) than in those with one human leukocyte antigen-A mismatch (69%) (p = 0.016 and p = 0.018). A similar effect of B mismatching was observed, with a 1-yr graft survival of 73% for those with one compared with 60% for those with two human leukocyte antigen-B mismatches. In contrast no correlation was found between DR mismatch and graft survival. Human leukocyte antigen class I matching appears to influence graft survival largely through the occurrence of acute rejection and the development of the vanishing bile duct syndrome. In those patients who underwent liver biopsies, 49% (28 of 57) without acute rejection had a single B mismatch compared with 32% (88 of 263) with acute rejection (x2 = 5.5, p < 0.025). In addition, a complete human leukocyte antigen-A mismatch was more common in those who developed the vanishing bile duct syndrome than in those with normal graft function (54% vs. 38%; X2 = 4.26, p < 0.05). In contrast to previous reports from this unit, no relationship between human leukocyte antigen-DR or -DQ mismatch and the vanishing bile duct syndrome could be detected. These findings indicate that human leukocyte antigen class I compatibility exerts a dual effect on the survival of primary liver allografts. Although some human leukocyte antigen-A and -B matching may be desirable for liver transplantation, full class I matching may have an adverse effect. (Hepatology 1993;17:1008-1015.)
Distribution of body water in patients with cirrhosis: The effect of liver transplantation
Authors: Crawford Darrell H. G. , Halliday June W. , Cooksley W. G. E. , Murphy Therese L. , Golding Suzanne D. , Wallace Jennifer D. , Cuneo Ross C. , Lynch Steven V. , Strong Russell J. , Powell Lawrie W.
Published: March 2007

We compared total body water and intracellularextracellular distribution of body water between male patients with mild liver disease without ascites (n = 9), male patients with severe liver disease and gross ascites (n = 6) and a group of age-, sex-, height- and weight- matched controls (n = 6). In addition, we documented the effects of liver transplantation on intracellular, extracellular and total body water in 12 patients (6 men and 6 women) by means of deuterium oxide dilution and whole-body potassium counting. We saw no significant difference in total body water between the healthy controls, patients without ascites and patients with ascites (46.5 ± 9.2 kg, 45.4 ± 6.6 kg and 50.4 ± 5.1 kg, respectively), although, as expected, extracellular water was increased in patients with ascites compared with healthy controls and cirrhotic patients without ascites (36.9 ± 6.5 kg vs. 25.4 ± 4.4 kg, p = 0.005; and 36.9 ± 6.5 kg vs. 27.0 ± 5.3 kg, p = 0.002, respectively). We found no difference between nonascitic patients and healthy controls (25.4 ± 4.4 kg vs. 27.0 ± 5.3 kg). However, intracellular water was significantly reduced in patients with severe liver disease compared with that in controls (13.6 ± 3.3 kg vs. 21.5 ± 4.2 kg, p = 0.005) or patients without ascites (13.6 ± 3.3 kg vs. 18.3 ± 2.9 kg, p = 0.01). The reduction of intracellular water appears to be due to loss of body cell mass. The mean body weight of the group of patients who were studied before and 3 mo after liver transplantation did not change (69.0 ± 10.2 kg vs. 69.0 ± 11.1 kg), but we noted significant decreases in mean total body water and mean extracellular water (43.5 ± 9.0 kg vs. 40.5 ± 7.6 kg, p = 0.02; and 27.8 ± 5.6 kg vs. 24.5 ± 4.8 kg, p = 0.02, respectively). This loss of water appeared to be compensated for by increases in body fat rather than body cell mass; the 3-mo posttransplant total body potassium value was not significantly different from the pretransplant value (98.1 ± 28.5 gm vs. 99.9 ± 19.0 gm). This study confirmed that abnormalities in water compartments occur in decompensated cirrhosis. However, in contrast to a previous report, we saw no significant increase in extracellular water in patients without obvious fluid retention. Furthermore, changes in water compartments occur soon after liver transplantation (loss of total body water and extracellular water), despite body weight maintenance. The constance of body weight in the early stages after liver transplantation is predominantly due to an increase in body fat stores rather than to an increase in body cell mass. (Hepatology 1993;17:1016-1021.)
Effect of ursodeoxycholic acid on the kinetics of cholic acid and chenodeoxycholic acid in patients with primary sclerosing cholangitis
Authors: Rudolph Gerda , Endele Richard , Senn Martin , Stiehl Adolf
Published: March 2007

Treatment of patients with cholestatic liver diseases with ursodeoxycholic acid has been shown to have beneficial effects that may be related to a shift in the balance between hydrophilic and hydrophobic bile acids in favor of hydrophilic bile acids. During treatment of patients with primary sclerosing cholangitis with ursodeoxycholic acid, plasma concentrations of some endogenous bile acids decrease. To test whether the changes in plasma bile acids are due to decreases of their pool sizes or synthesis rates, we determined bile acid kinetics of cholic and chenodeoxycholic acid in six patients with primary sclerosing cholangitis, of whom four also had ulcerative colitis. All patients were studied before and 3 mo after the start of ursodeoxycholic acid treatment. Six healthy subjects served as controls. In patients with primary sclerosing cholangitis, pool sizes of cholic and chenodeoxycholic acid were considerably smaller than those in healthy controls; after ursodeoxycholic acid treatment they were unchanged. Fractional turnover and synthesis of cholic acid increased significantly after ursodeoxycholic acid administration. Fractional turnover of chenodeoxycholic acid also increased significantly, whereas synthesis of this bile acid was unchanged. Our data indicate that in patients with primary sclerosing cholangitis, pool sizes of bile acids are reduced. The decrease of levels of endogenous bile acids in plasma under ursodeoxycholic acid treatment despite unchanged bile acid pool sizes indicates redistribution of the bile acids into the enterohepatic circulation, probably because of improved hepatic clearance after ursodeoxycholic acid treatment. (Hepatology 1993;17:1028-1032.)
Evaluation of structural change in diffuse liver disease with frequency domain analysis of ultrasound
Authors: Suzuki Kunio , Hayashi Norio , Sasaki Yutaka , Kono Michikazu , Kasahara Akinori , Imai Yutaka , Fusamoto Hideyuki , Kamada Takenobu
Published: March 2007

To evaluate structural changes in diffuse liver disease, frequency domain analysis was applied to ultrasonic signals from the liver. We assumed that liver tissue is a collection of semiregularly arrayed small scatterers of ultrasound. We applied cepstral analysis to the ultrasonic waveforms and evaluated the periodicity of scalloping of the power spectrum caused by an interference effect among liver scatterers of a given spacing. Patients with liver conditions involving nonspecific change (n = 6), chronic hepatitis (n = 11), cirrhosis (n = 7) or fatty liver (n = 6) were examined. One hundred ultrasonic signals were obtained noninvasively with a 3.5-MHz transducer, and the space among scatterers was calculated for each signal using cepstrum analysis. Two statistical parameters, mode and kurtosis, were determined from the distribution of the space among scatterers for each patient; these parameters were compared with the histological findings in the liver. Space among scatterers kurtosis decreased with progress of liver fibrosis, and space among scatterers mode increased in cirrhosis. Neither space among scatterers kurtosis nor space among scatterers mode was affected by pathological fat in the liver. These results suggest that we can evaluate fibrotic changes in diffuse liver disease and that we can also noninvasively discriminate diffuse fibrotic liver disease from fatty liver. (Hepatology 1993;17:1041-1046.)
Hepatocyte growth factor induces proliferation and morphogenesis in nonparenchymal epithelial liver cells
Authors: Johnson Mark , Koukoulis George , Matsumoto Kunio , Nakamura Toshikazu , Iyer Anand
Published: March 2007

Hepatocyte growth factor is the most potent mitogen known for hepatocytes, and increasing evidence suggests that hepatocyte growth factor plays an important role in liver regeneration. However, hepatocytes are not the only liver epithelial cell population that proliferates during regeneration. Experimental and clinical data indicate that the regenerative liver response also includes the participation of nonparenchymal epithelial cells. The possible role of hepatocyte growth factor in this nonparenchymal epithelial cell regenerative response has not been explored. We studied the effects of hepatocyte growth factor with a model of two normal mouse nonparenchymal epithelial cell-derived cell lines with varying differentiation potentials. Addition of hepatocyte growth factor induced mitogenesis and scattering of colonies growing on culture dishes in both cell lines. Furthermore, hepatocyte growth factor was found to exert a profound morphogenic effect on cells growing in collagen matrixes. Hepatocyte growth factor-treated embryonic BNL CL.2 cell colonies developed elaborately branching elongated cords with only minimal tubularization. Hepatocyte growth factor-treated postnatal NMuLi cell colonies developed a network of anastomosing tubules with wide lumens. These morphological changes were not inhibitable by transforming growth factor-β and were not induced by other hepatocellular growth factors including epidermal growth factor, transforming growth factor-α, acidic fibroblast growth factor and insulin. Histological sections of the hepatocyte growth factor-treated BNL CL.2 cell colonies resembled neocholangioles, believed to include facultative stem cells, which proliferate after submassive and massive hepatic necrosis. Sections of hepatocyte growth factor-treated NMuLi colonies resembled ductules proliferating in biliary tract obstruction from a wide variety of causes. This work represents the first examples of hepatocyte growth factor-induced mitogenesis, scattering and morphogenesis in the same cell lines. More important, our data suggest that hepatocyte growth factor mediates liver response to injury not only by acting on hepatocytes but also by exerting mitogenic and morphogenic influences on nonparenchymal epithelial cell components. (Hepatology 1993;17:1052-1061.)
Long-term ethanol consumption alters the hepatic response to the regenerative effects of tumor necrosis factor-α
Authors: Akerman Paul A. , Cote Piera M. , Yang Shi Qi , McClain Craig , Nelson Steve , Bagby Gregory , Diehl Anna Mae
Published: March 2007

The pathogenesis of chronic alcoholic liver disease is uncertain, but it may reflect an impaired wound healing response to ethanol-induced liver injury. Cellto-cell communication such as that mediated by the cytokine tumor necrosis factor is necessary for successful liver regeneration and complete recovery from liver injury. Hence disruption of intercellular regenerative signaling may contribute to the pathogenesis of chronic alcoholic liver disease. To test this hypothesis, the cytokine and regenerative responses triggered by partial hepatectomy were compared in ethanol-fed rats and isocalorically maintained, pair-fed controls. To further clarify the effect of ethanol on tumor necrosis factor-modulated regenerative effects, we evaluated some of the rats in each feeding group after pretreatment with antibodies to tumor necrosis factor. As expected, ethanol inhibited DNA synthesis and liver cell proliferation after partial hepatectomy. Ethanolassociated inhibition of liver regeneration occurred despite apparently similar serum concentrations of the tumor necrosis factor-inducible cytokine interleukin-6. Treatment with antibodies to tumor necrosis factor 1 hr before partial hepatectomy inhibited post-partial hepatectomy induction of interleukin-6 and liver regeneration in ethanol-fed and pair-fed rats. However, serum interleukin-6 was reduced more in ethanol-fed rats than in control rats (93% vs. 66%; p < 0.05). Antibodies to tumor necrosis factor also inhibited hepatic DNA synthesis more in ethanol-fed rats than in controls (85% vs. 50%; p < 0.05). In ethanol-fed rats, the increased effect of tumor necrosis factor antibody on post-partial hepatectomy DNA synthesis suggests heightened sensitivity of hepatocytes to tumor necrosis factor. Tumor necrosis factor antibody decreased hepatocyte proliferation more (93%) in ethanol-fed rats than in controls (62%) (p < 0.05). In contrast, proliferation of liver nonparenchymal cells was less inhibited in ethanol-fed rats(11%) than in controls (66%) (p <0.05). These data indicate that long-term ethanol feeding alters cell responsiveness to tumor necrosis factor during liver regeneration. Such ethanol-induced alterations in cell response to cytokines may disrupt intercellular communications and impede normal liver regeneration. (Hepatology 1993;17:1066-1073).
Mechanism of biliary lipid secretion in the rat: A role for bile acid-independent bile flow?
Authors: Verkade Henkjan J. , Wolters Henk , Gerding Albert , Havinga Rick , Fidler Vaclav , Vonk Roel J. , Kuipers Folkert
Published: March 2007

Bile acid-induced lipid secretion was compared in unanesthetized normal control and Groningen Yellow Wistar rats during variations in endogenous bile acid output. Groningen Yellow rats express a genetic defect in the biliary secretion of various organic anions. During a 5-hr period after interruption of the enterohepatic circulation, bile acid secretion decreased from 36.4 ± 1.8 to 1.9 ± 0.3 μmol per 30 min in normal control rats and from 37.1 ± 2.8 to 1.8 ± 0.2 μmol per 30 min in Groningen Yellow rats, respectively (mean ± S.E.M., n = 5). The relationship between bile acid secretion and bile flow showed similar slopes (normal control, 8.74 ± 0.44 μl/μmol and Groningen Yellow rats, 7.71 ± 0.42 μ1/μmol) but different y-intercepts (normal control, 243 ± 8 and Groningen Yellow, 127 ± 4 μ1 per 30 min; p < 0.001), corresponding to a 47% reduction of the bile acid-independent fraction of bile flow in Groningen Yellow rats. During the course of the experiment, the ratio of lipids (phospholipids plus cholesterol) to bile acids increased in both strains more than threefold but was permanently higher in Groningen Yellow than in normal control rats (p = 0.035), implying that Groningen Yellow rats continuously secreted more lipid per bile acid. No differences in bile acid pool composition or in bile canalicular membrane composition and fluidity between the two strains were detected. The results indicate that apart from previously demonstrated factors (bile acid concentration, bile acid composition and hydrophilic organic anion concentration in bile), another parameter affects the efficacy of bile acids to induce biliary lipid secretion. We hypothesize that the magnitude of bile acid-independent flow is a coregulating factor by influencing the exposure time of the canalicular membrane to intracanalicular bile acids. (Hepatology 1993;17:1074-1080.)
Bacterial translocation in acute and chronic portal hypertension
Authors: Garcia-Tsao Guadalupe , Albillos Agustin , Barden G. E. , West Brian A.
Published: March 2007

Patients with cirrhosis are predisposed to develop spontaneous bacteremias and peritonitis, mainly by enteric bacteria. Portal hypertension, by producing congestion and edema of the bowel wall, could increase the passage of bacteria from the intestinal lumen to regional lymph nodes to the systemic circulation or to both, a process termed bacterial translocation. The aim of this study was to investigate bacterial translocation at two stages of experimental portal hypertension: (a) acute (when shunting is minimal); and (b) chronic (when shunting is extensive and mimics the portal hypertension of cirrhosis). Rats were killed 2 days (acute) or 15 days (chronic) after partial portal vein ligation or control surgeries. Samples of mesenteric lymph nodes, blood, liver and spleen for standard bacteriological cultures and a fragment of ileum for histological examination were obtained. Two days after surgery, a significantly greater proportion of rats with acute portal hypertension (12 of 13 or 92%) had positive mesenteric lymph node cultures compared with both control groups: sham-operated (4 of 13 or 31%) and inferior vena cava-ligated (3 of 10 or 33%) animals (p < 0.01). However, 15 days after surgery no differences in translocation to mesenteric lymph nodes were found between rats with chronic portal hypertension (3 of 15 or 20%) and sham-operated controls (3 of 11 or 27%). In neither the acute nor the chronic rats were bacteria isolated from blood, spleen or liver. Rats with acute portal hypertension had significantly greater mesenteric inflammation than rats with chronic portal hypertension and control animals. Results suggest that portal hypertension alone may not be a major factor in the development of spontaneous infections in cirrhosis and that other mechanisms, such as a defective immune system, may be more important. (Hepatology 1993;17:1081-1085.)
Bile acid synthesis from newly synthesized vs. preformed cholesterol precursor pools in the rat
Authors: Scheibner Jürgen , Fuchs Michael , Schiemann Michael , Tauber Gisela , Hörmann Erwin , Stange Eduard F.
Published: March 2007

The present study defines the origin of cholesterol subserving bile acid synthesis in male rats with an extracorporal bile duct by labeling newly formed cholesterol with tritiated water. Within 6 hr after interruption of the enterohepatic circulation, the bile acid pool was depleted. At this early time point the proportion from de novo cholesterol was 8% and 12% for biliary cholesterol and cholate, but 18% and 19% for muricholate and chenodeoxycholate, respectively. This proportion gradually rose to 40%, 34%, 51% and 51%, respectively, at 15 to 30 hr. At 78 hr after bile diversion, 64% of cholate was labeled, compared with 84% to 88% of the other biliary lipids and 71% of plasma cholesterol. Total and labeled bile acid secretion exhibited the same diurnal rhythm. To allow differentiation between direct hepatocytic de novo synthesis of bile acids from acetate and recycling of labeled plasma cholesterol, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (pravastatin) was infused from 54 to 78 hr. It suppressed total synthesis of primary bile acids by 60% to 80% but decreased the tritium label of bile acids only from a range of 74% to 92% (54 hr) to a range of 54% to 63% (78 hr), which was in the range of plasma cholesterol (58%). We conclude that bile acids and biliary cholesterol are synthesized mostly from preformed (i.e., plasma) cholesterol, both immediately after depletion of the pool in enterohepatic circulation and after derepression. Moreover, the hepatic cholesterol pools subserving the synthesis of different bile acids and biliary cholesterol secretion are not identical. (Hepatology 1993;17:1095-1102.)
Differences in the steady-state levels of c- fos , c- jun and c- myc messenger RNA during mitogen-induced liver growth and compensatory regeneration
Authors: Coni Pierpaolo , Simbula Gabriella , de Prati Alessandra Carcereri , Menegazzi Marta , Suzuki Hisanori , Sarma Dittakavi S. R. , Ledda-Columbano Giovanna M. , Columbano Amedeo
Published: March 2007

The steady-state levels of c-fos, c-jun and c-myc messenger RNA were investigated in rat liver tissue after proliferative stimuli of different nature-namely, compensatory regeneration induced by partial hepatectomy or carbon tetrachloride administration - and direct hyperplasia induced by four different hepatomitogens: lead nitrate, ethylene dibromide, cyproterone acetate and nafenopin. We show here that whereas c-fos and c-jun expression increased soon after partial hepatectomy or carbon tetrachloride administration, an increased expression of c-jun in the absence of c-fos expression occurred during direct hyperplasia induced by lead nitrate and ethylene dibromide. When hyperplasia was induced by cyproterone acetate and nafenopin, the mitogenic response of the liver was not associated with an increased expression of c-jun or c-fos, despite the fact that the timing of the cell cycle was similar to that observed after partial hepatectomy. Finally, when c-myc expression was analyzed, it was found that proliferative conditions associated with an increased expression of this gene were characterized by an increased expression of c-jun. On the contrary, the hyperplasia induced by cyproterone acetate and nafenopin, which is characterized by a lack of increase in the expression of c-fos and c-jun, was also not associated with an increased c-myc expression. Similar results were obtained in these experiments with the mitogen nafenopin, a peroxisome proliferator. In fact, liver hyperplasia induced by this compound was not preceded or accompanied by an increased expression of c-fos and c-myc. This study suggests that depending on the nature of the proliferative stimulus, an increased expression of c-fos, c-jun and c-myc may not be necessary for in vivo induction of liver cell proliferation. (Hepatology 1993;17:1109-1116.)
Reduction of cerebral perfusion precedes rise of intracranial pressure in rats with ischemic fulminant liver failure
Authors: Shah Vijay , Webster Steve , Gottstein Jeanne , Blei Andres T.
Published: March 2007

In fulminant liver failure, brain edema may progress to intracranial hypertension. However, the rise in intracranial pressure is a late event in this sequence. We investigated the relationship between cerebral perfusion and development of intracranial hypertension in a well-characterized model of fulminant liver failure, the rat subjected to hepatic devascularization (n = 11). In addition, we examined the effects of hyperglycemia on the development of brain edema because high blood glucose level can exacerbate other forms of brain edema, as seen in stroke. Intracranial pressure was continuously monitored with a cisterna magna catheter; relative changes in blood flow were continuously assessed with a Doppler flow probe on the internal carotid artery. Cerebral perfusion decreased by 62%, with the greatest reduction before the onset of increased intracranial pressure. Intracranial pressure did not change until 2 hr before death, at which time it increased exponentially. Brain water in fulminant liver failure rats was significantly increased compared with that in controls. Hyperglycemia (200 to 220 mg/dI) had no effect on time elapsed until loss of corneal reflex, percentage of brain water, maximal intracranial pressure or pattern of change in cerebral perfusion compared with euglycemia (80 to 100 mg/dI). Sham-operated animals showed no changes in measured parameters. We conclude that a linear reduction in cerebral perfusion precedes the rise of intracranial pressure in this model, a decrease that may reflect changes in brain metabolic activity at the time that brain edema develops. Carotid blood flow monitoring may be a useful noninvasive tool for the detection of cerebral events in fulminant liver failure. (Hepatology 1993;17:1117-1121.)
Incidence of adverse reactions to cyclosporine after liver transplantation is predicted by the first blood level
Authors: Azoulay Daniel , Lemoine Antoinette , Dennison Ashley , Gries Jean Michel , Dolizy Isabelle , Castaing Denis , Beaune Philippe , Bismuth Henri
Published: March 2007

Despite the availability of whole-blood cyclosporine assays, the different responses of individual patients to its administration after transplantation continue to pose clinical problems, particularly with respect to toxicity. Fifty-seven recipients of first orthotopic liver transplants were studied between January 1992 and July 1992. Initial immunosuppression was carried out with azathioprine, methylprednisolone and cyclosporine, at a dose of 1 mg/kg/day adjusted to achieve blood levels between 400 and 600 ng/ml. Cyclosporine levels were measured 12 hr after the start of intravenous administration and correlated with the occurrence of toxic complications. Twelve patients experienced toxic complications in the first 7 days after orthotopic liver transplantation. These were neurological in six patients (of whom four also had kidney failure) and renal complications in the other six patients. All complications were reversed by reducing or stopping administration of cyclosporine. We noted excellent correlation between the occurrence of complications and cyclosporine whole-blood levels (p < 0.0001) despite the fact that levels did not exceed the therapeutic range. However, no correlation was observed between toxicity and cumulative dosage. In this study we were able to demonstrate that a standardized dose of cyclosporine does not prevent the occurrence of toxic side effects even when cyclosporine whole-blood levels are subsequently maintained in the therapeutic range. This highlights the importance of the first dose of cyclosporine and consequent early postoperative blood levels and indicates that these problems are unlikely to be overcome until a method of predicting individual requirements can be established in clinical practice. (Hepatology 1993;18:1123-1126.)
Probable visualization of the elusive hepatitis C virus
Authors: Alter Harvey J. , Shih James W.-K.
Published: March 2007

Hepatitis C virus (HCV) has not yet been cultured or visualized. We attempted to recover HCV-associated particles from plasma of infected humans to assess the natural properties of the virus. Starting with 720 ml of donor plasma containing high titer of HCV core antigen ELISA activities, we identified HCV core antigen activity and viral RNA enriched in a potassium bromide density gradient fraction with a density of 1.115 g/ml. Icosahedron-shaped particles with an average diameter of 33 nm were liberated by treatment of the fraction with the detergent Tween 80. These particles were selectively visualized with an electron microscope using a grid coated with a murine monoclonal antibody directed to HCV core peptide and were also observed in aggregated forms with an immune electron microscope (IEM) with use of the anti-core antibody. An ultracentrifugation pellet of the above fraction was treated with sodium dodecyl sulfate (SDS) and 2-mercaptoethanol(2ME) and run in SDS-PAGE. A protein that bound antibodies directed to the predicted core protein of HCV was found at a molecular size estimated as about 26,000 Da, significantly greater than the 191 amino acid residues predicted from the presumed core gene of HCV. It is possible that translation initiation and/or the COOH-terminal cleavage site for HCV core protein in vivo may differ from estimates derived from the amino acid sequence of the polyprotein precursor. The nucleocapsid could also be chemically altered in the infected cell, resulting in a gel mobility different from the native protein.
Can the liver be induced to say no?
Authors: Wiley John W.
Published: March 2007

The incubation of primary cultures of rat hepatocytes with lipopolysaccharide (LPS) or biologically active phorbol esters promotes the release of nitric oxide to the incubation medium. This process is the result of the induction of the Ca2+- and calmodulinindependent form of nitric oxide synthase. Both the release of nitric oxide to the incubation medium and the expression of nitric oxide synthase activity exhibited a lag period of about 45-60 min after cell stimulation. Exposure of hepatocytes to both stimuli produced an antagonistic effect on nitric oxide release, with a half-maximal inhibition obtained with 14 nM phorbol 12,13-dibutyrate at saturating concentration of LPS. Incubation of cells with α-phorbol 12,13- didecanoate failed to counteract the effect of LPS or to induce nitric oxide synthase, suggesting that activation of protein kinase C was involved in this process.
Characterization and clinical relevance of liver-pancreas antibodies in autoimmune hepatitis
Authors: Stechemesser Ernst , Klein Reinhild , Berg Peter A.
Published: March 2007

The isolation of a marker antigen from rat liver and pancreas tissue, which reacts with antibodies in a subtype of autoimmune hepatitis by complement fixation test, enzyme-linked immunosorbent assay and Western blot, is described. The liver-pancreas antigen could be detected in tissue from different human or animal organs, but liver and pancreas yielded the highest activity. A highly specific antigen fraction was obtained by gel filtration and ion exchange chromatography with a 100,000 g supernatant from rat liver tissue, and this preparation was shown to be devoid of nuclear, mitochondrial and microsomal antigens and cytokeratin 8 and 18, as demonstrated by appropriate marker antibodies. These data and absorption studies with cell organelles indicate that liver-pancreas antigen is a cytosolic protein. By Western blotting, two major epitopes at molecular weights 52 kD and 48 kD could be visualized. Sera from 175 patients previously shown to have high complement-fixing activity to a nonpurified liver-pancreas antigen fraction were further analyzed. All were positive by enzyme-linked immunosorbent assay with the purified liver-pancreas antigen fractions, and 111 were also positive by Western blot. Eighty-six sera reacted with the 52-kD determinant, 33 with the 48-kD determinant and 2 with both determinants. In 117 of the 175 patients, antibody to liver-pancreas antigen was associated with other autoantibodies known to characterize subgroups of autoimmune hepatitis. Thus 19 patients had antibodies to nuclei and 96 to actin but none to liver-kidney microsomes, hereby suggesting that antibody to liverpancreas antigen may define another subgroup of autoimmune hepatitis. Only 38 (9%) of 425 patients with autoimmune hepatitis types 1 (lupoid hepatitis) and 2 (liver-kidney microsome 1 antibody-positive hepatitis) and 4 (3%) of 128 patients with chronic hepatitis B and C were positive for the antibody to liver-pancreas antigen as tested by enzyme-linked immunosorbent assay. None of the 196 patients with nonhepatic disorders had this antibody type. A classification of three different subgroups of autoimmune hepatitis is proposed: type 1a, lupoid hepatitis (antinuclear antibody positive with or without actin antibody); type 1b, only actin antibody positive; type 2, liver-kidney microsome 1 antibody positive; and type 3, liver-pancreas antigen antibody positive (with or without other autoantibodies). With this classification, group 3 comprises around 30%. (Hepatology 1993;18:1-9.
Autoimmune cholangiopathy: Part of the spectrum of autoimmune chronic active hepatitis
Authors: Ben-Ari Ziv , Dhillon Amar Paul , Sherlock Sheila
Published: March 2007

We describe four patients with features overlapping those of primary biliary cirrhosis and autoimmune chronic active hepatitis. Three were female and one was male; only one was symptomatic. Serum biochemical study showed increases in alkaline phosphatase and α-glutamyltranspeptidase levels. Markers of hepatitis B and C viruses were absent. In all four patients, serum mitochondrial antibodies could not be detected on immunofluorescence study and serum M2 antibodies were absent. All four patients had high titers of serum antinuclear antibody of diffuse type. Serum actin antibodies were detected in all four patients. Liver biopsy specimens showed histological features of primary biliary cirrhosis, with marked cellular infiltration of the portal areas and bile duct damage. Intralobular inflammation and piecemeal necrosis were mild. Three patients were treated with prednisolone and showed rapid clinical and biochemical remission. Serial liver biopsy specimens showed reduced inflammation, but bile duct lesions persisted. These patients probably form a subgroup of autoimmune chronic active type 1 with predominant bile duct damage. The subgroup might be termed autoimmune cholangiopathy. (Hepatology 1993;18:10-15).
Increased hepatic arterial blood flow in acute viral hepatitis: Assessment by color doppler sonography
Authors: Tanaka Katsuaki , Mitsui Konomi , Morimoto Manabu , Numata Kazushi , Inoue Shuji , Takamur Yutaro , Masumura Makoto
Published: March 2007

To evaluate the effect of acute viral hepatitis on hepatic arterial blood flow, we performed color Doppler sonography with point-spectral analysis in 15 patients with acute viral hepatitis and compared the results with those in 15 normal volunteers. During the acute phase of hepatitis, the peak-systolic and enddiastolic velocity of the hepatic artery were significantly larger than those in normal arteries (p <0.01). During the recovery phase, these indexes of the hepatic artery decreased significantly to the control levels (p <0.01). The resistive indexes related to vascular resistance in the hepatic artery during the acute phase were significantly less than those in normal arteries (p <0.01), and they increased significantly to the control levels during the recovery phase (p <0.01). No significant correlation was found between these indexes of the hepatic artery and conventional liver function parameters. However, the interval between the acute phase and the recovery phase did correlate negatively with the peak-systolic velocity of the hepatic artery in the acute phase (r = −0.630, p <0.05) and with the end-diastolic velocity (r = −0.514, p < 0.05). We conclude that color Doppler sonography is useful for imaging increased hepatic arterial blood flow in patients with acute viral hepatitis. We believe that increased hepatic arterial blood flow during the acute phase may provide a marker for earlier recovery from hepatitis-induced damage. (Hepatology 1993;18:21-27).
Unresponsiveness of hepatic nitrogen metabolism to glucagon infusion in patients with cirrhosis: Dependence on liver cell failure
Authors: Fabbri Andrea , Marchesini Giulio , Bianchi Giampaolo , Bugianesi Elisabetta , Bortoluzzi Lucia , Zol Marco , Pis Emilio
Published: March 2007

Glucagon exerts an up-regulatory effect on hepatic nitrogen metabolism in healthy subjects, but its potential role in the presence of liver failure is uncertain. The effects of glucagon on urea synthesis and hepatic nitrogen clearance during alanine infusion were studied in five control subjects and six cirrhotic patients in paired experiments at spontaneous glucagon concentrations and at high physiological glucagon levels (≈ 300 to 500 pmol · L−1) induced by a 7.5-hr continuous glucagon infusion. In all experiments the urea nitrogen synthesis rate increased linearly with increasing α-amino-nitrogen concentrations. At spontaneous glucagon concentrations the dynamics of α-amino nitrogen to urea nitrogen conversion (functional hepatic nitrogen clearance) were significantly reduced in cirrhosis (23.2 ± 6.7 L · hr−1 vs. 35.3 ± 8.0 L · hr−1, p < 0.05) in relation to decreased liver function. Glucagon superinfusion caused a 63% increase in the dynamics of the process in controls (57.7 ± 11.0 L · hr−1; p vs. spontaneous glucagon, p < 0.01), whereas in cirrhosis it increased on average by only 15% (26.7 ± 10.7; p = NS). The glucagon-induced change in functional hepatic nitrogen clearance significantly correlated with galactose elimination capacity and antipyrine clearance (r = 0.905 and 0.964, respectively). Glucagon, in high physiological concentrations achieved with glucagon infusion, does not produce significant effects on hepatic nitrogen metabolism in cirrhosis. The reduced sensitivity of the cirrhotic liver to glucagon seems to be dependent on decreased hepatocellular function. These data do not support the role of glucagon as a “catabolic” hormone in cirrhosis. (Hepatology 1993;18:28-35).