bluuebunny/crossref_metadata_2025 huggingface dataset:
Light and electron microscopic study of the liver in paraquat poisoning
Authors: Takegoshi Kunio , Nakanuma Yasuni , Ohta Masayuki , Thoyama Tatsuhiko , Okuda Khoji , Kono Naoko
Published: August 2010

ABSTRACT— Intrahepatic cholestasis in paraquat poisoning in man has been thought to be secondary to extensive bile duct injuries, though its exact mechanism remains unsettled. We have examined liver biopsy specimens from two cases of paraquat poisoning. Case 1 (fatal) presented severe intrahepatic jaundice, and liver biopsy showed centrilobular cholestasis with extensive bile duct loss. Ultrastructurally, dilatation of bile canaliculi with decrease of microvilli and thickening of pericanalicular ectoplasm was found in the hepatocytes. Case 2 (alive) showed mild liver dysfunction without jaundice. While liver biopsy showed nonspecific reactive changes with intact bile ducts and ductules, electron microscopy disclosed dilatation of bile canaliculi with decrease of microvilli and thickening of pericanalicular ectoplasm in the hepatocytes, suggesting that damage to the bile secretory apparatus in the hepatocytes develops irrespective of extensive bile duct loss. These findings suggest that bile secretory apparatus in the hepatocytes as well as biliary epithelial cells could be a target of paraquat or its metabolites.
Estimate of prevalence of glucose intolerance in chronic liver disease. Degree of agreement among some diagnostic criteria
Authors: Buzzelli Giampiero , Chiarantini Elena , Cotrozzi Giorgio , Relli Patrizia , Matassi Luciano , Romanelli Roberto Giulio , Gentilini Paolo
Published: August 2010

ABSTRACT— In patients with chronic liver disease, the reliability of various criteria generally used to diagnose impaired glucose tolerance and diabetes was evaluated. Twenty‐one patients with chronic persistent hepatitis, 68 patients with chronic active hepatitis and 57 patients with liver cirrhosis were studied. All subjects underwent an oral glucose tolerance test (75 g). Impaired glucose tolerance and diabetes were diagnosed according to the criteria established by: the National Diabetes Study Group; Fajans and Conn; the European Diabetes Study Group; Deutsche Diabetes Gesellschaft; Kobberling & Creutzfeld criteria 1 and 2; Wilkerson; and the University Group Diabetes Program. The results obtained are in partial agreement with other reported data, showing a high prevalence of both impaired glucose tolerance and diabetes in chronic liver disease, with a positive correlation to the severity of hepatic involvement. However, our results show that the agreement among the criteria most frequently used for diagnosing impaired glucose tolerance and diabetes is still far from satisfactory.
Randomized controlled study of propranolol for prevention of recurrent esophageal varices bleeding in patients with cirrhosis
Authors: Sheen I. S. , Chen T. Y. , Liaw Y. F.
Published: August 2010

ABSTRACT— A randomized controlled trial of propranolol was conducted in 36 adult cirrhotic patients after active esophageal variceal hemorrhage had been controlled. Seventy‐eight percent of the 18 patients on propranolol and 72% of the patients on a placebo were of Pugh's class A. Of the patients treated with propranolol, 94%, 87%, 68% and 57% were free from rebleeding 6, 12, 18 and 24 months after entry, respectively. The corresponding figures in control patients were 81%, 59%, 30% and 15%, respectively. The percentages of patients free from rebleeding were significantly higher in the propranolol group than in the control group (P < 0.05). No significant adverse effect was observed during the study, except for a patient who developed hepatic decompensation 14 months after propranolol therapy. It was concluded that propranolol was a safe and effective drug for the prevention of variceal rebleeding in patients with good liver functional reserve.
Differential effects of interleukin‐1α, tumor necrosis factor α, and transforming growth factor β1 on cell proliferation and collagen formation by cultured fat‐storing cells
Authors: Matsuoka Masaki , Pham Ngan‐thuy , Tsukamoto Hidekazu
Published: August 2010

Fat‐storing cells (FSCs), perisinusoidal cells wich normally participate in metabolism of vitamin A, have been suggested to participate in collagen synthesis in fibrotic liver. However, key mediators which regulate collagen metabolism in FSCs are yet to be elucidated. In fibroblasts, Interleukin‐1 (IL‐1), Tumor Necrosis Factor α (TNFα), and Transforming Growth Factor β (TGFβ) have been shown to induce diverse modulations of collagen metabolism and cell proliferation. In the present study, these cytokines were tested for their abilities to regulate collagen formation and proliferation by cultured rat FSCs. FSCs primary culture was established and incubated in the absence or presence of various concentrations of IL‐1α, TNFα, and TGFβ1. Tritiated proline and thymidine were used to examine collagen formation and cell proliferation. IL‐1α (2.5–10 U/ml) had a concentration‐dependent stimulatory effect on FSC proliferation with a maximal response of 160% compared to that of untreated FSCs. This mitogenic effect resulted in slight but significant increases (15–20%) in the net collagen formation. However, when this parameter was standardized relative to DNA content, significant inhibition of both collagen and noncollagen protein formation by IL‐1α was demonstrated. TNFα also exhibited a similar mitogenic effect but induced a more selective inhibition of collagen formation. In contrast, TGFβ1 (0.01–1 ng/ml) specifically enhanced collagen formation by 60–80%, as also evidenced by significant increases in the ratio of [3H]hydroxyproline to [3H]proline incorporated in newly formed proteins. Unlike IL‐1α or TNFα, TGFβ1 significantly inhibited FSC proliferation, and this inhibition was correlated (p<0.05) with the enhancement of collagen accumulation in the medium induced by this cytokine. These data suggest that regulation of collagen production and proliferation of FSCs can be mediated through independent mechanisms, and these mediators with differential effects may play important roles in liver fibrogenesis. In particular, TGFβ1 may be of pathobiological importance in inducing collagen accumulation and possibly inhibiting differentiation of FSCs.
Natural course of patients with chronic type B hepatitis following acute hepatitis delta virus superinfection
Authors: LIN HSIEN‐HONG , LIAW YUN‐FAN , CHEN TONG‐JONG , CHU CHIA‐MING , HUANG MIAU‐JU
Published: August 2010

A 6–96‐month prospective follow‐up study on the natural course of chronic type B hepatitis after contracting acute hepatitis delta virus (HDV) superinfection was conducted in 30 patients with clear‐cut onset of acute HDV superinfection (HDV group). Thirty patients with acute exacerbation without evidence of HDV infection, and well matched in terms of age, sex and hepatitis B e antigen/antibody status, served as the control group. The clinical and biochemical presentations tended to be more severe in the HDV group. More patients in the HDV group had persistent abnormal liver biochemical tests (69% vs 47%) and progressed to chronic active hepatitis (46% vs 20%) or cirrhosis (9.4%/year vs 5.2%/year), but the differences were not significant statistically. The results suggest that HDV superinfection induces slow progression of liver disease. However, in the early stage, the impact of HDV superinfection is not particularly different from that of the acute exacerbation unrelated to HDV in patients with chronic type B hepatitis.
A rapid method for the in vivo measurement of liver volume
Authors: ZOLI M. , PISI P. , MARCHESINI G. , BIANCHI G. P. , TURCI G. A. , PISI E.
Published: August 2010

A method is described to calculate liver volume at US using real‐time equipment. The method is based on the measurement of the 3 maximum diameters of the liver. Equations were derived by correlation vs CT volume measurement using the 3 diameters (multiple regression) or their product (simple regression) as independent variables in 20 subjects with and without liver disease. It is suggested that liver volume may be estimated as:

where y is the volume (in ml), and C – C, A – P, and L – L are the 3 diameters (in cm). The two equations were validated in a second set of 22 subjects. US volume estimated according to Eq. 2 explained approximately 82% of the variance of the actual liver volume. The method is reproducible (interobserver variations <8%), rapid and easy‐to‐repeat. These features make it potentially useful in prospective longitudinal studies.
A follow‐up study of an outbreak of non‐A, non‐B hepatitis in a plasmapheresis unit
Authors: Laskus Tomasz , Cianciara Janusz , Šlusarczyk Janusz
Published: August 2010

ABSTRACT—A cluster of acute non‐A, non‐B hepatitis comprising 12 blood donors was diagnosed in a plasmapheresis unit. Nine cases were followed‐up for 2–5.5 years and seven out of them progressed to chronicity, as judged by biochemical abnormalities. In six, liver biopsy was performed 1 year after the acute disease revealing chronic active hepatitis in two, chronic persistent hepatitis in two, chronic lobular hepatitis in one and normal liver in one. Repeated biopsies showed progression to cirrhosis in one case of chronic active hepatitis, and resolution of the disease in another one, while in the remaining patients liver morphology remained unchanged. Circumstantial epidemiologic evidence suggests a single agent being the cause of the outbreak, which resulted in a broad spectrum of liver disease.
Mouse strain differences in susceptibility to sporidesmin‐induced biliary tract injury
Authors: Bhathal Prithi S. , Jordan T. William , Mackay Ian R.
Published: August 2010

Abstract—Biliary tract injury was examined in four inbred strains of mice orally dosed with 500 μg of the fungal toxin sporidesmin. Semiquantitative histological analysis was used to assess the grade of necroinflammatory changes in the gall bladder, intra‐ and extrahepatic biliary tree and lobular parenchyma. Injury was greatest in the C57BL/6 and C3H strain mice and was least in SJL/J mice. In these strains injury was greatest at 4 days and had regressed by 10 days. In BALB/c mice the damage, although similar to that in SJL/J mice at 4 days, persisted at the same severity at day 10 and was accompanied by periductal fibrosis and occasionally by obliteration of ducts typical of sclerosing cholangitis. Analysis of the time‐course of development of the lesions in C57BL/6 mice showed that the primary target for the toxin is the biliary epithelium. The severity of the lesions within the liver increased centripetally and the worst affected ducts were found at the confluence of the lobar ducts with the common bile duct. The variation in the degree of damage and rate of healing between strains may be due to differences in sporidesmin excretion in bile or interactions with biliary epithelial cells and/or efficacy of protective cellular repair mechanisms.
Surecut® 0.6 mm liver biopsy in the diagnosis of cirrhosis
Authors: Torp‐Pedersen Søren , Vyberg Mogens , Smith Else , Højgaard Liselotte , Hansen Ulla , Stadeager Carsten , Schlichting Poul , Juul Niels , Gluud Christian
Published: August 2010

Abstract— Liver biopsy with the 0.6 mm (23 gauge) Surecut® needle was compared to conventional Menghini biopsy in the diagnosis of cirrhosis. Seventy‐seven consecutive patients (mainly alcoholics) with a clinical indication for liver biopsy had both biopsies performed simultaneously. In 71 patients sufficient material for a morphological diagnosis concerning liver architecture was obtained with both biopsy techniques (Surecut insufficient in 5 cases and Menghini insufficient in 2 cases). The biopsies were classified as cirrhosis or non‐cirrhosis. There was agreement in 69 cases (97%, confidence limits 90–100%). Using the result of the Menghini biopsy as the final diagnosis, the predictive values for a positive and negative diagnosis for the Surecut needle were 96% and 98%, respectively. There were no complications to either of the biopsies. It is suggested that the 0.6 mm Surecut biopsy may be used in the diagnosis of cirrhosis in cases where conventional Menghini needle biopsy is contraindicated.
The role of pericentral fibrosis in experimental portal hypertension in rats
Authors: Shibayama Yuro , Nakata Katsuji
Published: August 2010

ABSTRACT— To clarify the relation of pericentral fibrosis to portal hypertension, measurements of portal vascular resistance in vitro and blood pressures of several key points in hepatic vascular pathways in vivo were undertaken in rats given dimethylnitrosamine. Administration of dimethylnitrosamine induced tortuosity and narrowing of the peripheral branches of the hepatic vein due to pericentral fibrosis. No significant change was produced in the sinusoids and the portal vein branches. The portal vascular resistance was increased and the portal vein pressure was elevated markedly. The blood pressure gradient was steep in the intrahepatic vein, but not in the intrahepatic portal vein or the sinusoids, as compared to control. These data suggest that deformation of the peripheral branches of the hepatic vein due to pericentral fibrosis causes a marked increase in vascular resistance in the intrahepatic hepatic vein, i.e. postsinusoidal portal hypertension.
Interferon therapy of chronic delta hepatitis in patients cured of pediatric malignancies: possible harmful effect
Authors: Rossetti Flavio , Pontini Francesca , Crivellaro Carlo , Cadrobbi Paolo , Guido Maria , Pontisso Patrizia , Pintus Cristina , Bortolotti Flavia , Zanesco Luigi
Published: August 2010

ABSTRACT— In our Pediatric Haemato‐Oncology Unit, 42 young patients cured of their malignancy were left with chronic delta hepatitis. The severity of liver disease in many of these patients prompted us to start a pilot study on the effect of recombinant alpha 2b interferon, given at a dose of 5 MU/square meter thrice weekly. All nine patients included in the study (five males, mean age: 15 years) had well‐compensated liver disease, including five cases with active hepatitis and cirrhosis. At the end of the 3rd month of therapy, two patients with cirrhosis developed a biochemical exacerbation leading to hepatic decompensation, which was fatal in one case. The reasons for this unfavourable outcome remain unclear. Basic immunological tests were normal, but one of the two patients was the single case with anti‐liver‐kidney microsome antibodies. On the other hand, both patients seroconverted from hepatitis B e antigen to antibody at the time of exacerbation, suggesting that liver damage could have been the result of cell‐mediated cytotoxicity to hepatitis B virus antigens. The results of this study, which has been interrupted at the 4th month, suggest that interferon therapy for chronic delta hepatitis has to be considered cautiously in young patients cured of pediatric malignancies. In fact, no beneficial effect was seen and the treatment appeared to be harmful in at least two out of nine patients treated.
Tenascin expression in human chronic liver disease and in hepatocellular carcinoma
Authors: Yamada Shinji , Ichida Takafumi , Matsuda Yasunobu , Miyazaki Yutaka , Hatano Tohru , Hata Koujirou , Asakura Hitoshi , Hirota Norio , Geerts Albert , Wisse Eddie
Published: August 2010

Abstract: Tenascin is an oligomeric glycoprotein of the extracellular matrix synthesized during embryonic development. It is prominently expressed in a variety of tumors. The role of tenascin in liver tissue is, however, unknown. We used immunocytochemistry to define the localization of tenascin and compare this with the localization of non‐collagenous proteins, such as laminin and fibronectin, in normal human liver and pathological liver from patients with chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. In normal liver, tenascin expression was localized along the sinusoidal and vascular wall. In fibrotic liver, tenascin was also observed in the region between the hepatic parenchyma and the fibrosing portal tracts, especially in areas of piecemeal necrosis in chronic hepatitis. Immuno‐EM study of liver tissue in chronic hepatitis strongly suggested the synthesis and secretion of tenascin by fat‐storing cells into the space of Disse. In hepatocellular carcinoma, tenascin was expressed in both the capsule and lobular septa, but not in the sinusoidal walls of the tumors. These results led us to postulate a close relationship between the occurrence of this protein and disease processes such as fibrosis and cancer invasion.
Adenomatous hyperplasia of the liver as a precancerous lesion
Authors: Nakanuma Yasuni , Terada Tadashi , Ueda Kazuhiko , Terasaki Shuichi , Nonomura Akitaka , Matsui Osamu
Published: August 2010

ABSTRACT— Adenomatous hyperplasia (AH), a hyperplastic parenchymal nodule, is detected most often through radiological and pathological observations in chronic advanced liver disease. AH can be classified into two categories: ordinary type or macroregenerative nodule (MRN) type I, and atypical type or MRN type II. Characteristically, both types contain portal tracts with portal veins and biliary elements. Ordinary AH may represent a large regenerative nodule with limited growth potential. Atypical AH shows slightly cellular and structural atypia, altered phenotypic expression, and increased proliferative activity compared to the surrounding liver. Histologic differentiation of atypical AH from well‐differentiated hepatocellular carcinoma (HCC) is controversial, and generally accepted diagnostic criteria are still lacking. Atypical AH occasionally contains overt malignant foci. Histological observations and portography show that nodules of AH are supplied by portal venous blood. While AH nodules appear to be hypoperfused according to arteriographic studies, atypical AH contains small arterial branches which are abundant in contrast to the surrounding liver. The data obtained so far indicate that atypical AH may be a hepatocellular neoplasm which belongs nosologically to a gray area of neoplasm, in which overt HCC is likely to develop. It is clinically recommended that atypical AH is treated as “malignant” because of the occasional inclusion of HCC foci. For its treatment, percutaneous ethanol injection is becoming popular.
Liver biopsy features of acute hepatitis C compared with hepatitis A, B, and non‐A, non‐B, non‐C
Authors: Kobayashi Kiyomasa , Hashimoto Etsuko , Ludwig Jürgen , Hisamitsu Toju , Obata Hiroshi
Published: August 2010

ABSTRACT—The diagnosis of acute hepatitis C (AHC) often can only be suspected because current serologic tests remain negative for over 3 months. Because histologic features might provide useful clues, we reviewed 85 liver biopsy specimens from 85 patients with acute viral hepatitis, comparing 22 cases of AHC with 23 cases of acute hepatitis A (AHA), 30 cases of acute hepatitis B (AHB), and 10 cases of acute hepatitis non‐A, non‐B, non‐C (AHNC). AHC was characterized by dense portal lymphoid aggregates (7 cases) and Poulsen‐Christoffersen‐type cholangitis (8 cases); these lesions were not found in any other type of acute viral hepatitis, and thus appeared to be diagnostic. Sinusoidal inflammatory infiltrates also were common in AHC, particularly in biopsy specimens obtained during the early phase of the disease. These inflammatory infiltrates did not appear to affect adjacent hepatocytes. Necrosis in AHC usually was spotty and accompanied by mixed inflammatory cells. In AHNC, necrosis was also spotty but, as an added feature, pigmented macrophages predominated in them. In AHA, necrosis was predominantly periportal, whereas in AHB, severe zone‐3 necrosis predominated. Fatty changes were predominantly microvesicular; they were common in AHC but were also found in other groups. Collectively, the described histologic features allowed diagnosis of AHC in biopsy specimens with reasonable confidence. However, histologic findings failed to predict the prognosis in individual cases.
Effect of colchicine on acetaminophen‐induced liver damage
Authors: Muriel Pablo , Quintanar Ma. Elena , Perez‐Alvarez Victor
Published: August 2010

ABSTRACT—The effect of colchicine on liver damage induced by acetaminophen (APAP) intoxication was studied. Wistar male rats pretreated (72 h) with 3‐methylcholantrene (3‐MC) (20 mg/kg i.p.) were divided into six groups: animals in group 1 were treated with acetaminophen (APAP) (500 mg/kg p.o.); group 2 consisted of animals that received colchicine (65 μg/kg/day p.o.) for 7 days before APAP intoxication; group 3 was treated like group 2, but the dose of colchicine was 300 μg/kg/day; animals in groups 4 and 5 received the same doses of colchicine as groups 2 and 3, respectively, but received the vehicle instead of APAP; and rats in group 6 (control) received the equivalent amount of the vehicles. Animals were sacrificed at different times after APAP administration. Reduced glutathione (GSH), lipid peroxidation and glycogen were measured in liver and, γ‐glutamyl transpeptidase (γ‐GTP), and glutamic pyruvic transaminase (GPT) activities were measured in serum. After APAP intoxication, GSH and glycogen decreased very fast (1 h) and remained low for 6 h. Lipid peroxidation increased three times over control 4 h after APAP treatment. Enzyme activities increased at 18 h after intoxication. Pretreatment with 65 μg/kg of colchicine failed to prevent liver damage induced by APAP. However, when a dose of 300 μg/kg of colchicine was given, levels of lipid peroxidation and serum γ‐GTP activity remained within the control values, while GPT activity and glycogen content were only partially attenuated. It was concluded that colchicine protects against APAP intoxication, probably through its antioxidant properties, possibly acting as a free radical scavenger.
Role of hepatic vitamin A and lipocyte distribution in experimental hepatic fibrosis
Authors: Yamane Michio , Tanaka Yujiro , Marumo Fumiaki , Sato Chifumi
Published: August 2010

ABSTRACT—Lipocytes are the major site of hepatic vitamin A storage, and they have been demonstrated to lose their vitamin A content in the process of hepatic fibrosis. To investigate the relationship between hepatic vitamin A content and the degree of hepatic fibrosis, we measured levels of retinyl palmitate and retinol in the CCl4‐induced fibrotic liver using high‐performance liquid chromatography. We estimated hepatic collagen content using a spectrophotometric analysis with sirius red, and also by measuring hydroxyproline levels. Lipocytes were detected by an immunoperoxidase method with anti‐desmin antibody, and were counted morphometrically through a Texture Analyzing System. A significant negative correlation was observed between the level of retinyl palmitate and collagen content (r = –0.64) as well as the hydroxyproline level (r = –0.69) in the CCl4‐induced fibrotic liver. In the process of fibrosis, hepatic retinol levels were elevated in association with a decrease in retinyl palmitate. In particular in the early stage of fibrosis, lipocytes increased remarkably in number in fibrotic areas in spite of a decrease in total hepatic vitamin A. The present study suggests that an increase in hepatic retinol as well as a decrease in retinyl palmitate may facilitate the process of hepatic fibrosis produced by lipocytes.
Bone marrow transplantation in thalassemia: modifications of hepatic iron overload and associated lesions after long‐term engrafting
Authors: Muretto Pietro , Del Fiasco Sergio , Angelucci Emanuele , De Rosa Ferdinando , Lucarelli Guido
Published: August 2010

Abstract: Among 450 thalassemic patients treated in the Hematologic Department, 50 patients who were disease‐free 4–6 years after allogeneic bone marrow transplantation were sequentially studied by liver biopsy. The patients received marrow from siblings who were genotypically HLA identical at A, B, C and DR loci. For evaluation of siderosis and associated lesions, each patient underwent liver biopsy before, and again 6 months and yearly for 4 to 6 years after bone marrow transplant. Spontaneous reversibility of liver iron overload, once the need for transfusions ceased when a functioning graft had been established, was observed in the youngest patients, aged 1–8 years, whereas iron excess remained at the end of follow‐up in many patients aged 9–15 years. Hypotheses about the mechanism of the iron decrease are discussed. Several cases also obtained improvement of associated pathologies such as hepatitis, probably through modifications in the mechanisms controlling their immunological status.
Receptor‐mediated endocytosis of chemically modified albumins by sinusoidal endothelial cells and Kupffer cells in rat and human liver
Authors: Yoshioka Toshifumi , Yamamoto Kazuhide , Kobashi Haruhiko , Tomlta Minoru , Tsuji Takao
Published: August 2010

Human serum albumin (HSA), formaldehyde‐treated HSA (FHSA), and HSA polymerized with glutaraldehyde (pHSA) were conjugated with colloidal gold (15 (15G) or 50 (50G) nm in diameter). The labeled proteins were injected into the portal veins of rats and followed by electron microscopy. Both 15G‐FHSA and 15G‐pHSA were taken up by sinusoidal endothelial cells (Ec) and Kupffer cells (Kc). Five minutes after injection, gold particles were observed on the surface of Ec and Kc. At 10 min, most gold particles were gathered in the coated pits and vesicles of Ec. In Kc, gold particles were observed in both coated vesicles and macropinocytotic vesicles. At 15 min, the gold particles were localized mainly in the endosomes and some lysosomes of Ec and in the large vacuoles of Kc. At 30 min, the gold particles had been gathered into the secondary lysosomes and condensed. At 60 min, some gold particles were observed in the cytoplasm of Ec. The fate of 15G‐pHSA was the same as that of 15G‐FHSA. Simultaneous injection of 15G‐pHSA and 50G‐FHSA revealed that particles of both sizes were taken up together into the coated pits and vesicles of Ec. Preperfusion of livers with unlabeled FHSA, pHSA, or formaldehyde‐treated bovine serum albumin (FBSA) inhibited the uptake of 15G‐FHSA or 15G‐pHSA by Ec. In a human liver biopsy specimen, both 15G‐FHSA and 15G‐pHSA were taken up by Ec and Kc through coated vesicles, as in the rat liver. These results suggest that aldehyde‐modified albumin is taken up by both Ec and Kc, and that both FHSA and pHSA share a common receptor on Ec.
Phenotypical analysis and cytokine release of liver‐infiltrating and peripheral blood T lymphocytes from patients with chronic hepatitis of different etiology
Authors: Löhr Hanns F. , Schlaak Jörg F. , Gerken Guido , Fleischer Bernhard , Dienes Hans‐Peter , zum Büschenfelde Karl‐Hermann Meyer
Published: August 2010

Cytokines released by infiltrating T cells may contribute to the hepatic injury in chronic hepatitis. Therefore, we characterized peripheral blood‐ and liver‐infiltrating T cells from patients with chronic hepatitis of different etiology and determined the T cell phenotypes and the cytokine release. Liver tissue and peripheral blood‐derived T cells from patients with autoimmune hepatitis and primary biliary cirrhosis predominantly expressed CD4‐molecules and the α‐ and β‐chains of the T cell receptor (TCR). In chronic viral hepatitis B and C, liver‐ and blood‐derived T cells were preferentially CD8+ T cells expressing the αβ TCR. Mitogenic stimulation with irradiated Daudi lymphoma cells and phytohemagglutinin led to a strong release of interferon‐gamma (IFN‐γ), tumor necrosis factor‐alpha (TNF‐α) and interleukin‐2 (IL‐2) by T cells in patients with chronic hepatitis and in healthy controls. T cells from patients with primary biliary cirrhosis and some patients with autoimmune hepatitis showed a significantly higher secretion of interleukin‐4 (IL‐4) and interleukin‐10 (IL‐10) than T cells from patients with chronic viral hepatitis or healthy controls. Histologic inflammatory activity did not correlate with the amount of cytokines released after mitogenic activation. In conclusion, liver tissue and peripheral blood T cells of patients with autoimmune hepatitis and primary biliary cirrhosis were dominated by CD4+ TCR αβ+ T helper/inducer cells, whereas in chronic viral hepatitis an enrichment of CD8+ TCR αβ+ cytotoxic/suppressor T cells was observed. In addition, analysis of the cytokine release showed that T cells in autoimmune and chronic viral liver diseases secreted high amounts of IFN‐γ and TNF‐α, cytokines predominantly secreted by Thl‐like cells. The secretion of the Th2 cytokines. IL‐4 and IL‐10, however, was increased in autoimmune hepatitis and primary biliary cirrhosis. These data show that in autoimmune and chronic viral liver diseases different functional T cell subsets are activated.
Alterations in intrahepatic expression of duck hepatitis B viral markers with ganciclovir chemotherapy
Authors: Luscombe Carolyn , Pedersen John , Bowden Scott , Locarnini Stephen
Published: August 2010

Ducks congenitally infected with duck hepatitis B virus (DHBV) were treated with the guanosine analogue, ganciclovir, and the effect on serum and intrahepatic expression of DHBV DNA and viral proteins was examined. After 21 days of ganciclovir treatment, a substantial reduction in viraemia occurred; in contrast, the level of circulating DHBV surface antigen was unchanged. Ganciclovir therapy also substantially reduced the level of DHBV DNA replicative intermediates and the expression of viral core and surface antigen in hepatocytes. However, despite the antiviral treatment some liver cells, including the bile duct epithelial cells and putative oval cells, maintained their intense staining for the viral proteins. Furthermore, DHBV‐infected cells in extrahepatic sites such as the pancreas, kidney and spleen were also unaffected by ganciclovir treatment. These results suggest that monotherapy with nucleoside analogues is unlikely to eliminate chronic hepadnaviral infection, and antiviral programs should be designed to target all cell populations infected by the virus.
Effects of phalloidin and colchicine on diethylmaleate‐induced choleresis and ultrastructural appearance of rat hepatocytes
Authors: Dumont M. , D'Hont C. , Lamri Y. , Durand‐Schneider A. M. , Jacquemin E. , Feldmann G. , Erlinger S.
Published: August 2010

ABSTRACT:Diethylmaleate is used as a model compound whose glutathione conjugates are secreted into bile, and which induce choleresis and the formation of Golgi‐derived vesicles in hepatocytes. This study was performed to test the assumption that these vesicles are involved in the bile canalicular secretion of diethylmaleate. We reasoned that phalloidin and colchicine, two drugs acting on microfilaments and microtubules, respectively, can modify the movements of diethylmaleate‐induced vesicles towards the bile canaliculus. Phalloidin induced the formation of a thick microfilamentous network around the bile canalicular plasma membrane domain. A significant decrease in diethylmaleate‐stimulated choleresis was observed, associated with a striking accumulation of pericanalicular vesicles, which were confirmed by morphometric analysis. In contrast, in rats pretreated with colchicine, after diethylmaleate administration, only a few vesicles were observed around the bile canaliculus, while diethylmaleate‐induced choleresis also decreased. These results suggest that: a) the thick microfilament network induced by phalloidin prevents diethylmaleate‐associated vesicles reaching the bile canalicular plasma membrane; and b) colchicine produces a dispersion of these vesicles in the cytoplasm of hepatocytes by inhibiting the polymerization of microtubules. These observations support a role of vesicles in the transport of diethylmaleate by hepatocyte into bile, and are consistent with the existence of a vesicular pathway for the biliary secretion of diethylmaleate and possibly other organic anions.
Protective effect of diltiazem against acetaminophen hepatotoxicity in mice
Authors: Satorres Javier , Pérez‐Mateo Miguel , Mayol María J. , Esteban Angel , Graells María L.
Published: August 2010

There is evidence that an increase in cytosolic Ca++ concentration is a terminal event in the progression to cell death in toxic liver injury. We have compared the hepatoprotective effects of N‐acetylcysteine (1 g/kg) and the calcium channel blocking agent, diltiazem (24 mg/kg), when given at 30 min, 3 h and 6 h after single intraperitoneal overdoses of acetaminophen (500 mg/kg) in mice. Overall beneficial effects on mortality, liver necrosis score, and plasma alanine aminotransferase (ALT) activity were found in diltiazem‐treated mice 24 h after acetaminophen overdose. However, the most marked effects were obtained when diltiazem was given 6 h after acetaminophen. N‐acetylcysteine was more effective than diltiazem at 30 min and 3 h, although it was less effective at 6 h. Mean plasma concentrations of the mercapturate metabolite (hepatic oxidative metabolism) were not significantly different among animals receiving acetaminophen alone or in combination with diltiazem, which suggests that the hepatoprotective effects of diltiazem are not exerted by inhibition of drug metabolic enzymes.
Prediction of prognosis of primary biliary cirrhosis in Japan
Authors: Inoue Kyoichi , Hirohara Junko , Nakano Toshiaki , Seki Toshihito , Sasaki Hiroshi , Higuchi Kiyohiro , Ohta Yasuyuki , Onji Morikazu , Muto Yasutoshi , Moriwaki Hisataka
Published: August 2010

The clinical profile of primary biliary cirrhosis in Japan was clarified on the basis of data on 1066 patients attending 212 hospitals and institutions in this country. Six hundred and twelve patients (57.4%) were asymptomatic. The majority of the patients were middle‐aged women. Pruritus was the most frequent initial symptom of symptomatic primary biliary cirrhosis. Antimitochondrial antibodies were positive in 877 patients (82.5%). Sjögren's syndrome was the most common associated autoimmune disease. Liver biopsy was performed in 753 patients at the time of diagnosis, and histological staging by Scheuer's classification indicated that 307 (43.7%) patients were in stage I and 222 (31.6%) were in stage II. The most frequent causes of death were hepatic failure and/or gastrointestinal bleeding, which affected 166 (78.3%) of the 212 patients who died. Statistical analysis using Cox's regression method revealed that the patient's age and the serum bilirubin, albumin, and total cholesterol concentrations were significant predictors of the prognosis. A prognostic index was also calculated that could be used to predict the duration of survival for patients with primary biliary cirrhosis.
1‐Naphthyl isocyanate and 1‐naphthylamine as metabolites of 1‐naphthylisothiocyanate
Authors: Li Yao , Yousef Ibrahim M. , Plaa Gabriel L.
Published: August 2010

Abstract:The importance of the bioactivation of 1‐naphthylisothiocyanate was studied. Forty minutes after 1‐naphthylisothiocyanate administration to rats, bile was collected over a 2.5‐h period; the liver was then excised and homogenized. 1‐naphthylisothiocyanate and its metabolites in bile and liver of rats were identified and quantified using coupled gas chromatography‐mass spectrometry. Three main compounds were found in all 1‐naphthylisothiocyanate‐treated animals. They were identified as 1‐naphthyl isocyanate, 1‐naphthylamine and the parent compound, 1‐naphthylisothiocyanate. When rats were given cycloheximide, which attenuates 1‐naphthylisothiocyanate toxicity, 30 min before 1‐naphthylisothiocyanate (300 mg/kg), 1‐naphthyl isocyanate concentration was significantly lower than in rats receiving only 1‐naphthylisothiocyanate. The appearance of 1‐naphthylamine was also inhibited by cycloheximide, although not to the same extent as 1‐naphthyl isocyanate. On the other hand, phenobarbital, which potentiates 1‐naphthylisothiocyanate hepatotoxicity, enhanced 1‐naphthyl isocyanate and 1‐naphthylamine formation. It is suggested that 1‐naphthyl isocyanate, 1‐naphthylamine and the highly reactive sulfur released from 1‐naphthylisothiocyanate might be involved in the hepatotoxic effect of 1‐naphthylisothiocyanate.
A double‐blind, placebo‐controlled, pilot trial of thymosin alpha 1 for the treatment of chronic hepatitis C
Authors: Andreone Pietro , Cursaro Carmela , Gramenzi Annagiulia , Buzzi Andrea , Covarelli Maria Grazia , Di Giammarino Loriana , Miniero Rita , Arienti Vincenzo , Bernardi Mauro , Gasbarrini Giovanni
Published: August 2010

Abstract: A randomized, double‐blind, placebo‐controlled trial was performed to evaluate the efficacy and safety of thymosin alphal (α1) in treating chronic hepatitis C. Nineteen Italian patients with chronic active hepatitis C, proven by biopsy were randomly assigned to receive a six month course of thymosin α1 (900 μg/m2 of body surface area twice weekly) or a placebo. All had HCV‐RNA in their serum (by PCR), with serum ALT levels more than double the upper limit of the normal range for at least six months before enrollment. After treatment, patients were followed for an additional six months. All patients completed the trial. One patient treated with thymosin α1, but no patient in the placebo group, normalized serum ALT levels by the end of the treatment. This patient, however, relapsed at the sixth month of the follow‐up. Overall, there were no significant changes in mean serum ALT levels in either group during the treatment or follow‐up period. No patient cleared HCV‐RNA. No side effects were reported except for local discomfort at the injection sites, reported by some patients treated with thymosin α1. In conclusion, this regimen of thymosin α1 is not effective in the treatment of chronic hepatitis C.
Liver ischemia/reperfusion induces an increase of microvascular leukocyte flux, but not heterogeneity of leukocyte trafficking
Authors: Vollmar Brigitte , Richter Sven , Menger Michael D.
Published: August 2010

Abstract: Leukocytic response plays a major role in the manifestation of hepatic ischemia/reperfusion (I/R) injury. To clarify whether post‐ischemic hepatic leukocyte accumulation is based on increased leukocyte flux to the hepatic tissue due to systemic inflammation or chemoattractant activities or whether it represents solely a local tissue response without changing overall leukocyte flux and trafficking characteristics through the microvasculature, we studied acinar and sinusoidal leukocyte flux and distribution in rat livers in vivo both under normal (sham, n=8) and post‐ischemic (60′ ischemia/75′ reperfusion) conditions (I/R, n=8), using fluorescence epi‐illumination microscopy (rhodamine‐6G). Hepatic ischemia/reperfusion significantly (p<0.05) increased acinar leukocyte flux (58.4±20.9 cells/min vs 36.4±12.8 cells/min in sham controls); however, it did not exhibit increased heterogeneity of acinar leukocyte distribution, as indicated by the unchanged coefficient of variance (CV) of 0.36±0.16 (sham controls: 0.31 ±0.14). In parallel, analysis of individual sinusoidal leukocyte flux demonstrated significantly (p<0.05) higher values (8.9±3.7 cells/min) after ischemia/reperfusion when compared with sham controls (5.7±1.9 cells/min), which, however, was not associated with increased heterogeneity of sinusoidal leukocyte trafficking (CV: 0.85±0.15 vs 0.85±0.16 in sham controls) and manifestation of preferential pathways. Analysis of blood cell count did not demonstrate an overall increase of total blood leukoycte count; however, an increased (p<0.01) fraction of polymorphonuclear leukocytes (65.2±11.2%) and stab cells (9.5±7.9%) during post‐ischemic reperfusion when compared with sham controls (8.8±3.5% and 0.2±0.4%) was demonstrated. Thus, the increase of hepatic leukocyte flux after ischemia/reperfusion may be the result of both the manifestation of a systemic inflammatory response and the increase of local chemoattractant activities, such as the production and release of the cytokine‐induced neutrophil chemoattractant of the IL‐8 family.
Allopurinol improves scavenging ability of the liver after ischemia/reperfusion injury
Authors: Karwinski Witold , Søreide Odd
Published: August 2010

Abstract: Deterioration of energy metabolism and oxidative stress represent fundamental mechanisms in ischemia and reperfusion injury. In a normothermic ischemia/reperfusion rat model, we investigated whether allopurinol (ALL) may improve the scavenging ability of the liver after ischemia. ALL was given prior to ischemia and reperfusion (concentration 100 or 50 mg/kg) and controls were given a placebo. After a basal period of 30 min, 1 h normothermic ischemia was induced in the median and left liver lobes followed by 24 h observation. The overall liver function was assessed by bile secretion, and free oxygen production was assessed by glutathione efflux into bile during the first 60 min of reperfusion and at 24 h. Allopurinol (concentration 100 mg/kg) protected hepatocyte function as bile flow improved significantly in this group after 1 and 24 h of reperfusion compared with that of controls. Oxidative stress was also significantly attenuated in this group, as efflux of glutathione into bile was significantly higher in the ALL group (100 mg/kg) after 24 h but not after 1 h of reperfusion compared with that of controls. ALL given in a concentration 50 mg/kg had some, but a non‐significant, effect. We conclude that biliary glutathione is an important marker of oxidative stress and may reflect the scavenging ability of the liver after ischemic injury. Significant correlation of bile flow with biliary glutathione during reperfusion indicates that oxidative stress is an important mechanism attenuating liver function after ischemia/reperfusion injury.
Effluent levels of thrombomodulin predict early graft function in clinical liver transplantation
Authors: Suehiro Taketoshi , Boros Peter , Sheiner Patricia , Emre Sukru , Guy Stephen , Schwartz Myron E. , Miller Charles M.
Published: August 2010

Abstract: Thrombomodulin is a surface protein on vascular endothelial cells that serves as a binding site for thrombin and plays an important role as an anticoagulant factor. We correlated plasma thrombomodulin levels with early graft function after liver transplant in 58 recipients. Blood samples were collected at the following time points: before surgery, just before reperfusion, 30, 60, 120 min after reperfusion, and post‐operative day 1. The first and last 20 cc of caval effluent were also collected. Plasma thrombomodulin levels were measured by a sandwich enzyme‐binding assay in the blood samples; tissue expression was determined by immuno‐histochemistry. Poor early graft function was defined as peak aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2500 U/1 during the first 3 post‐operative days and prothrombin time >16 s on post‐operative day 2. Thrombomodulin levels in the first 20 cc of caval effluent ranged from 1.33 to 91 FU/ml and showed a significant positive correlation with ischemic time, intra‐operative blood transfusion requirement, and early graft function. In grafts with high effluent thrombomodulin (>20 FU/ml, n=12), the incidence of poor early graft function and primary nonfunction was 66.7% and 25.0%, respectively; in grafts with low effluent thrombomodulin (<20 FU/ml, n=46), graft function was not impaired. By immunohistochemistry, thrombomodulin was detected in large vessels of every donor liver. Sinusoidal cells, however, showed positive staining only in livers with poor early graft function. Effluent thrombomodulin levels reflect the extent of preservation injury and might be a useful marker for predicting graft function after liver transplantation.
The first decade of the transjugular intrahepatic portosystemic shunt (TIPS): state of the art
Authors: Rössle Martin , Siegerstetter Volker , Huber Michael , Ochs Andreas
Published: August 2010

ABSTRACT— The transjugular intrahepatic portosystemic shunt (TIPS) is an interventional treatment resulting in decompression of the portal system by creation of a side‐to‐side portosystemic anastomosis. Since its introduction 10 years ago, more than 500 publications have appeared demonstrating rapid acceptance and increasing clinical use. This review summarizes the present knowledge of technical aspects and complications, follow‐up of patients, and indications. With respect to the technique, the TIPS procedure is probably one of the most difficult interventions and, therefore, technical success and complications clearly depend on the skills of the operator. Thus, the number and kind of complications reported in this review do not necessarily relate to the procedural complications of an experienced center. The follow‐up of the TIPS patient has to assess shunt patency, liver function and hepatic encephalopathy. Shunt patency can best be monitored by duplex‐sonography. Routine radiological revision seems not to be helpful and does not improve results, i.e., rebleeding and survival. Short term patency may be improved by anticoagulation, while such a treatment does not influence long‐term patency. With respect to the indications of TIPS, much is known about treatment of variceal bleeding. The nine randomized studies that are available to date show that survival is comparable between patients receiving TIPS or endoscopic treatment. The second group of patients is the group with refractory ascites and related complications, such as hepatorenal syndrome and hepatic hydrothorax. It has been demonstrated that TIPS improves these complications, but randomized studies are still lacking. In addition, TIPS has been applied successfully to patients with Budd‐Chiari syndrome, portal vein thrombosis, before liver transplantation, and for the treatment of ectopic portal hypertensive bleeding.
A comparative histochemical and immunohistochemical study of aminergic, cholinergic and peptidergic innervation in rat, hamster, guinea pig, dog and human livers
Authors: Akiyoshi Hideo , Gonda Tatsuo , Terada Tadashi
Published: August 2010

Abstract:Aims/Background:The mammalian liver receives both sympathetic and parasympathetic nerves that contain aminergic, cholinergic and peptidergic components. The intrahepatic distribution of nerve fibers are highly species‐dependent; and also, even within one species, there are notable variations. To reveal the pattern and type of hepatic innervation in different species, we examined the distribution and density of these nerve fibers.Methods:The livers of rats, golden hamsters, guinea pigs, dogs and humans were used. Aminergic and peptidergic nerve fibers were identified by immunohistochemistry for tyrosine hydroxylase (TH), neuropeptide Y (NPY), substance P (SP), vasoactive intestinal polypeptide (VIP), calcitonin gene‐related peptide (CGRP), and galanin (GAL), and cholinergic fibers were identified by the acetylcholinesterase (AChE) neurohistochemistry method.Results:AChE‐, TH‐, NPY‐, CGRP‐, VIP‐, and SP‐positive nerves were observed in the connective tissue of the portal region, and they were in close contact with hepatic arteries, portal veins and bile ducts in all five species. Within the parenchyma of guinea pig, dog and human livers, TH‐, NPY‐ and SP‐positive fibers were observed, but no AChE‐ and CGRP‐positive fibers were observed. In rat and hamster livers, no parenchymal nerve fibers could be demonstrated, but CGRP‐, NPY‐ and SP‐positive fibers were observed in the border of periportal areas. The density of CGRP‐positive nerve fibers were slightly higher around bile ducts than around hepatic arteries and portal veins. GAL‐positive fibers were not detected in any animal.Conclusions:These data indicate that there were differences in the patterns of hepatic innervation among rats, golden hamsters, guinea pigs, dogs and humans. The data also show that: 1) in rat and hamster livers, hepatic functions may be regulated by both sympathetic and parasympathetic nerves in the portal region; 2) in guinea pig, dog and human livers they may be regulated by these fibers both in the interlobular region (parasympathetic and sympathetic systems) and in the intraparenchymal region (sympathetic system); and thus, 3) in the latter three species, hepatocytes and sinusoidal cells may be innervated by sympathetic nerves.
PROLIFERATIVE MYOSITIS
Authors: Heyden R. , Hägerstrand I. , Linell F. , Nordén G. , ÅKesson B. Å. , ÖStberg G.
Published: August 2010

Two cases of proliferative myositis are described with gross and microscopic photographic reproductions. It is stressed that the condition, which is benign, should not be confused with sarcoma.