Liver[JOURNAL]
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200 papers
Regulation of cholangiocyte proliferation.
LeSage G, Glaser S, Alpini G
Liver · 2001 Apr · PMID 11318975 · Publisher ↗
Intrahepatic bile duct epithelial cells (i.e., cholangiocytes) are the target cells of chronic cholestatic liver diseases (i.e., cholangiopathies), which makes these cells of great interest to clinical hepatologists. Thi...
Intrahepatic bile duct epithelial cells (i.e., cholangiocytes) are the target cells of chronic cholestatic liver diseases (i.e., cholangiopathies), which makes these cells of great interest to clinical hepatologists. This review will focus on "typical" cholangiocyte proliferation, whereas "atypical" (extension of cholangiocyte proliferation into parenchyma), and premalignant "oval" cell proliferation are reviewed elsewhere. The bile duct ligated (BDL) rat model, where most of the known mechanisms of cholangiocyte proliferation have been illustrated, was the first and remains the prototype animal model for "typical" cholangiocyte proliferation. Following a short overview of cholangiocyte functions, we briefly discuss the: (i) in vivo models [i.e., BDL (Fig. 1 and 4), chronic alpha-naphthylisothiocyanate (ANIT) or bile acid feeding (Fig. 2), acute carbon tetrachloride (CCl4) feeding and partial hepatectomy; and (ii) in vitro experimental tools [e.g., purified cholangiocytes and isolated intrahepatic bile duct units (IBDU)] that are key to the understanding of the mechanisms of "typical" cholangiocyte growth. In the second part of the review, we discuss a number of potential factors or conditions [e.g., gastrointestinal hormones, nerves, estrogens, blood supply, and growth factors] as well as the intracellular mechanisms [e.g., adenosine 3',5'-monophosphate (cAMP), and protein kinase C (PKC)] that may regulate "typical" cholangiocyte hyperplasia.
Endotoxin clearance and its relation to hepatic and renal disturbances in rats with liver cirrhosis.
Nakatani Y, Fukui H, Kitano H … +6 more , Nagamoto I, Tsujimoto T, Kuriyama S, Kikuchi E, Hoppou K, Tsujii T
Liver · 2001 Feb · PMID 11169075 · Publisher ↗
BACKGROUND/AIMS: Little is known about endotoxin clearance and secretion of cytokines from macrophages in liver cirrhosis. The aims of this study were to investigate the relationship of endotoxin clearance and release of...
BACKGROUND/AIMS: Little is known about endotoxin clearance and secretion of cytokines from macrophages in liver cirrhosis. The aims of this study were to investigate the relationship of endotoxin clearance and release of tumor necrosis factor alpha by various macrophages to hepatic and renal disturbances in liver cirrhosis. METHODS: Male Sprague-Dawley rats were given 0.04% thioacetamide orally for 6 or 12 months. The organ distribution of infused [3H]-endotoxin (10 microg/kg b.w.) was analyzed at 30 min or at 24 h. Uptake of [3H]-endotoxin and secretion of tumor necrosis factor alpha by Kupffer cells, splenic macrophages and peripheral blood monocytes (1 x 10(4) cells/ml) from cirrhotic and control rats were determined. RESULTS: In cirrhotic rats, more endotoxin was left in the body and more endotoxin accumulated in the spleen and kidney, and thus was related to elevation of serum total bilirubin, aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, creatinine and tumor necrosis factor alpha. Endotoxin uptake and tumor necrosis factor alpha release by the Kupffer cells were decreased and those by the splenic macrophages and peripheral blood monocytes were increased in cirrhotic rats. CONCLUSIONS: In liver cirrhosis, impaired clearance of endotoxin together with increased secretion of tumor necrosis factor alpha by extrahepatic macrophages may play an important role in the progression of hepatic and renal disturbances.
Major liver resection results in a changed plasma amino acid pattern as reflected by a decreased Fischer ratio which improves by bactericidal/permeability increasing protein.
Nijveldt RJ, Wiezer MJ, Meijer C … +14 more , Prins HA, Statius Muller MG, Gouma DJ, Teerlink T, van Gulik TM, Borel Rinkes IH, Tilanus HW, van de Velde CJ, Wiggers T, Zoetmulder FA, Scotté M, Cuesta MA, Meijer S, van Leeuwen PA
Liver · 2001 Feb · PMID 11169074 · Publisher ↗
BACKGROUND/AIMS: Major liver resection results in a high morbidity and mortality, and endotoxin plays a role in post-resection hepatic failure. Severe hepatic failure as seen in hepatitis and cirrhosis may be accompanied...
BACKGROUND/AIMS: Major liver resection results in a high morbidity and mortality, and endotoxin plays a role in post-resection hepatic failure. Severe hepatic failure as seen in hepatitis and cirrhosis may be accompanied by hepatic encephalopathy and is characterized by a typical plasma amino acid pattern reflected by a decreased Fischer ratio. This study was performed to evaluate the plasma amino acid pattern in patients undergoing major liver surgery receiving placebo or the endotoxin-neutralizing agent bactericidal/permeability-increasing protein (rBPI21). PATIENTS AND METHODS: Forty-eight patients were randomized in this phase II, dose escalation, multicenter trial. Plasma amino acid profiles were determined preoperatively, and on the first (day 1) and third (day 3) postoperative day. RESULTS: In the placebo group the Fischer ratio decreased significantly on both postoperative days. Administration of rBPI21 also resulted in a decreased Fischer ratio on day 1, but not on day 3. Highly elevated alanine plasma levels were observed on day 1 in placebo-treated patients, whereas rBPI21 prevented this elevation. Plasma alanine levels on day 1 correlated with the duration of post-resection hepatic failure. CONCLUSIONS: Major liver resection results in a decreased Fischer ratio and a rise in plasma alanine levels. Plasma levels of alanine on the first postoperative day correlated with the duration of the post-resection hepatic failure. rBPI21 improved the Fischer ratio and prevented the rise of plasma alanine levels.
Aberrant expression of cytokeratin 7 as a histological marker of progression in primary biliary cirrhosis.
Yabushita K, Yamamoto K, Ibuki N … +5 more , Okano N, Matsumura S, Okamoto R, Shimada N, Tsuji T
Liver · 2001 Feb · PMID 11169073 · Publisher ↗
AIM: We evaluated the aberrant expression of cytokeratin 7 (CK-7) in hepatocytes as a marker of cholestasis and progression in primary biliary cirrhosis (PBC). PATIENTS AND METHODS: The expression of CK-7 was studied by...
AIM: We evaluated the aberrant expression of cytokeratin 7 (CK-7) in hepatocytes as a marker of cholestasis and progression in primary biliary cirrhosis (PBC). PATIENTS AND METHODS: The expression of CK-7 was studied by immunohistochemistry in 83 cases of PBC. This expression was compared with biochemical data, the deposition of copper-associated protein, and previous histological classifications. RESULTS: In normal liver, CK-7 was expressed exclusively in bile duct epithelial cells (BDE). In PBC, the expression was also observed in hepatocytes. The expression pattern was classified as follows: Grade 0, BDE as in normal; Grade 1, proliferated bile ductules; Grade 2, periportal hepatocytes in addition to proliferated bile ductules; Grade 3, intralobular hepatocytes; Grade 4, the majority of hepatocytes. The grades correlated with serum bilirubin levels but not with serum levels of biliary enzymes. A discrepancy between the CK-7 grading and Ludwig's classification was noted in cases with Stage 1 of the CK-7 grading who were considered Stage 2 or 3 in Ludwig's classification, suggesting that cholestasis and inflammatory activity might be independent events. CONCLUSIONS: These results suggest that the aberrant expression of CK-7 in hepatocytes may be a marker of chronic cholestasis and progression in PBC.
Suppression of hepatitis B virus replication mediated by hepatitis A-induced cytokine production.
van Nunen AB, Pontesilli O, Uytdehaag F … +2 more , Osterhaus AD, de Man RA
Liver · 2001 Feb · PMID 11169072 · Publisher ↗
BACKGROUND: Acute hepatitis A virus (HAV) infection can cause severe hepatitis especially in patients with underlying chronic liver disease. In patients with pre-existing chronic hepatitis B (HBV) acute HAV infection can...
BACKGROUND: Acute hepatitis A virus (HAV) infection can cause severe hepatitis especially in patients with underlying chronic liver disease. In patients with pre-existing chronic hepatitis B (HBV) acute HAV infection can suppress HBV replication. The exact mechanism of HBV suppression during acute HAV infection is still a subject of debate. One mechanism may be the production of HAV infection-induced cytokines leading to suppression of HBV replication and viral clearance. AIM: To evaluate cytokine production and HBV-specific lympho-proliferative responses (LPR) during acute HAV infection in a patient with chronic HBV infection-clearing markers of active HBV replication. DESIGN: Early detection of a case of acute HAV infection in an HBeAg-positive, HBV DNA-positive chronic HBV patient treated with lamivudine. RESULTS: At the time of HAV infection a sharp peak in the gamma-interferon (IFN-gamma) level occurred just before the rise in serum transaminase activity. This was subsequently followed by a decrease in HBV DNA and HBeAg below the limit of detection of the assay. However the HBV-specific T-cell response was not modified. After resolution of the acute HAV infection and withdrawal of antiviral therapy HBV replication relapsed. CONCLUSION: The sharp rise in IFN-gamma production mediated by the acute HAV infection may be pivotal in the suppression of HBV replication in chronic hepatitis B.
Assessment of hepatic ischaemia reperfusion injury by measuring intracellular tissue oxygenation using near infrared spectroscopy.
El-Desoky AE, Delpy DT, Davidson BR … +1 more , Seifalian AM
Liver · 2001 Feb · PMID 11169071 · Publisher ↗
AIMS/BACKGROUND: Hepatic ischaemia/reperfusion (I/R) injury is a major cause of liver damage during liver surgery and transplantation. The relationship between the severity of I/R injury and the degree of intracellular h...
AIMS/BACKGROUND: Hepatic ischaemia/reperfusion (I/R) injury is a major cause of liver damage during liver surgery and transplantation. The relationship between the severity of I/R injury and the degree of intracellular hypoxia has not been investigated. METHODS: New Zealand white rabbits were used in 4 groups (n=6 each). At laparotomy, left lobe hepatic ischaemia was produced for 30, 45, or 60 min followed by 60 min reperfusion and compared with controls. Liver function, bile flow, and flow in the hepatic microcirculation (HM) were measured. Near infrared spectroscopy (NIRS) was used to monitor hepatic oxyhaemoglobin (HbO2), deoxyhaemoglobin (Hb), and cytochrome oxidase (Cyt Ox). RESULTS: I/R injury produced deranged liver function tests, reduced bile flow, and reduced flow in the microcirculation in comparison with controls. During ischaemia, HbO2 and Cyt Ox were significantly reduced in comparison with controls. After reperfusion, a biphasic change in tissue oxygenation was observed, with an initial increase in HbO2 and Cyt Ox followed by a progressive reduction. The reduction in tissue oxygenation with ischaemia and reperfusion paralleled the ischaemia time. After I/R, the changes in Cyt Ox (intracellular oxygenation) significantly correlated with the parameters of hepatocellular injury to a higher degree than HbO2 (extracellular oxygenation). CONCLUSION: This study shows the potential of monitoring the degree of I/R injury by measuring hepatic tissue intracellular oxygenation.
Severe veno-occlusive disease after allogeneic bone marrow or peripheral stem cell transplantation--role of transjugular intrahepatic portosystemic shunt (TIPS).
Zenz T, Rössle M, Bertz H … +3 more , Siegerstetter V, Ochs A, Finke J
Liver · 2001 Feb · PMID 11169070 · Publisher ↗
AIMS: Veno-occlusive disease of the liver is a severe complication of allogeneic bone marrow or peripheral stem cell transplantation with a high mortality. In its severe form, the portal vein is used as an outflow tract...
AIMS: Veno-occlusive disease of the liver is a severe complication of allogeneic bone marrow or peripheral stem cell transplantation with a high mortality. In its severe form, the portal vein is used as an outflow tract for the arterial hepatic perfusion. A portosystemic side-to-side shunt, e.g. a transjugular intrahepatic portosystemic shunt, may facilitate portal outflow thus increasing hepatic (i.e. arterial) perfusion. METHODS: The effect of a transjugular shunt on liver function and blood flow was studied in three patients receiving shunt treatment 0-2 days after the diagnosis of severe veno-occlusive disease occurring 28, 20, and 17 days after allogeneic transplantation for acute myeloid leukemia, Hodgkin's disease and chronic myeloid leukemia, respectively. RESULTS: The transjugular shunt reduced the portosystemic pressure gradient from 23 to 8, 18 to 5, and 33 to 13 mmHg in patients 1, 2, and 3, respectively, increased the stagnant portal vein flow to normal, and decreased the arterial resistive index, indicating an increase in the arterial perfusion of the liver. This was accompanied by rapid relief from abdominal pain and removal of ascites. The AST concentration dropped from 1230, 417, and 2930 U/l before to 93, 20, and 41 U/l and the PT-time ratio improved 3-7 days after shunt treatment while the bilirubin concentration continued to rise until the patients died 26, 42, and 33 days after transplantation from multiorgan failure (two patients) or intracerebral hemorrhage. CONCLUSIONS: The transjugular shunt may have improved abdominal and hepatic perfusion and prevented further necrosis of hepatocytes. It did not, however, affect jaundice or survival, which was limited by extrahepatic complications.
Quantitative testing of liver function in patients with cirrhosis due to chronic hepatitis C to assess disease severity.
Herold C, Heinz R, Radespiel-Tröger M … +3 more , Schneider HT, Schuppan D, Hahn EG
Liver · 2001 Feb · PMID 11169069 · Publisher ↗
BACKGROUND/AIMS: Quantitative testing of liver function (QTLF) may allow a prognostic assessment of patients with various liver diseases. However, there are insufficient data about patients with liver cirrhosis due to he...
BACKGROUND/AIMS: Quantitative testing of liver function (QTLF) may allow a prognostic assessment of patients with various liver diseases. However, there are insufficient data about patients with liver cirrhosis due to hepatitis C. PATIENTS/METHODS: 86 consecutive patients (58 males, 28 females, age: 48.3 +/- 11.7 years) with chronic hepatitis C (HCV RNA pos.) underwent sonographically guided liver biopsy to confirm the diagnosis of cirrhosis. QTLF included aminopyrine breath test (microsomal liver function), galactose elimination capacity (cytosolic liver function), sorbitol clearance (liver plasma flow) and indocyanine green clearance (liver perfusion). Values were correlated with the Child-Pugh classification. RESULTS: 55% of the patients (n=47) had cirrhosis of Child-Pugh grade A, 28% of grade B (n=24) and 17% of grade C (n=15). QTLF showed a steady decrease from Child-Pugh grade A to grade B and to grade C. Contrary to markedly reduced tests of metabolic liver function in Child-Pugh grade patients, surrogate tests of hepatic perfusion were at the lower normal limit. All QTLF were significantly reduced in Child-Pugh grade B and C patients compared to healthy controls. Differences between the three Child grades were significant. CONCLUSION: In patients with cirrhosis due to hepatitis C, QTLF correlated inversely with Child-Pugh grades. Since in cirrhosis of grade A, surrogate tests of hepatic perfusion remained at the lower normal limit, whereas those of metabolic function were decreased, QTLF may be a tool to predict prognosis or complications in early cirrhosis due to chronic hepatitis C.
T cell receptor Vbeta chain restriction and preferred CDR3 motifs of liver-kidney microsomal antigen (LKM-1)-reactive T cells from autoimmune hepatitis patients.
Arenz M, Pingel S, Schirmacher P … +2 more , Meyer zum Büschenfelde KH, Löhr HF
Liver · 2001 Feb · PMID 11169068 · Publisher ↗
AIMS/BACKGROUND: The liver-kidney-microsomal antigen (LKM-1) has been recognized as a major CD4+ T cell antigen in autoimmune hepatitis (AIH). The aim of this study was to characterize the antigen recognition sites of th...
AIMS/BACKGROUND: The liver-kidney-microsomal antigen (LKM-1) has been recognized as a major CD4+ T cell antigen in autoimmune hepatitis (AIH). The aim of this study was to characterize the antigen recognition sites of the variable T cell receptor beta-chain (TCRBV) of T cells specific to LKM-1. METHODS: By repeated stimulation of T cells with a recombinant LKM-1 antigen or an LKM-derived peptide followed by limited dilution, we generated T cell clones. Usage of TCRBV was analyzed by RT-PCR and CDR3 antigen recognition sites were sequenced. RESULTS: The 18 LKM-1 specific T cell clones isolated from six AIH patients preferentially expressed the TCR elements BV9, BV5S2+S3, BV6, and BV13S1. Four BV9+ T cell clones rearranged the joining element JB1S3 within their CDR3 regions. JB2S3 was detected in another four clones together with BV5S2+S3 or BV13S1. A conserved sequence motif, Q(N)G(X)N, was seen in the diversity regions of five clones (36%). In order to identify T cells expressing the preferred TCRBV molecules in situ, immunohistologic examination of liver biopsies was performed. In AIH patients an accumulation of T cells expressing TCRBV 13S1, BV8 and BV5S3 was observed. CONCLUSIONS: Our data define TCRBV restriction and preferred CDR3 features of LKM-1 specific T cells. The in situ localization of T cells expressing these restricted TCR molecules may suggest a pathogenic relevance of LKM-1 specific cellular immune responses.
Seventh Day Syndrome--acute hepatocyte apoptosis associated with a unique syndrome of graft loss following liver transplantation.
Memon MA, Karademir S, Shen J … +4 more , Koukoulis G, Fabrega F, Williams JW, Foster P
Liver · 2001 Feb · PMID 11169067 · Publisher ↗
AIM: The aim of this study is to describe a unique 7th day syndrome (7DS), quite different from other causes of post-transplantation allograft dysfunction in a group of orthotopic liver transplant (OLT) patients who need...
AIM: The aim of this study is to describe a unique 7th day syndrome (7DS), quite different from other causes of post-transplantation allograft dysfunction in a group of orthotopic liver transplant (OLT) patients who needed retransplantation. METHODS: A retrospective analysis of 594 consecutive OLT over an 8-year period revealed that 10 patients developed allograft dysfunction approximately 7 days following an initially normal graft function. RESULTS: The features included: (a) severe liver failure; (b) sudden peak of extremely high liver enzymes at approximately day 7; (c) serial liver biopsy findings of central lobular hemorrhage with minimal inflammatory cell infiltrate and (d) an explant with no evidence of vascular thrombosis. The biochemical and morphometric pathological data of these patients were compared with data of patitents who had early acute rejection (AR), hepatic artery thrombosis (HAT), primary nonfunction (PNF), severe sepsis and no dysfunction. Lastly, serial liver core biopsies and explants were tested for evidence of apoptosis, which revealed a significantly higher number of apoptotic hepatocytes in 7DS compared to all control groups. CONCLUSIONS: Seventh Day Syndrome is a distinct entity associated with early graft dysfunction characterized by a marked apoptosis of hepatocytes. Fas receptor activation or other pathways of program cell death may be implicated in occurrence of 7DS.
Involvement of reactive oxygen species and nitric oxide radicals in activation and proliferation of rat hepatic stellate cells.
Svegliati-Baroni G, Saccomanno S, van Goor H … +3 more , Jansen P, Benedetti A, Moshage H
Liver · 2001 Feb · PMID 11169066 · Publisher ↗
BACKGROUND/AIMS: Reactive oxygen species (ROS) induce HSCs activation, proliferation and collagen gene expression in vitro. Nitric oxide (NO) represents a reactive molecule that reacts with ROS, yielding peroxynitrite. W...
BACKGROUND/AIMS: Reactive oxygen species (ROS) induce HSCs activation, proliferation and collagen gene expression in vitro. Nitric oxide (NO) represents a reactive molecule that reacts with ROS, yielding peroxynitrite. We thus verified the effect of NO on ROS-induced HSCs proliferation in vitro and correlated iNOS expression and ROS formation to HSCs activation in the early phase of liver injury leading to hepatic fibrosis in vivo. METHODS/RESULTS: HSCs were incubated with iron ascorbate (FeAsc) in vitro, which induced ROS production, ERK1/2 phosphorylation and increased cell proliferation. This effect was significantly reduced by the presence of the NO donor S-nitroso-N-acetylpenicillamine. Liver injury was induced in vivo in rats by dimethylnitrosamine administration. HSCs activation started 6 h after DMN administration and peaked at 1 week. ROS generation and neutrophil infiltration were evident for at least 48 h after DMN treatment, showing an identical distribution pattern. Only a few inflammatory cells expressed iNOS 6 h after DMN administration. CONCLUSIONS: we have shown that NO acts as a ROS scavenger in vitro, thus inhibiting HSCs proliferation. ROS production by infiltrating neutrophils occurs in the early phase of liver fibrosis and can represent a stimulus to HSCs activation in vivo. The reduced iNOS expression may account for the low NO levels and the inability to prevent the ROS-induced HSC activation in vivo.
Acute thrombocytopenic purpura after ingestion of Sho-saiko-to for hepatitis.
Kiguchi T, Kimura F, Niiya K … +2 more , Katayama Y, Harada M
Liver · 2000 Dec · PMID 11169065 · Publisher ↗
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18F-fluorodeoxyglucose (FDG)-PET features of focal nodular hyperplasia (FNH) of the liver.
Kurtaran A, Becherer A, Pfeffel F … +9 more , Müller C, Traub T, Schmaljohann J, Kaserer K, Raderer M, Schima W, Dudczak R, Kletter K, Virgolini I
Liver · 2000 Dec · PMID 11169064 · Publisher ↗
AIM: The aim of this paper is to describe the imaging pattern of focal nodular hyperplasia (FNH) by l8F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET). METHODS: Eight consecutive asymptomatic patients wi...
AIM: The aim of this paper is to describe the imaging pattern of focal nodular hyperplasia (FNH) by l8F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET). METHODS: Eight consecutive asymptomatic patients with histologic proof of FNH underwent 18F-FDG PET imaging. The lesions were found incidentally. The 18F-FDG PET imaging was performed with a dedicated PET tomograph after intravenous injection of 300-370 MBq 18F-FDG. The 18F-FDG accumulation in the lesions was (semi)quantified by calculating the standardized uptake value (SUV) and SUV has been corrected for the lean body mass (LBM). Eight patients with liver metastases spread from melanoma (n=2) and colorectal carcinoma (n=6) served as controls. The size of the FNH lesions and of the control group ranged from 2.0 to 8.5 cm (mean 4.83 cm +/- 2.37) and from 1.5 to 6 cm (mean 3.28 +/- 1.52), respectively. RESULTS: While in malignant liver lesions the accumulation of 18F-FDG was significantly increased, all FNH lesions showed normal or even decreased accumulation of 18F-FDG. In FNH lesions, SUV ranged between 1.5 and 2.6 (mean 2.12 +/- 0.38), whereas all liver metastases showed an increased SUV ranging between 6.20 and 16.00 (mean 10.07 +/- 3.79). The SUV corrected for LMB (SUVLBM) was similar to the SUV and ranged between 0.9 and 2.2 (mean 1.81 +/- 0.41) for FNH and between 5.9 and 16.3 (mean 9.15 +/- 4.03), respectively. CONCLUSION: In contrast to liver metastases, there is no increased glucose metabolism in FNH in vivo. The imaging feature of FNH by 18F-FDG-PET imaging is not specific for FNH; however, it may be helpful to differentiate FNH from liver metastases in cancer patients if radiological methods are not diagnostic.
Heterozygosity for the hemochromatosis gene in liver diseases--prevalence and effects on liver histology.
Höhler T, Leininger S, Köhler HH … +2 more , Schirmacher P, Galle PR
Liver · 2000 Dec · PMID 11169063 · Publisher ↗
BACKGROUND/AIMS: The effect of heterozygosity for the C282Y mutation in the HFE hemochromatosis gene on iron accumulation and disease progression in liver disease patients is unclear. METHODS: We investigated the prevale...
BACKGROUND/AIMS: The effect of heterozygosity for the C282Y mutation in the HFE hemochromatosis gene on iron accumulation and disease progression in liver disease patients is unclear. METHODS: We investigated the prevalence of this mutation in 531 patients and 205 healthy controls. In addition, we assessed the influence of the mutation on liver histology in 34 C282Y heterozygous and 124 age-, sex- and disease-matched controls without the mutation using the modified HAI and Chevallier score. RESULTS: The highest prevalence of the C282Y mutation was observed in patients with autoimmune hepatitis (17.2%, p<0.01) compared to 6.4% in healthy controls. Heterozygotes with hepatitis C and B virus infection showed higher ferritin and hepatic iron concentrations than patients without the mutation. However, we did not detect significant differences in necroinflammatory or fibrosis scores between carriers of the mutation and controls. CONCLUSIONS: There are marked differences in the prevalence of the C282Y mutation in patients with different liver diseases, with the highest prevalence rates in autoimmune hepatitis and PBC. However, the C282Y mutation alone only leads to a mild increase in iron accumulation in the majority of the patients, with the exception of H63D/C282Y compound heterozygotes. We found no evidence for more pronounced fibrosis in C282Y heterozygotes.
Divergent expression of midkine in the human fetal liver and kidney: immunohistochemical analysis of developmental changes in hilar primitive bile ducts and hepatocytes.
Kato M, Shinozawa T, Kato S … +1 more , Terada T
Liver · 2000 Dec · PMID 11169062 · Publisher ↗
BACKGROUND/AIMS: Midkine (MK) is a novel heparin-binding growth factor whose gene has been identified in embryonal carcinoma cells in early stages of retinoic acid-induced differentiation. In this study, we investigated...
BACKGROUND/AIMS: Midkine (MK) is a novel heparin-binding growth factor whose gene has been identified in embryonal carcinoma cells in early stages of retinoic acid-induced differentiation. In this study, we investigated the developmental expression of MK protein in the human fetal liver and kidney. METHODS: Twenty-one specimens each of the liver and kidney from fetuses (gestational weeks from 9 to 40) and neonates less than 4 weeks old were examined. Immunohistochemical and Western blot analyses were performed using a rat IgG2a monoclonal antibody against the carboxyl terminal region of human MK. RESULTS: Immunohistochemical analysis revealed MK expression in the human fetal liver and kidney. The MK expression in the fetal liver showed a strong reaction from 9 to 16 gestational weeks. MK was expressed in the ductal plate, migrating biliary cells and newly formed bile ducts, and in hepatocytes of the hilar region in all specimens in the first and second trimesters. By contrast, the MK expression decreased gradually and was weak or not detected in the third trimester and neonatal period. However, MK expression in the kidney was found at 16 gestational weeks, as well as during both gestation and the neonatal period. CONCLUSIONS: Divergent MK-expression was detected in the human fetal liver and kidney, and its expression may be related to fetal development, maturation, and functions of the liver and kidney.
Lipopolysaccharide-induced cytokine and receptor expression and neutrophil infiltration in the liver of osteopetrosis (op/op) mutant mice.
Jiang S, Naito M, Kaizu C … +4 more , Kuwata K, Hasegawa G, Mukaida N, Shultz LD
Liver · 2000 Dec · PMID 11169061 · Publisher ↗
BACKGROUND/AIMS: Mice homozygous for the osteopetrosis (op) mutation are genetically deficient in macrophage colony-stimulating factor (M-CSF/CSF-1) and are characterized by defective differentiation and function of macr...
BACKGROUND/AIMS: Mice homozygous for the osteopetrosis (op) mutation are genetically deficient in macrophage colony-stimulating factor (M-CSF/CSF-1) and are characterized by defective differentiation and function of macrophages. The aim of this study is to assess the contribution of M-CSF to lipopolysaccharide (LPS)-induced cytokine expression and neutrophil infiltration in the liver. METHODS: We investigated the effects of LPS administration in M-CSF-deficient op/op mutant mice. The expression of cytokines and receptors in the liver was studied by immunohistochemistry and RT-PCR. Neutrophil infiltration in the liver was also examined. RESULTS: After LPS administration, cytokine production and expression of LPS receptors, such as CD14 and scavenger receptor class A (MSR-A), were induced at lower levels in op/op mice than those in littermate mice. Neutrophil infiltration in the liver of op/op mice did not differ significantly from that of littermate mice. Anti-IL-8 receptor homologue and anti-C5a receptor antibody reduced the number of infiltrating neutrophils. CONCLUSIONS: These findings indicate that deficient macrophage activation following LPS injection in op/op mice is associated with decreased expression of CD14 and MSR-A in the liver. Thus, M-CSF plays a critical role in LPS-induced macrophage activation but does not exert a dominant role in neutrophil infiltration in the liver.
Hepatic sinusoidal endothelial fenestrae express plasma membrane Ca++pump and Ca++Mg++-ATPase.
Yokomori H, Oda M, Ogi M … +4 more , Kamegaya Y, Tsukada N, Nakamura M, Ishii H
Liver · 2000 Dec · PMID 11169060 · Publisher ↗
BACKGROUND/AIM: In general, intracytoplasmic free calcium ions (Ca++) are maintained at a very low concentration in mammalian tissue by extruding Ca++ against a high concentration of extracellular Ca++, mainly through th...
BACKGROUND/AIM: In general, intracytoplasmic free calcium ions (Ca++) are maintained at a very low concentration in mammalian tissue by extruding Ca++ against a high concentration of extracellular Ca++, mainly through the activity of the plasma membrane Ca++pump-ATPase. The aim of the present study was to demonstrate by electron cytochemical and immunogold methods the ultrastructural localization of two different types of plasma membrane Ca++-ATPase, i.e. Ca++Mg++-ATPase and Ca++pump-ATPase in the hepatic sinusoidal endothelium. METHODS: Liver tissues and the isolated hepatic sinusoidal endothelial cell (SEC)s were subjected to the following procedures. The ultrastructural localizations of Ca++Mg++-ATPase were examined by an electron cytochemical method. The ultrastructural localization of Ca++pump-ATPase was identified by an electron immunogold method. RESULTS: The cytochemical reaction of Ca++Mg++-ATPase was found to be localized on the outer sites of the plasma membrane of sinusoidal endothelial fenestrae (SEF). The immunogold particles indicating the presence of Ca++pump-ATPase were identified on the inner sites (cytoplasmic) of the invaginated plasma membrane of SEF CONCLUSIONS: Both Ca++Mg++-ATPase and Ca++pump-ATPase demonstrated on the SEF plasma membrane may be involved in the regulation of intracytoplasmic Ca++ concentration.
Protein expression of double-stranded RNA-activated protein kinase (PKR) in intrahepatic bile ducts in normal adult livers, fetal livers, primary biliary cirrhosis, hepatolithiasis and intrahepatic cholangiocarcinoma.
Terada T, Ueyama J, Ukita Y … +1 more , Ohta T
Liver · 2000 Dec · PMID 11169059 · Publisher ↗
BACKGROUND/AIM: The protein expression of double-stranded RNA-activated protein kinase (PKR) in intrahepatic bile ducts has not been investigated. METHODS: Immunohistochemistry and a semiquantitative scoring method in no...
BACKGROUND/AIM: The protein expression of double-stranded RNA-activated protein kinase (PKR) in intrahepatic bile ducts has not been investigated. METHODS: Immunohistochemistry and a semiquantitative scoring method in normal liver and biliary diseases were used for the investigation. RESULTS: In "normal" adult livers (n=10), intrahepatic bile ducts were negative for PKR. In normal fetal livers (n=25), primitive biliary epithelia were almost negative for PKR. In primary biliary cirrhosis (PBC) (n=30), damaged bile ducts were frequently positive for PKR, while uninvolved bile ducts were negative. In hepatolithiasis (n=27), proliferated bile ducts were positive for PKR, and the PKR score correlated with the degree of proliferation. In cholangiocarcinoma (CC) (n=44), PKR expression was frequently noted, and the PKR score correlated with good differentiation of CC, being highest in well-differentiated CC and lowest in poorly-differentiated CC. The PKR score decreased in the following order: CC (mean PKR score=3.96), hepatolithiasis (2.56), PBC (1.60), normal fetal liver (0.40), and normal adult livers (0.00). The PKR expression in hepatocytes was "baseline" in normal adult livers, while moderately increased in fetal livers, PBC, hepatolithiasis and CC. CONCLUSIONS: Although the significance of these data is unclear, they suggest (i) that PKR is absent in bile ducts in normal adult and fetal livers, (ii) that PKR in bile duct cells newly emerges or increases in PBC, hepatolithiasis, and CC, (iii) that PKR accumulates in damaged bile ducts in PBC, (iv) that PKR increases in parallel with biliary cell proliferation in hepatolithiasis, and (v) that PKR expression correlates with differentiation in CC. PKR expression in intrahepatic bile ducts seems to be associated with inflammation or cell proliferation of the bile duct cells.
Neopterin and interleukin-8--prognosis in alcohol-induced cirrhosis.
Homann C, Benfield TL, Graudal NA … +1 more , Garred P
Liver · 2000 Dec · PMID 11169058 · Publisher ↗
BACKGROUND: Neutrophil cytotoxity and activated macrophages have been implicated in the pathogenesis of alcohol-induced liver disease. The aim of this study was to relate plasma levels of neopterin, a marker of activatio...
BACKGROUND: Neutrophil cytotoxity and activated macrophages have been implicated in the pathogenesis of alcohol-induced liver disease. The aim of this study was to relate plasma levels of neopterin, a marker of activation of the cellular immune system, and IL-8, a neutrophil chemotactic factor, with severity of liver disease and prognosis in patients with alcohol-induced cirrhosis. METHODS: Plasma concentrations of neopterin and IL-8 were assessed in 81 patients with alcohol-induced cirrhosis admitted to the Department of Medicine B, Bispebjerg Hospital, Copenhagen, Denmark, and in 16 healthy controls. After a median follow-up period of 5 years, mortality and death causes were registered. The patients were divided into groups according to the major contributing cause of death: infection, upper gastrointestinal bleeding or hepatic coma. RESULTS: Neopterin and IL-8 levels were increased in the cirrhosis patients, but not significantly related to Child-Pugh classification. Five-year mortality was 67%. High neopterin levels (>upper quartile) were an independent predictor of death (p=0.01, Log rank and p<0.02, Cox). High IL-8 levels (>upper quartile) were of no significant prognostic value for overall mortality. Causes of death related mortality were as follows (Log rank): Neopterin; p=0.009, p=0.84 and p=0.94, and IL-8; p=0.36, p=0.002 and p=0.27, respectively, according to infection, bleeding and coma as causes of death. CONCLUSIONS: Neopterin and IL-8 plasma levels are raised in patients with alcohol-induced cirrhosis, and are predictive of mortality associated with infections and upper gastrointestinal bleeding, respectively.
A pilot study of recombinant interferon beta-1a for the treatment of chronic hepatitis C.
Habersetzer F, Boyer N, Marcellin P … +5 more , Bailly F, Ahmed SN, Alam J, Benhamou JP, Trépo C
Liver · 2000 Dec · PMID 11169057 · Publisher ↗
AIMS: Interferon alpha monotherapy induces a sustained response in less than 20% of patients treated for chronic hepatitis C. Interferon beta represents a potential therapeutic alternative for the treatment of chronic he...
AIMS: Interferon alpha monotherapy induces a sustained response in less than 20% of patients treated for chronic hepatitis C. Interferon beta represents a potential therapeutic alternative for the treatment of chronic hepatitis C. The aim of this pilot study was to evaluate the efficacy and tolerance of recombinant interferon beta-la administered subcutaneously. METHODS: Twenty-one drug-naive patients with chronic hepatitis C were treated with recombinant interferon beta-la administered, subcutaneously, for 24 weeks using two different regimens: 9 MU, three times per week (n=11) and 12 MU, three times per week (n=10). RESULTS: At the end of the treatment period, nine (43%) patients had a biochemical and virological response (i.e. normal ALT and absence of hepatitis C virus RNA by PCR). Four of these patients were in the 9 MU group and five in the 12 MU group. A biochemical and virological sustained response occurred in four (19%) patients, all in the 9 MU dose group. The 4 patients with a sustained response maintained their response during a follow-up period of 33 to 58 months. Side effects were mild and 19 (90%) patients completed the treatment period. CONCLUSIONS: The results of this pilot study indicate that interferon beta-la administered subcutaneously is an effective therapy for some patients with chronic hepatitis C, and suggest that interferon beta-1a deserves further evaluations in larger trials especially in combination with ribavirin.
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