Search

To evaluate the long-term efficacy of entecavir in nucleoside-naïve chronic hepatitis B patients.One hundred and sixty-seven patients treated with entecavir 0.01mg, 0.1mg or 0.5mg for 24-52weeks in Phase II studies entered rollover study ETV-060 and received entecavir 0.5mg daily. Responses were evaluated among patients with available samples.After 96weeks in ETV-060 (120-148weeks total entecavir treatment time), 88% (127/144) of patients had HBV-DNA400 copies/ml; 90.1% (128/142) had alanine aminotransferase (ALT) 1x the upper limit of normal (ULN) among those with abnormal baseline ALT; and 26% (32/121) achieved HBe seroconversion among those HBeAg(+) at baseline. A subset of 66 patients received entecavir 0.5mg (approved dose) from Phase II baseline: at week 96 in ETV-060, 83% (48/58) had HBV-DNA400 copies/ml, 88% (52/59) had ALT 1x ULN, and 20% (10/49) achieved HBe seroconversion. Twenty-one out of 66 patients had paired baseline and on-treatment biopsies: 100% (21/21) and 57% (12/21) demonstrated histologic improvement, and improvement in fibrosis, respectively, over 3years. The 3-year cumulative probability of resistance was 3.3% for all patients and 1.7% for the 0.5mg subset.Long-term entecavir for nucleoside-naïve patients resulted in high rates of virological, biochemical, and histological response, with minimal resistance.

Elevation of the serum angiotensin-converting enzyme (sACE) level and hepatic granulomas were found during a clinical relapse in a 22 year old patient with acute viral hepatitis type A (AVH-A). The serum transaminase level and sACE level remained high for more than 6 months. In the biopsied specimen of the liver, fibrous rings of granulomas composed of collagen types I, III, and V were observed. Furthermore, the localization of ACE was visible in the rough endoplasmic reticulum of epithelioid cells of granulomas in the liver under electron microscopy using the indirect immunoperoxidase method. These results suggest that granuloma cells in the liver caused by hepatitis A may be involved in ACE production. In addition, other diseases associated with the presence of granulomas in the liver, such as lymphoma, cytomegalovirus infection, visceral leishmaniasis, and lupoid hepatitis, were ruled out. However, the hepatic granulomas disappeared with the healing of AVH-A. In this regard, the present case is considered to be one of the very few cases of hepatic sarcoidosis.

To clarify the relationship between hepatitis C virus infection and excessive alcohol intake, we carried out histological examination of the liver in 46 alcoholics with chronic hepatitis C virus infection and compared the findings in 55 patients with chronic hepatitis C, 38 with alcoholic liver disease, and 27 with chronic hepatitis B. The majority of alcoholics with chronic hepatitis C virus infection displayed virus-related histological changes very similar to those in chronic hepatitis C, including frequent lymphoid follicles (34.7%) or aggregates (93.3%) in the portal tracts, mild necroinflammatory change (76.1%) in the parenchyma, and lymphocytosis in sinusoids (82.7%). Liver cell dysplasia and irregular regenerative activity of hepatocytes were rarely observed. The effects of alcohol on the liver were found to be minimal in the majority. These findings could suggest that the hepatic injury in the majority of alcoholics with chronic hepatitis C virus infection in Japan is due to persistent hepatitis C virus infection rather than to alcoholic injury. In addition, our study disclosed that the perivenular fibrosis which is designated as a histological characteristic of alcoholic liver disease is frequently observed in chronic hepatitis C. These similarities suggest that a similar fibrogenesis is present in chronic hepatitis C and alcoholic liver disease.

The role of vacuolar type H+-ATPases (v-ATPases) and pH gradient between the endocytic compartments and cytoplasm in the endocytosis of horseradish peroxidase, a mannose-terminated glycoprotein, was investigated morphologically in isolated rat sinusoidal endothelial cells. Toward this purpose, a specific inhibitor of v-ATPases, bafilomycin A1, was used to inhibit v-ATPases in the vacuolar system. Uptake of horseradish peroxidase was examined by electron microscopy. Fluorescent staining by acridine orange showed that bafilomycin A1 inhibited the acidification of the endocytic compartments. Horseradish peroxidase was taken up via mannose receptors and was distributed in the endocytic structures in the isolated sinusoidal endothelial cells. Uptake of horseradish peroxidase was significantly inhibited by bafilomycin A1, and this finding was confirmed by morphometrical analysis. These results suggest that: a) v-ATPases are necessary for acidification of the endocytic compartments in the sinusoidal endothelial cells and b) the pH gradient between the endocytic compartments and the cytoplasm that is generated by v-ATPases is necessary for the receptor-mediated endocytosis of a mannose-terminated glycoprotein, horseradish peroxidase.

Entecavir (ETV) is a potent nucleoside analogue against hepatitis B virus (HBV), and emergence of drug resistance is rare in nucleoside-naive patients because development of ETV resistance (ETVr) requires at least three amino acid substitutions in HBV reverse transcriptase. We observed two cases of genotypic ETVr with viral rebound and biochemical breakthrough during ETV treatment of nucleoside-naive patients with chronic hepatitis B (CHB).Case 1: A 44-year-old HBeAg-positive man received ETV 0.1 mg/day for 52 weeks and 0.5 mg/day for 96 weeks consecutively. HBV DNA was 10.0 log(10) copies/ml at baseline, declined to a nadir of 3.1 at week 100, and rebounded to 4.5 at week 124 and 6.7 at week 148. Alanine aminotransferase (ALT) level increased to 112 IU/l at week 148. Switching to a lamivudine (LVD)/adefovir-dipivoxil combination was effective in decreasing HBV DNA. Case 2: A 47-year-old HBeAg-positive man received ETV 0.5 mg/day for 188 weeks. HBV DNA was 8.2 log(10) copies/ml at baseline, declined to a nadir of 2.9 at week 124, and then rebounded to 4.7 at week 148 and 6.4 at week 160. ALT level increased to 72 IU/l at week 172. The ETVr-related substitution (S202G), along with LVD-resistance-related substitutions (L180M and M204V), was detected by sequence analysis at week 124 in both case 1 and case 2.ETVr emerged in two Japanese nucleoside-naive CHB patients after prolonged therapy and incomplete suppression and in one patient after0.5 mg of dosing. ETV patients with detectable HBV DNA or breakthrough after extended therapy should be evaluated for compliance to therapy and potential emergence of resistance.

Background: Combined pegylated interferon and ribavirin has improved chronic hepatitis C (CH-C) therapy, however sustained virologic response is achieved in about half of patients with a 1b genotype infection. We assessed oral ursodeoxycholic acid (UDCA) on serum biomarkers as a possible treatment for interferon nonresponders. Methods: CH-C patients with elevated alanine aminotransferase (ALT) were assigned randomly to 150 (n = 199), 600 (n = 200), or 900 mg/day (n = 197) UDCA intake for 24 weeks. Changes in ALT, aspartate aminotransferase (AST), and gamma-glutamyl transpeptidase (GGT) were assessed. This study is registered at ClinicalTrial.gov, NCT00200343. Results: ALT, AST, and GGT decreased at week 4 then remained constant during drug administration. The median changes (respectively 150, 600, and 900 mg/day) were: ALT, -15.3, -29.2, and -36.2%; AST, -13.6, -25.0, and -29.8%; GGT, -22.4, -41.0, and -50.0%. These biomarkers decreased significantly less in the 150 mg/day than in the other two groups. Although changes in ALT and AST did not differ between the 600 and 900 mg/day groups, GGT was significantly lower in the 900 mg/day group. In subgroup analysis, ALT decreased significantly in the 900 mg/day group when the baseline GGT exceeded 80 IU/L. Serum HCV-RNA did not change in any group. Adverse effects were reported by 19.1% of the patients, with no differences between groups. Conclusions: A 600 mg/day UDCA dose was optimal to decrease ALT and AST levels in CH-C patients. The 900 mg/day dose decreased GGT levels further, and may be preferable in patients with prevailing biliary injuries.

Hepatitis B virus (HBV)- or hepatitis C virus (HCV)- associated liver diseases are now one of the important health problems in the world because of the high numbers of patients and the serious consequences. Recently, however, relatively effective treatments with antiviral agents have become available. Interferon (IFN), lamivudine and adefovir are now approved for treatment of HBV-associated liver diseases and they have been shown to be fairly effective. The goal of treatments for HBV-associated liver disease is to achieve a clinical cure in as short a period as possible without producing resistance mutation of the virus. Several nucleotide analogues with more potent antiviral activities are now in clinical trials. In the case of HCV-associated liver diseases, Pegylated IFN (Peg IFN) + ribavirin combination therapy is the standard and most effective treatment with a sustained response of 60-70%. The goal of the treatments for these liver diseases is to induce the complete eradication of the infected virus and at present new anti HCV drugs targeting the molecular segments of the virus are under development. It is expected that the complete eradication of infected virus will be possible in most cases in the near future.

Oxidative stress has recently been shown to play an important role in various liver diseases. Therefore, further studies on oxidative stress in liver diseases are urgently required. In this review, oxidative stress is discussed from the aspects of molecular morphology, metabolism, and aging.

The possibility of delaying progression to hepatocellular carcinoma in chronic hepatitis C patients with genotype 1 and high viral titers with baseline ALT levels of ≥50 IU/L was examined by administration of IFN plus ribavirin combination therapy using ALT normalization as index and IFN monotherapy as control. The rate of sustained ALT normalization (ALT normal at 24 weeks after the end of treatment) was 28.1% with combination therapy and 10.5% with IFN monotherapy ( P = 0.001). Furthermore, the number of patients with sustained viral response (SVR) and with sustained ALT normalization in non-SVR patients was also significantly higher in the combination therapy versus monotherapy group. Mean ALT values during treatment and for 6 months after the end of treatment were significantly lower with combination therapy versus monotherapy even in virological nonresponders, as well as significantly lower during the post-treatment observation period in patients who relapsed after the end of treatment. Since increase in the rate of sustained ALT normalization and SVR were successfully achieved, inhibition of progression to hepatocellular carcinoma should be studied with long-term IFN and ribavirin combination therapy.

アルコール性肝硬変で, 顕性の肝性脳症を発症した5症例にフルマゼニルを3～6日間, 静脈内に持続投与し, 投与前後の脳波およびアルコール性肝硬変にもとづく肝性脳症昏睡度の変化を観察した. 脳波は5例すべてにおいてθ～δ波並びに群発的に認められていた三相波からα波あるいは slow α波へ改善し, 肝性脳症昏睡度は2例でII度から意識清明に, 2例ではIII度からI度に, 更に1例ではIII度から意識清明に改善した. フルマゼニル投与中止後の脳症の再発は1例で認められた. なお, フルマゼニルによる副作用は認められなかった. これらの結果より, フルマゼニル持続投与は安全で, アルコール性肝硬変に伴う肝性脳症の改善に有効であることが示唆された.

Vascular endothelial growth factor (VEGF) plays a major role in angiogenesis, which is essential for both healing of injured tissue and proliferation of carcinoma cells. In this study we elucidated the expression and role of VEGF in rat liver regeneration after partial hepatectomy. VEGF expression was mainly detected in periportal hepatocytes and reached a maximal level 48–72 hr after partial hepatectomy by both immunohistochemistry and in situ hybridization. Similarly, immunohistochemistry for Ki-67 showed that the proliferative activity of sinusoidal endothelial cells was highest in the periportal area and reached a maximal level 72 hr after partial hepatectomy. Moreover, neutralization of VEGF significantly inhibited proliferative activity of hepatocytes ( p < 0.0001), as well as sinusoidal endothelial cells ( p < 0.001), at 48 and 96 hr after partial hepatectomy. Conversely, injection of VEGF significantly promoted proliferative activity of hepatocytes ( p < 0.0001) as well as sinusoidal endothelial cells ( p < 0.0005) at 48 hr after partial hepatectomy. These results suggest that VEGF promotes proliferation of hepatocytes through reconstruction of liver sinusoids by proliferation of sinusoidal endothelial cells. Furthermore, these data point to a new therapeutic strategy, the use of VEGF and other hepatocyte growth factors in fulminant or severe acute hepatitis.

Recently, lamivudine has been used to treat chronic hepatitis B. The effect of lamivudine has been evaluated in short-term (6 months) follow-up studies after treatment. Here, we report the long-term (2 years) follow-up results of lamivudine therapy for chronic hepatitis B. The subjects were seven patients with chronic hepatitis B, with evidence of hepatitis B virus (HBV) replication. All patients were treated with 100 mg lamivudine daily for 12 months. The patients were monitored for up to 2 years after treatment. Serum HBV DNA by branched DNA assay of all patients became undetectable during the therapy. In two patients, sustained suppression of serum HBV DNA was found after treatment. The remaining five patients exhibited rebound of ALT (>2 times baseline) and returned to seropositive for HBV DNA and HBeAg after lamivudine cessation. One of these five patients died of liver failure 3 months after treatment. However, in two of five patients whose alanine aminotransferase (ALT) had rebounded, HBV DNA became undetectable, and the ALT levels markedly decreased 2 years after the end of therapy. Since the disappearance of HBV DNA and stabilization of the ALT level were observed within two patients by 2 years after cessation of treatment, the patients whose ALT had rebounded should be followed up for a long-term period. To confirm the effect of lamivudine, long-term follow-up in many patients is necessary.

Hepatitis C virus (HCV) causes various extrahepatic immunologic abnormalities. Recently, an association between HCV infection and antiphospholipid syndrome, including thrombocytopenia, has been reported. However, the precise relationship between thrombocytopenia and anticardiolipin antibodies in patients with chronic HCV infection is not fully understood; likewise, the association of antiphospholipid syndrome and various liver diseases is not well understood. To evaluate the prevalence and importance of antiphospholipid antibodies in various chronic liver diseases, we determined the levels of anticardiolipin antibodies, platelet numbers, and levels of platelet-associated immunoglobulin G (PA-IgG) and thrombin-antithrombin III complex (TAT) in patients with chronic HCV infection, chronic hepatitis B virus (HBV) infection, and primary biliary cirrhosis (PBC). The prevalence of anticardiolipin antibodies in patients with HCV infection was significantly higher than that in control subjects or individuals with the other liver diseases examined. However, there was no significant correlation between anticardiolipin antibodies and platelet counts or TAT. The frequency of thrombotic complications was similar in anticardiolipin antibody-positive and -negative patients with chronic HCV infection. Further, sera from all but one anticardiolipin antibody-positive HCV patient were negative for phospholipid-dependent anti-beta2 glycoprotein I antibodies. Our results suggest that anticardiolipin antibodies are frequently found in patients with chronic HCV infection, but they do not appear to be of clinical importance. Immunologic disturbances induced by HCV or prolonged tissue damage in systemic organs as a result of the extrahepatic manifestations of HCV infection may induce the production of antibodies to various cardiolipin-binding proteins or phospholipids.

It is a developing problem that long-term treatment with lamivudine, which is a therapeutic drug for chronic hepatitis B under clinical study, causes mutation in the region encoding the YMDD motif in the HBV DNA polymerase gene, inducing lamivudine-resistant HBV in some cases. Therefore, we developed a new method of detecting gene mutation using the mini-sequencing method. Serum samples collected from patients with HBV infection (60 cases untreated with lamivudine and four cases treated with lamivudine) were examined for gene mutation by this method. As a result, while there were no mutations detected in lamivudine-untreated cases, a mutation from YMDD to YVDD or YIDD was detected in cases with lamivudine administration. In cases in which the mutation was detected, HBV gene obtained from the serum was subcloned and sequenced to detect the mutation, confirming that this method is appropriate for detecting gene mutations. This method may be a rapid, simple, and reliable method of detecting resistant virus that can process a number of serum samples that will be necessary to be tested when lamivudine is approved and administration to chronic hepatitis B patients is initiated.

Backgroundl Aims. To identify injured cells in the liver of patients with primary biliary cirrhosis (PBC) and to determine the effects of ursodeoxycholic acid (UDCA) on these cells, we examined the cellular expression of heat shock proteins (HSPs) in PBC both before and after treatment with UDCA. Methods: Expression of HSP70 and ubiquitin in PBC livers (n=34) was evaluated immunohistochemically as well as by immunoblot analysis, and compared with chronic viral hepatitis type C (n= 9), primary sclerosing cholangitis (n=8), and controls (n=7). Results. Immunoblot analysis demonstrated a marked expression of HSP70 and ubiquitin in PBC. Immunohistochemical staining for both HSP70 and ubiquitin was observed to be strong in biliary epithelial cells (BECs) and moderate in both hepatocytes and arteries in PBC. Cellular labelling rates for HSP70 and ubiquitin of bile ducts in PBC were significantly higher (p

Background/Aims: Tumor invasion and metastasis consist of a series of complex events. During this process, the ability of tumor cells to adhere to laminin, a major component of basement membranes, is required at various steps. The expression of laminin-binding integrins and the extent of tumor metastasis and progression appear to be related. In hepatocellular carcinoma, increased expression of laminin-binding integrins is observed. However, little is known concerning the possible functional interactions between laminin-binding integrins and laminin. Therefore, we investigated the participation of laminin-binding integrins in the attachment of hepatoma cells to laminin. Methods: Human hepatoma cell lines (KIM-1, KYN-1,2) were used. We investigated the expression of integrin α 1 , α 2 , α 3 , α 6 , β 1 and β 4 subunits on hepatoma cells by immunocytochemical and flow cytometric analysis. Participation of these integrin subunits in the attachment of hepatoma cells to laminin was evaluated by an inhibition of cell adhesion assay. Results: Integrin α 1 , α 2 , α 3 , α 6 and β 1 subunits were expressed at the marginal areas of hepatoma cells, while the integrin β 4 subunit was scarcely detected. Laminin promoted the attachment of hepatoma cells in a dose-dependent manner. Although anti-integrin α 1 , α 2 , α 3 and β 4 subunit antibodies did not inhibit cell attachment to laminin, anti-integrin α 6 and β 1 subunit antibodies inhibited the attachment by 50% or more. Conclusions: These findings indicate that integrin α 6 β 1 is very important in the attachment of hepatoma cells to laminin, suggesting the participation of this integrin in metastasis and invasion of hepatoma cells.

A 33-year-old woman with a history of photosensitivity, persistent abdominal pain, and liver dysfunction was admitted to our department because of abdominal pain and progression of liver dysfunction. On admission, levels of protoporphyrin and coproporphyrin within erythrocytes were markedly increased. Autofluorescent erythrocytes were also detected, leading to a diagnosis of erythropoietic protoporphyria. A liver biopsy specimen revealed cirrhosis with dark brown granules filling hepatocytes, bile canaliculi, and bile ductules. Transfusion of washed erythrocytes, hemodialysis, and administration of cholestyramine and beta-carotene transiently improved levels of porphyrins and liver function. The patient died of rupture of esophageal varices followed by multiple organ failure. However, the treatments were believed to have extended survival.

Asialoglycoproteins are internalized via specific receptors localized on the hepatic parenchymal cells. The role of vacuolar type H + -ATPase (v-ATPase) and vacuolar pH in intracellular transport of asialoglycoproteins was investigated in isolated rat hepatocyte couplets. Two specific inhibitors of v-ATPase, bafilomycin A1 and concanamycin B, were used to inhibit acidification of the vacuolar system. Intracellular transport of asialoglycoproteins was investigated using gold-conjugated asialofetuin with electron microscopy. Fluorescent staining by acridine orange showed that bafilomycin A1 and concanamycin B each inhibited acidification of endocytic compartments. Electron microscopy demonstrated that the number of autophagic vacuoles was increased, and the uptake of gold-conjugated asialofetuin was significantly inhibited by these agents. Vesicle budding and membrane fusion between endocytic structures in the peripheral area and intracellular transport of endocytosed asialofetuin to lysosomes were inhibited by these agents. These results suggest that the intracellular transport of endocytosed asialoglycoproteins to lysosomes depends on acidification of the vacuolar system (vacuolar pH) in hepatocytes.

A 17-year-old woman with arterial and venous thrombosis of the leg diagnosed as antiphospholipid syndrome (APS) associated with systemic lupus erythematosus (SLE) is reported. Her serum C-reactive protein (CRP) was elevated and complement concentrations were normal. Symptoms of APS were improved with prednisolone, when the serum CRP concentration decreased, and low serum complement concentration and white blood cell count appeared. These are characteristic features of SLE. It is suggested that APS is a possible complication of SLE and may modify the clinical features of SLE.

The presence of Helicobacter pylori (H. pylori) in the natural environment has been demonstrated in a number of studies. However, its route of infection into humans is unknown. To study this further, we attempted to detect H. pylori in the natural environment in a region of Japan with a high infection rate. Tap and well water and field soil samples were collected from around the residences of subjects who had participated in an epidemiological survey in 1996. Samples of water from rivers and ponds, and specimens of flies and cow faeces were collected in the region. DNA was extracted from the water, field soil and faecal samples after selective collection of H. pylori by the immunomagnetic-bead separation technique. H. pylori-specific DNA was detected in water, field soil, flies and cow faeces by nested polymerase chain reaction (PCR), and the ureA partial sequences of the PCR products were aligned. The nucleotide sequences of the samples amplified by PCR were highly homologous (96-100%) with the H. pylori sequence in the GenBank database and the H. pylori-specific DNA sequences were highly homologous with each other. These findings suggest the existence of H. pylori in the natural environment and a possible transmission route.

We conducted an epidemiological study of 509 residents of H town, Fukuoka, Japan, to investigate the high mortality rate from liver disease. Antibodies to hepatitis C virus (HCV) (anti-HCV) were detected in 120 residents (23.6%); HCV RNA in 91 (17.9%), and hepatitis B surface antigen (HBsAg) in 13 (2.6%). Multivariate logistic regression analyses showed that presence of anti-HCV, male gender, and history of liver disease were associated with the presence of liver dysfunction, and that age of more than 40 years and a particular district were associated with the presence of anti-HCV. HCV RNA was more frequently detected in anti-HCV-positive men than women (41, or 85.4% versus 50, or 69.4%) (P < 0.05). The incidence of liver dysfunction was significantly higher in HCV RNA-positive men than women (32, or 66.7% versus 22, or 30.6%) (P < 0.05). These findings suggest that: (1) HCV was correlated with the high mortality rate from liver diseases, (2) there were district-related differences in the incidence of HCV, and (3) the lower frequency of elimination of HCV from men may explain why they showed a high mortality from liver disease.

A component of fungus Thielavia minor, OPC-15161, has been shown to inhibit the proliferation and extracellular matrix production of extracellular matrix-producing mesangial cells in the kidney in vivo. In this study, we examined the effects of OPC-15161 on the proliferation and extracellular matrix production of rat cultured hepatic stellate cells (HSCs). To determine the effect of OPC-15161 on proliferation of HSCs, the cell number and the uptake of [3H]thymidine were investigated in the presence and absence of interleukin-1β (IL-1β). IL-1β significantly increased the uptake of [3H]thymidine in the HSCs, and the addition of OPC-15161 inhibited the uptake in a dose-dependent manner. The cell number of HSCs was also increased by IL-1β, which was inhibited by OPC-15161. Production of extracellular matrix by OPC-15161 was studied by the production of [3H]-hydroxyproline in the presence and absence of transforming growth factor-β1 (TGF-β1). TGF-β1 significantly increased the production of [3H]-hydroxyproline in the cells, whereas the addition of OPC-15161 inhibited this effect dose dependently. We also investigated the effects of OPC-15161 on Ca2+ mobilization and measured D-myo-inositol 1,4,5-triphosphate (IP3) in the HSCs. IL-1β induced the increase of intracellular Ca2+ and IP3 concentrations in the HSCs, which were decreased by OPC-15161. Based on these results, we conclude that OPC-15161 inhibited the proliferation and production of hydroxyproline in cultured rat HSCs, and thus, it may have a role in prevention of liver fibrosis in vivo. J. Cell. Physiol. 174:398–406, 1998. © 1998 Wiley-Liss, Inc.

Ascites and serum levels of vascular permeability factor (VPF) were measured by enzyme-linked immunosorbent assay in 30 patients with liver cirrhosis (19 had uninfected ascites and 11 had spontaneous bacterial peritonitis (SBP)) and in 15 patients with peritoneal carcinomatosis. Patients with SBP and peritoneal carcinomatosis had significantly higher ascites VPF levels than cirrhotic patients without SBP, whereas the serum levels did not differ between cirrhotic patients with and those without SBP. A paired analysis showed lower ascites VPF levels compared to the serum levels in cirrhotic patients without SBP and conversely, the levels were higher in patients with SBP. A longitudinal study revealed a marked increase in ascites VPF levels during the occurrence of SBP, which declined after successful treatment. Ascites VPF levels were found to correlate significantly with conventional markers of exudative effusions. These findings indicate that ascites VPF may be useful clinically as a marker of SBP.

Patients with cirrhosis tend to have esophageal variceal bleeding episodes at night, rather than during the day time. Since human beings carry on ordinary activities in the upright posture in the day time and are recumbent at night, we hypothesized that posture may be a factor related to a circadian variation of variceal bleeding. The aim of this study was to examine the effect of upright posture on esophageal varices hemodynamics in patients with cirrhosis.Nine patients with cirrhosis and esophageal varices were included in a crossover study performed on 2 separate days. On the non-endoscopic day, cardiac output, portal vein flow velocity, and superior mesenteric artery flow velocity were measured with percutaneous Doppler ultrasonography. Plasma renin activity and plasma norepinephrine concentrations were also determined. On the endoscopic day, in addition to the above measurements, esophageal varices flow velocity was measured using transesophageal Doppler ultrasonography. These measurements were performed in the supine position and 20 min after the assumption of the upright position.On the non-endoscopic day, the upright posture significantly decreased cardiac output, portal vein flow velocity, and superior mesenteric artery flow velocity. Plasma renin activity and plasma norepinephrine concentration were significantly increased after assumption of the upright position. On the endoscopic day, similar hemodynamic and hormonal changes were observed. In addition, the upright posture significantly decreased esophageal varices flow velocity. Furthermore, the magnitude of the reduction in esophageal varices flow velocity (-42%) was significantly greater than that in portal vein flow velocity (-22%, p0.01) and that in superior mesenteric artery flow velocity (-25%, p0.01). Although the change in esophageal varices flow velocity was not significantly correlated with that in plasma renin activity (r=-0.28) and that in plasma norepinephrine concentration (r=-0.10), it was significantly correlated with the change in superior mesenteric artery flow velocity (r=0.73, p0.05).The upright posture decreases esophageal varices flow velocity mainly because of the reduction in splanchnic blood flow. This effect may contribute to a low prevalence of esophageal variceal bleeding in the day time in patients with cirrhosis.

We examined the changes of hepatic fibrosis for several years following interferon- α (IFN- α ) treatment in patients with chronic hepatitis C. This study included 37 complete responders (CR) and 37 non-responders (NR) to IFN- α treatment. The period of post-treatment was 6–50 months. The scores for periportal necrosis, intralobular inflammation, portal inflammation and fibrosis before and after treatment were compared. Furthermore, the serum fibrosis markers (hyaluronic acid (HA), N-terminal amino peptide of type III procollagen (PIIIP), Type IV collagen) before and after treatment were compared in 11 CR and 14 NR. In the CR, the scores for histological findings were significantly decreased compared to those before treatment. Especially, in five of the 37 CR, the hepatic fibrosis disappeared and improved to almost normal after treatment. In the CR, the serum levels of HA and PIIIP after treatment were also significantly decreased compared to those before treatment. In the NR, however, the grade of fibrosis after treatment was more severe than that before treatment. These findings suggest that liver histology containing hepatic fibrosis is improved in patients who are continuously negative for hepatitis C virus (HCV) RNA through several years after IFN- α treatment.

We examined the effects of OK-432, a biological response modifier, on matrix metalloproteinase-9 (MMP-9) expression and activity in rat cultured Kupffer cells. Kupffer cells were isolated from the normal rat liver, and cultured for 48 h. Thereafter, cultured cells were divided into the OK-432-treated group and the untreated group, then cultured for 48 h. Types I and IV collagenase activity in each medium were measured using a collagenase activity assay kit. In addition, MMPs 2 and 9 activity was examined by gelatin zymography. Furthermore, MMP-9 expression in Kupffer cells was examined by Northern blot analysis. In the OK-432-treated group, type IV collagenase activity in medium was significantly increased, but type I collagenase was not changed, compared to that in the untreated group 24–48 h after treatment. Zymography detected latent and active types of MMP-9, but did not detect these types of MMP-2. Furthermore, Northern blotting detected MMP-9 mRNA expression in cultured Kupffer cells 48 h after OK-432 treatment. The results of this study showed that OK-432 increased MMP-9 expression in rat cultured Kupffer cells.

Hepatitis A virus (HAV) is generally excreted in the feces, and secretory immunoglobulin (Ig) A anti-HAV may play an important role in protecting re-infection of HAV. To determine whether secretory IgA anti-HAV is present in the saliva of patients with HAV infection, saliva samples from 13 patients with acute hepatitis A and 11 with acute hepatitis B or C were tested for secretory IgA and IgA anti-HAV. IgA, IgM and IgG concentrations in saliva were also measured in these patients. Secretory IgA and IgA anti-HAV were assayed using radioimmunoassay. IgA, IgM and IgG concentrations were significantly higher in acute phase (within 3 weeks of clinical onset) than convalescence phase (after 4 weeks of clinical onset) of hepatitis A patients. There were no elevations in immunoglobulin concentrations in acute hepatitis B and C. Secretory IgA and IgA anti-HAV was found only in the acute phase of hepatitis A patients; they returned to normal range in the convalescence phase. Secretory IgA and IgA anti-HAV in saliva of hepatitis A patients may have a role in protecting against HAV re-infection.

Backgrounds and Study Aims: Effect of endoscopic variceal ligation (EVL) on gastric mucosal hemodynamics would differ in patients with and without large fundal varices. The aim of this study was to test this hypothesis. Patients and Methods: Twenty-seven patients with cirrhosis and large sized esophageal varices were prospectively studied. There were eight patients with large fundal varices and 19 patients without large fundal varices. Before EVL, gastric mucosal hemodynamics were endoscopically assessed by laser-Doppler velocimetry and reflectance spectrophotometry in the antrum and the corpus. In the reflectance spectrophotometric measurements, gastric mucosal hemoglobin content (IHb) and gastric mucosal oxygen saturation (ISO 2 ) were determined. The severity of portal-hypertensive gastropathy (PHG) was also recorded at the antrum and the corpus. For data analysis, PHG was scored (absent, 0; mild, 1; severe, 2; bleeding, 3). These measurements were repeated after initial (three days after initial session) and repeated (seven days after last session) EVL. Results: At the antrum, neither PHG score nor gastric mucosal hemodynamic parameters were modified after initial and repeated EVL in patients with and without large fundal varices. In addition, no significant differences of the integrated changes in PHG score and gastric mucosal hemodynamic parameters were observed in the two groups. At the corpus, PHG score significantly increased after initial and repeated EVL in patients without large fundal varices. In these patients, laser-Doppler signal and ISO 2 significantly decreased and IHb significantly increased after initial and repeated EVL. In contrast, PHG score, laser-Doppler signal, and ISO 2 did not change significantly in patients with large fundal varices, although IHb transiently increased after initial EVL. Furthermore, the integrated changes in PHG score and gastric mucosal hemodynamic parameters were significantly lower in patients with large fundal varices than in those without. Conclusion: The aggravation of PHG after EVL is due to congestion of the gastric mucosal circulation. The presence of large fundal varices plays a protective role in the development of EVL-induced gastric mucosal hemodynamic derangement.

Deep abdominal lymph node enlargement has been detected by ultrasound examination in patients with hepatitis C virus (HCV) infection. To clarify the potential for extrahepatic existence and/or replication of HCV in such abdominal lymph node, positive- and negative-strand HCV RNA were investigated in abdominal lymph node mononuclear cells (MNC) as well as in the serum of patients with HCV. The study population consisted of eight hepatocellular carcinoma (HCC) patients positive for antibody to HCV (anti-HCV). Lymph nodes of hepatoduodenal ligament were resected at surgery for HCC. Both HCV RNA strands were examined using highly strand-specific r Tth reverse transcription-polymerase chain reaction (r Tth RT-PCR) followed by Southern blotting analysis. Positive-strand HCV RNA was detected in three (37.5%) abdominal lymph node MNC and in seven (87.5%) serum samples. Negative-strand HCV RNA was not detected in abdominal lymph node MNC, while it was observed in two (25%) serum samples. Histologically, the lymph nodes taken from subjects showed reactive follicular hyperplasia with or without the presence of HCV RNA. These observations suggest that HCV is located in the abdominal lymph nodes, but does not replicate within them. Negative-strand HCV RNA detected in serum samples may have been due to contamination with circulating HCV RNA from hepatocytes.

The clinical significance of circulating vascular endothelial growth factor (VEGF) in patients with various liver diseases was investigated. Twenty-one patients with acute hepatitis (AH), 40 with chronic hepatitis (CH), 34 with cirrhosis (LC), 16 with fulminant hepatitis (FH), 10 with primary biliary cirrhosis (PBC), 12 with autoimmune hepatitis (AIH), and 120 healthy individuals were included. Serum VEGF levels were measured by a chemiluminescence enzyme-linked immunosorbent assay. The mean values of serum VEGF levels in the patients with AH, CH, LC, FH, AIH, PBC, and control were 172.7, 58.0, 44.1, 37.3, 49.7, 74.9, and 65.0 pg/ml, respectively. The patients with AH had a level of serum VEGF significantly higher than that of the control group (P < 0.001). The serum VEGF levels in survivors of FH were significantly increased, but not in the nonsurvivors in the recovery phase compared with the levels on admission (P < 0.05). In the LC patients, serum VEGF levels were significantly lower than those of the control group (P < 0.05). These findings suggest that serum VEGF level may be associated with hepatocyte regeneration grade.

We examined the characteristics and usefulness of a third generation anti-HCV test kit, SYNPEPTM HCV-EIA II (Kyokuto Pharmaceutical Inc., Tokyo, Japan). The sera of inhabitants from a hepatitis C virus (HCV) hyperendemic area were used. The kit had even or more anti-HCV detection sensitivity and reproducibility than ORTHO HCVIII ELISA Test SystemTM (Ortho-Clinical Diagnostic K.K., Tokyo, Japan) or HCV PHA 2nd GenerationTM (Dinabot Co., Ltd., Tokyo, Japan). SYNPEPTM HCV-EIA II needed less total reaction time than other EIA kits, resulting in a simple procedure. Also, HCV RNA was detected in 90% of subjects who had a 7.5 or greater cut-off index (COI) of SYNPEPTM HCV-EIA II kit. In conclusion, SYNPEPTM HCV-EIA II require cheap cost and simple procedure and it could be applied to mass screening to find out HCV RNA positive persons who may need clinical care.

To examine the role of vascular endothelial growth factor (VEGF), an endothelial cell specific growth factor, in rheumatoid arthritis (RA), serum concentration of VEGF was examined in patients with RA, osteoarthritis (OA), systemic lupus erythematosus (SLE), systemic sclerosis (SS) and control subjects. Serum C-reactive protein (CRP) level, erythrocyte sedimentation rate, white blood cell count and rheumatoid factor titer were also determined in patients with RA. The serum concentration of VEGF was significantly higher in patients with RA than in controls (p0.01), and patients with OA (p0.05), SLE (p0.05), and SS (p0.05). The serum concentration of VEGF correlated with serum levels of CRP (r = 0.698, p0.0001). The serum concentration of VEGF before treatment was significantly higher than that after treatment in patients with RA who experienced clinical remission (p0.05). Our data suggest that VEGF is involved in the pathogenesis of RA and that measurement of serum concentration of VEGF is a noninvasive, useful method for monitoring the disease activity of RA.

最近3年間に当施設で経験した劇症肝炎12例の総医療費について調べ, さらに予後予測と実際の予後との見直しを行い, 予後判定の有用性の有無や社会的問題点などについて検討した. 非A非B非C型の劇症肝炎亜急性型の8例はすべて死亡した. 予後予測による予後判定では, 高橋らのLogistic analysisおよび肝移植適応ガイドライン案では全例に転帰の一致をみた. 60日以上延命できたが肝不全のために死亡した亜急性型の3症例では, 総医療費も膨大となった. 平均15日の治療期間で, 1日あたりの医療費が40万円を超える例が5例 (42%) に認められた. 劇症肝炎の集中治療においては, 1カ月に約1000万の医療費が必要と考えられた. 以上より劇症肝炎亜急性型で死亡が予測された症例では, 早期に肝移植を考慮すべきであり, 十分なインフォームドコンセントのもとに家族の同意を得た治療法を選択する必要がある.

Objective and design The aim of this study was to identify prognostic factors in cirrhotic patients receiving long-term sclerotherapy for their first bleeding from oesophageal varices. Methods Ninety-eight patients with acute bleeding from oesophageal varices receiving long-term endoscopic injection sclerotherapy were retrospectively investigated. Thirteen variables (five qualitative and eight quantitative) related to clinical, biological, and radiographic features were collected at admission. The qualitative variables were: gender, hepatocellular carcinoma, cause of cirrhosis, ascites and degree of encephalopathy. The quantitative variables were age, bilirubin, albumin, prothrombin index, number of sessions of sclerotherapy, volume of ethanolamine oleate, time taken to reach the hospital and shock index. These variables were examined with a multivariate analysis using stepwise logistic regression procedures and a prognostic index was calculated from the Cox equation. The predictive power of the final Cox model was prospectively tested in 43 patients with cirrhosis receiving long-term sclerotherapy for their first variceal bleeding. Results Of the 13 variables studied in a multivariate analysis using a logistic regression model, four had an independent prognostic value: the presence of hepatocellular carcinoma, bilirubin, albumin and time taken to reach the hospital. When the Cox model was examined in an independent set of 43 patients, there were no statistically significant differences between the observed and expected survival. Conclusion Prognosis of patients with bleeding from oesophageal varices is related to residual liver function and time taken to reach the hospital. Furthermore, the presence of hepatocellular carcinoma is an additional risk factor.

To describe the appearance of focal nodular hyperplasia (FNH) on various diagnostic imaging modalities, we retrospectively reviewed images obtained in eight patients with histologically-proven FNH. Patients underwent ultrasonography (US), carbon-dioxide enhanced US (CO 2 -US), incremental dynamic CT (ID-CT), MR imaging (MRI), dynamic MRI and digital subtraction angiography (DSA). The lesions were visualized on all imaging modalities, but a central scar was seen in only the three largest lesions (>30 mm diam). On US, the lesions were hypoechoic and showed central enhancement on CO 2 -US. On ID-CT, the lesions were enhanced immediately after contrast injection and shown isoattenuation thereafter. On MRI, the lesions were hypointense or isointense to surrounding liver on T1 weighted image (WI) and hyperintense on T2WI. On dynamic MRI, the lesions were enhanced immediately after contrast injection, followed by a gradual fading of the enhancement. All lesions showed typical histologic features of FNH. On dynamic MRI and CO 2 -US, FNH lesions appear to show characteristic features that may permit the imaging diagnosis of these lesions.

Seventy-five cirrhotic patients with hyperammonemia in the past or at the time of the study were randomly divided into two groups (treated with lactulose or nontreated) in 14 hospitals in Japan. Thirty-six cirrhotic patients were diagnosed as having subclinical hepatic encephalopathy (SHE), and 39 were diagnosed as non-SHE. SHE was diagnosed when the results of all three of the quantitative psychometric tests used (number connection test, and symbol digit and block design tests of the Wechsler adult intelligence scale [revised]) were abnormal as compared with age-matched normal values. The mean number of abnormal psychometric test results and the prevalence of SHE were used for a quantitative evaluation of the efficacy of the lactulose treatment. Twenty-two of the SHE patients were treated with lactulose (45 mL/d) for 8 weeks, and the other 14 SHE patients did not receive lactulose. In the SHE patients administered lactulose, the results of the quantitative psychometric evaluation were significantly improved at 4 and 8 weeks after the beginning of the lactulose administration. The SHE had disappeared in 10 (50%) of the 20 treated patients at week 8, but it persisted in 11 (85%) of the untreated 13 patients. We concluded that lactulose treatment in cirrhotic patients with SHE is effective with respect to psychometric tests.

The aim of this study was to clarify whether arterial blood supply by tumor vessels was involved in the proliferation of hepatocellular carcinoma. Proliferative activity was evaluated by the tumor volume doubling time determined on ultrasonography and the number of silver-staining nucleolar organizer regions in biopsy specimen. The degree of arterial blood supply to the tumor was evaluated based on the degree of contrast enhancement during the early phase on incremental dynamic computed tomography. The tumor volume doubling time negatively correlated with the number of silver-staining nucleolar organizer regions. The number of silver-staining nucleolar organizer regions in hepatocellular carcinoma cells was significantly increased with the increase of arterial blood supply. In well-differentiated hepatocellular carcinomas, the number of silver-staining nucleolar organizer regions in the group showing arterial blood supply on computed tomography was significantly increased compared with that in the group without arterial blood supply to the tumor. These findings suggest that the arterial blood supply is involved in the proliferation of hepatocellular carcinoma.

We examined the clinical and laboratory factors related to natural disappearance of hepatitis C virus (HCV) RNA by multiple logistic analysis after two rounds of testing in H town (3708 subjects) from 1990 to 1996. Liver function parameters, HBsAg and anti-HCV antibodys were determined in sera. In HCV seropositive individuals, abdominal ultrasonography, HCV RNA testing and where appropriate, HCV genotype and RNA level determinations were performed. Among 517 HCV RNA-positive subjects in the first screening, 270 subjects could be tested after an average interval of 4.3 years. Of these, 235 (87%) were RNA-positive at the second screening (positive persisted) and 35 (13%) had become negative (seroconversion to negative). The natural disappearance rate of serum HCV RNA was estimated as 2.8% per year. Significant independent factors related to disappearance were: serum HCV RNA levels (below 1.0 Meq ml −1 ); alanine aminotransferase (below 30 IU l −1 ) and zinc turbidity test (below 7.9 KU). These factors should help in elucidating mechanisms of HCV exclusion from the host, in predicting prognostication and in patient selection for interferon therapy.

The aim of this study was to investigate the effect of cigarette smoking on splanchnic hemodynamics. Ten healthy smoking men were studied. Using Doppler ultrasonography, portal vein (PV) flow velocity and superior mesenteric artery (SMA) pulsatility index were measured. These measurements were repeated just after one cigarette smoking and 10, 20, and 30 min after smoking. Plasma noradrenaline and vasopressin levels were determined before and just after smoking and 30 min after smoking. Doppler measurements for PV were feasible in all ten subjects whereas Doppler measurements for SMA were feasible in only six subjects. PV flow velocity was significantly decreased after smoking (from 14.1±1.2 to 11.0±1.1 cm s −1 , P −1 , P P P −1 , P −1 , P −1 , P r =−0.48, P r =0.76, P r =0.53, P =0.07). This data demonstrates that acute cigarette smoking decreases PV blood flow in healthy humans. This effect is mainly due to splanchnic arterial vasoconstriction mediated by smoking-induced vasopressin release.

We examined the seroconversion rate and level of hepatitis A virus antibodies induced by inactivated hepatitis A vaccine. Inactivated hepatitis A vaccine was administered intramuscularly to 127 healthy antibody negative subjects at doses of either 0.5 and 1.0 μ g two or three times. Convalescent sera from 21 adults with acute hepatitis A were also assayed. Serum antibody titers were measured by enzyme-linked immunosorbent assay. Seroconversion occurred in all 127 subjects (43 children, 84 adults). Acquired antibody levels in children in the early stage were higher than those in adults. Protective titers appeared 6 weeks after initial inoculation in 126 of 127 subjects and were maintained for at least 3 years in a 11 subjects. Mean maximum titer in subjects inoculated twice and three times after the initial vaccination were 393 mIU ml −1 at 6 weeks and 2745 mIU ml −1 at 7 months, respectively. Titers at 6 and 12 months after the initial vaccination were significantly higher in subjects with the 1.0 μ g inoculation than with 0.5 μ g. Titers in females were significantly higher than in males. The mean titer after inoculation was 1.1% of the convalescent titer in patients with acute hepatitis A. Neither adverse clinical events nor abnormal laboratory tests were observed after vaccination. Hepatitis A virus antibodies appeared reliably after inoculation with inactivated vaccine, persisting for at least 3 years. Although seroconversion rate was not age- or sex-dependent, the acquired titer was higher in children and females than in elderly males.

This study was designed to assess the contribution of splanchnic and extrasplanchnic vascular hemodynamics to the hyperdynamic circulation in patients with cirrhosis.Cardiac index and flow volume index and pulsatility index (PI) of superior mesenteric artery (SMA) and femoral artery (FA) were measured with Doppler ultrasonography in 40 controls and 86 patients with cirrhosis (Child-Pugh grade A=41, grade B=30, and grade C=15). Mean arterial pressure was also recorded to calculate systemic vascular resistance index.Systemic vascular resistance index was significantly lower in each Child-Pugh group than in controls. SMA blood flow index was significantly higher in each Child-Pugh group than in controls and the increase in SMA blood flow index paralleled the degree of liver dysfunction. SMA-PI was significantly lower in each Child-Pugh group than in controls and the decrease in SMA-PI paralleled the degree of liver dysfunction. FA blood flow index was slightly higher in Child-Pugh grade A patients and significantly higher in grade B patients than in controls, whereas grade C patients had normal FA blood flow index. FA-PI was significantly lower in grade A and grade B patients than in controls, whereas grade C patients had normal FA-PI. When all patients were examined together, SMA-PI significantly correlated with systemic vascular resistance index (r=0.69, p0.01). In contrast, FA-PI did not significantly correlate with systemic vascular resistance index (r=0.15, p=0.18).Splanchnic arterial vasodilatation plays an important role in the pathogenesis of decreased systemic vascular resistance seen in patients with cirrhosis.

Background/Aims: Basic fibroblast growth factor has mitogenic and angiogenic properties. In this study, we aimed to evaluate the role of fibroblast growth factor in the development and progression of human hepatocellular carcinoma. Methods: The expression of basic fibroblast growth factor, fibroblast growth factor receptor-1, and a receptor isoform was investigated by in situ hybridization, immunohistochemistry, reverse transcription-polymerase chain reaction, Western blot analysis and confocal laser-scanning microscopy. The influence of exogenous basic fibroblast growth factor on DNA synthesis and motility of human hepatoma cells were also evaluated. Results: Basic fibroblast growth factor and fibroblast growth factor receptor-1 messenger RNAs were present mainly in tumor cells and less so in hepatocytes from noncancerous liver tissue. Immunoreactive products of basic fibroblast growth factor and fibroblast growth factor receptor-1 were observed in tumor cells. The isoform IIIc was expressed in hepatocellular carcinoma tissue and hepatoma cell lines. Exogenous basic fibroblast growth factor stimulated DNA synthesis and motility of hepatoma cells. The effect was more marked in poorly-differentiated hepatoma cells than in well-differentiated hepatoma cells. Fibroblast growth factor-1 expression on hepatoma cells was also more marked in poorly-differentiated hepatoma cells than in well-differentiated hepatoma cells. The stimulated motility on basic fibroblast growth factor was suppressed by an anti-fibroblast growth factor receptor-1 antibody. Conclusions: Basic fibroblast growth factor may play an important role in the development and progression of hepatocellular carcinoma via an autocrine mechanism involving fibroblast growth factor and its receptor.

Gender difference in alcoholic liver disease was evaluated in histologically-proven, hepatitis C virus-negative Japanese patients. The mode of drinking and cumulative alcohol intake were compared according to histological groups. Daily amount of alcohol did not differ between men and women. Mean duration of drinking was shorter and cumulative alcohol intake was smaller in women. However, the mean daily alcohol consumption was greater in women and cumulative alcohol intake did not differ in both gender when alcohol amount was adjusted to body weight. A significant predominance in female patients was shown by analysis on contingency tables in histologically-matched patient group with cumulative alcohol intake less than 500 kg for alcoholic hepatitis, less than 600 kg for hepatic fibrosis and less than 800 kg for liver cirrhosis. In conclusion, women are at risk of developing alcoholic liver disease with fewer cumulative alcohol intake compared with men in hepatitis C virus-negative patients.

We have investigated the incidence of oral precancerous lesions among the inhabitants in a hepatitis C virus (HCV) hyperendemic area. Two oral surgeons examined the oral lesions of 685 (295 men, 390 women; mean age of 56.1 years) adult inhabitants, hyperendemic area of HCV infection. All sera were examined for antibodies to HCV (anti-HCV) and serum HCV RNA. Anti-HCV or HCV RNA were detected in sera from 84 (12.3%) or 61 (8.9%) of all. Oral lichen planus (OLP), leukoedema, or leukoplakia were observed in 10 (1.5%), 82 (12%), or 47 (6.9%) subjects, respectively. The incidences of OLP, leukoedema, and leukoplakia in the subjects with HCV infection were significantly higher than those without HCV. These results indicated that HCV may play an important role in oral cancer and related precancerous lesions. Moreover, our study also emphasized the need for periodic examination of the oral cavity in patients with HCV.

In normal and cirrhotic human liver tissues, we examined immunolocalization of alpha-smooth muscle actin (alpha-SMA), endothelin-1 receptor (ET-1R), and S-100 protein, with special emphasis on the intralobular spaces, using immunohistochemical methods. The ratio of the number of hepatic stellate cells (HSCs) with closely apposing nerve endings to the total number of HSCs in normal livers was compared with that in cirrhotic livers by electron microscopy. Immunolocalization of alpha-SMA and ET-1R was obviously recognized along the sinusoidal walls in cirrhotic liver and was significantly increased in cirrhotic liver compared with that in normal liver. Immunoreactive products for these substances were mainly localized in HSCs. However, immunolocalization of S-100 protein in intralobular spaces was markedly decreased in cirrhotic liver compared with that in normal liver. Nerve fibers were ultrastructurally hardly visible in intralobular spaces of cirrhotic livers. The ratio of the number of HSCs with closely apposing nerve endings to the total number of HSCs was significantly reduced in cirrhotic liver compared with that in normal liver. These results indicate that in liver cirrhosis, alpha-SMA-positive HSCs may play an important role in hepatic sinusoidal microcirculation through vasoactive agents such as ET-1 rather than through intralobular innervation.

The aim of this study was to select prognostic factors from information available on admission in order to list patients for liver transplantation before the onset of hepatic encephalopathy in patients with fatal hepatitis type non-A, non-B. Information regarding patient profile and biochemical data obtained on admission was analyzed by multiple stepwise logistic regression, and independent prognostic factors related to death were selected. Four parameters were selected as independent prognostic factors. Patient age (over 50 years), serum total bilirubin level (over 10 mg/dl), peripheral leukocyte count, and prothrombin time were independently related to death. Positive predictive value, negative predictive value, and predictive accuracy were 0.86, 0.79, and 0.84, respectively. Our model is able to predict a patient's fatal outcome much earlier than other currently used models. It will be helpful for early referral to a transplant center.

Background/Aims: The aim of this prospective study was to examine the association of portal-hypertensive gastropathy and fundal varices in patients with cirrhosis. Methods: We carried out an endoscopic observation in 476 patients with cirrhosis (study 1), including 62 patients undergoing endoscopic obliteration of esophageal varices (study 2). In study 1, patients were classified into five subgroups: no esophagofundal varices ( n =119), small esophagofundal varices ( n =127), dominant esophageal varices ( n =177), dominant fundal varices ( n =27), and large esophagofundal varices ( n =26). The severity of liver dysfunction was assessed by Pugh-Child classification: class A ( n =222), class B ( n =200), and class C ( n =54). In study 2, two groups, poorly developed fundal varices ( n =50) and well developed fundal ( n =12), were distinguished and the follow-up endoscopic examinations were performed on the basis of 3-month intervals for 2 years. In each study, the severity of portal-hypertensive gastropathy was scored: 0 (absent), 1 (mild), 2 (severe), and 3 (bleeding). Results: Study 1: One-way ANOVA showed that both variceal pattern and Pugh-Child class significantly influenced portal-hypertensive gastropathy score. However, two-way ANOVA indicated that variceal pattern was the only significant variable. Portal-hypertensive gastropathy score was significantly higher in patients with dominant esophageal varices than in either patients with no esophagofundal varices or patients with small esophagofundal varices. In contrast, portal-hypertensive gastropathy score in patients with dominant fundal varices was similar to that in patients with no esophagofundal varices and was significantly lower compared with that in patients with dominant esophageal varices. Furthermore, portal-hypertensive gastropathy score was significantly lower in patients with large esophagofundal varices than in patients with dominant esophageal varices. Study 2: After the obliteration of esophageal varices, portal-hypertensive gastropathy score in patients with poorly developed fundal varices became significantly higher at 3-, 6-, 9-months while it was not modified in patients with well developed fundal varices during the follow-up period. Furthermore, the integrated incremental change in portal-hypertensive gastropathy score during the first 1-year follow-up period was significantly lower in patients with well developed fundal varices than in patients with poorly developed fundal varices. Conclusions: These results indicate that both spontaneous and obliteration-induced portal-hypertensive gastropathy lesions develop less in patients with cirrhosis and fundal varices.