A novel cytoplasmic protein with RNA-binding motifs is an autoantigen in human hepatocellular carcinoma.
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In hepatocellular carcinoma (HCC), autoantibodies to intracellular antigens are detected in 30-40% of patients. Patients with chronic hepatitis or liver cirrhosis develop HCC, and when this occurs, some patients exhibit autoantibodies of new specificities. It has been suggested that these novel autoantibody responses may be immune system reactions to proteins involved in transformation-associated cellular events. One HCC serum shown to contain antibodies to unidentified cellular antigens was used to immunoscreen a cDNA expression library, and a full length cDNA clone was isolated with an open reading frame encoding 556 amino acids with a predicted molecular mass of 62 kD. The 62-kD protein contained two types of RNA-binding motifs, the consensus sequence RNA-binding domain (CS-RBD) and four hnRNP K homology (KH) domains. This protein, provisionally called p62, has close identity (66-70%) to three other proteins at the amino acid sequence level, and all four proteins may belong to a family having CS-RBD in the NH2-terminal region and four KH domains in the mid-to-COOH- terminal region. The homologous proteins are: KH domain-containing protein overexpressed in cancer (Koc); zipcode binding protein, a protein which binds to a conserved nucleotide element in chicken beta-actin mRNA (ZBP1); and a protein which binds to a promoter cis element in Xenopus laevis TFIIIA gene (B3). p62 protein is cytoplasmic in location, and autoantibodies were found in 21% of a cohort of HCC patients. Patients with chronic hepatitis and liver cirrhosis, conditions which are frequent precursors to HCC, were negative for these autoantibodies, suggesting that the immune response might be related to cellular events leading to transformation. However, the possible involvement of p62 autoantigen as a factor in the transformation process remains to be elucidated. (+info)
Chronic hepatitis in interferon-gamma transgenic mice is associated with elevated CPP32-like activity and interleukin-1beta-converting enzyme activity suppression.
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Interferon-gamma (IFN-gamma) transgenic mice strongly express IFN-gamma in the liver and develop chronic hepatitis. Furthermore, hepatocyte apoptosis was shown by the TdT-mediated dUTP-biotin nick endlabeling method. In the present study, interleukin-1beta-converting enzyme (ICE) and CPP32-like protease activities in the liver of IFN-gamma transgenic mice were measured, using the synthetic substrates Ac-YVAD-MCA and Ac-DEVD-MCA. Plasma aspartate aminotransferase and alanine aminotransferase activities as well as CPP32-like activity were significantly elevated, while ICE activity was significantly reduced. The addition of the ICE inhibitor Ac-YVAD-CHO to IFN-gamma transgenic mouse liver cell cytosol had no effect on the CPP32 activity, in contrast to a CPP32 inhibitor. The present results indicate that chronic hepatitis in the IFN-gamma transgenic mouse is associated with a decrease in ICE and induction of CPP32-like activity. (+info)
Clinical manifestations and immunological features of primary Sjogren's syndrome with liver involvement: analysis of thirty cases.
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OBJECTIVE: To evaluate the incidence, severity, clinical manifestations and immunological features relevant to liver involvement in 135 cases of primary Sjogren's syndrome. METHODS: One hundred and thirty-five patients with definite primary Sjogren's syndrome were analyzed retrospectively for liver involvement by the abnormalities of the liver enzymes, bilirubin level and liver biopsied section. RESULTS: The liver involvement in 30 patients (22.2%) could be etiologically ascribed to Sjogren's syndrome itself. The clinical spectrum and severity of this entity differed widely, 36.6% showed no relevant clinical symptoms, however jaundice was found in 46.7% of patients. Six patients showed pathological changes of chronic active hepatitis. 73.3% of all patients with liver involvement responded to steroid and immunosuppressive drugs, yet with a tendency to relapse (two cases). Liver cirrhosis was developed in five cases. The spectrum of serum autoantibodies in the patients with liver involvement showed no difference from those without liver involvement. Most of them were compatible with the serum profile of autoimmune hepatitis type-1. CONCLUSIONS: Liver involvement was complicated in 22.2% patients of primary Sjogren's syndrome. Clinical manifestations were non-specific and the main pathological change was chronic active hepatitis. The differential diagnosis between Sjogren's syndrome with liver involvement and type-1 autoimmune hepatitis could be only ascribed to other systemic clinical manifestations of Sjogren's syndrome. (+info)
Effectiveness of the analogue of natural Schisandrin C (HpPro) in treatment of liver diseases: an experience in Indonesian patients.
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OBJECTIVE: To determine the effect of dimethyl-4,4'-dimethoxy-5,6, 5',6-dimethylene dioxybiphenyl-2,2'-dicarboxylate (HpPro) on patients with acute and chronic liver diseases. METHODS: An open trial and a prospective randomized and controlled study were performed. The open trial consisted of 56 cases (16 cases of acute hepatitis, 20 cases of chronic hepatitis, 14 cases of liver cirrhosis and 6 cases of fatty liver). Controlled study consisted of 20 cases of Child A chronic hepatitis which were randomly treated with either HpPro or a mixture of known drugs which used as a liver protective agent in Indonesia as control for one week. The patients were then crossed over those two drugs in the next week. RESULTS: In the open trial, after 4 weeks' treatment with HpPro 7.5 mg orally three times daily, acute hepatitis, chronic hepatitis and fatty liver cases showed rapid decrease of SGOT and SGPT. In the liver cirrhosis cases, SGOT and SGPT were decreased slowly. In the controlled trial, nine patients received HpPro 7.5 mg three times daily orally and eleven were treated with a mixture of known drugs as the controls. After one week treatment, HpPro group clinically showed significant decrease of SGPT and SGOT levels compared to control group (P = 0.035). At the second week, HpPro group showed significant decrease of SGOT compared to control group (P = 0.038) but the decrease of SGPT was not significant (P = 0.096). CONCLUSION: Treatment with HpPro is effective to reduce liver impairment in acute and chronic liver diseases on Indonesian patients. No side effect of HpPro was observed. (+info)
Cryptic epitopes on alpha-fetoprotein induce spontaneous immune responses in hepatocellular carcinoma, liver cirrhosis, and chronic hepatitis patients.
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To determine alpha-fetoprotein (AFP) immunogenicity in vivo, the presence of antibodies in sera of 60 hepatocellular carcinoma, 15 liver cirrhosis, and 15 chronic hepatitis patients was evaluated by Western blotting and immunoprecipitation analyses using purified human AFP. High titers of anti-AFP immunoglobulins were detected in 14 hepatocellular carcinomas (P = 0.0006), 3 liver cirrhosis (P = 0.0173), and 1 chronic hepatitis patient, but they were not detected in 40 healthy individuals. Therefore, spontaneous immune responses to AFP are significantly associated to liver diseases (P = 0.0015). Patient immunoglobulins recognized proteic linear epitopes that were cryptic in the native protein, as demonstrated by their restricted reactivity with denatured deglycosylated AFP. Thus, in pathological liver conditions, tolerance to this self-molecule is circumvented. The identification of AFP immunogenic epitopes may contribute to defining novel immunotherapeutic strategies targeting this antigen. (+info)
Pathologic features of chronic hepatitis. A review and update.
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The general histopathologic changes of chronic hepatitis and those related to the various causes are reviewed. Consideration also is given to underlying or associated diseases and to mixed infections in chronic viral hepatitis. Changes occurring in exacerbations or relapses are described. Selected histopathologic changes are illustrated. The nomenclature is reviewed briefly, with emphasis on separation of activity from stage of disease. (+info)
Adhesion of lymphocytes to hepatic endothelium.
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Chronic inflammation occurs when factors that regulate the process of leucocyte recruitment are disrupted, and it is dependent on recruitment, activation, and retention of lymphocytes within tissue microenvironments. The molecular mechanisms that mediate lymphocyte adhesion to vascular endothelial cells have been described by several groups, but the signals involved in the recruitment of lymphocytes via the hepatic circulation have yet to be elucidated fully. This article considers the liver as a model of organ specific lymphocyte recruitment. In this context, the roles of leucocyte and endothelial adhesion molecules and chemokines in lymphocyte recruitment are discussed. The article also reviews the mechanisms that regulate lymphocyte recirculation to the liver under both physiological and pathological conditions and draws parallels with other organs such as the gut and skin. (+info)
Cerebral blood flow and oxygenation in liver transplantation for acute or chronic hepatic disease without venovenous bypass.
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The autoregulation of cerebral blood flow (CBF) is impaired in patients with end-stage liver disease and encephalopathy. These patients are vulnerable to sudden deterioration of cerebral perfusion and oxygenation during liver transplantation. We compared CBF and metabolism during liver transplantation without venovenous bypass and 24 hours postoperatively in 9 patients with acute liver failure (ALF) and 16 patients with chronic liver disease. A fiberoptic catheter was inserted cranially through the left internal jugular vein for determination of jugular venous oxygen saturation, cerebral oxygen extraction ratio (COER), lactate level, and neuron-specific enolase (NSE) level. Arterial concentrations of lactate were also measured. Flow velocity in the middle cerebral arteries was monitored bilaterally using transcranial Doppler sonography. Mean flow velocity and pulsatility index (PI) were regarded as indicators of intracranial pressure. Core body temperatures were recorded. Mild hyperventilation, perioperative hemofiltration, and N-acetylcysteine infusion were used according to our clinical practice. NSE level was greater in acute patients at the end of surgery (P <.05), but not 24 hours later. Lactate concentrations were greater in patients with ALF (P <.001) preoperatively and intraoperatively but were similar in both groups 24 hours postoperatively. There was no difference between arterial and jugular venous concentrations of lactate. Changes in blood flow velocity, PI, and COER were parallel and without statistical significance between the groups. The patients' core temperature did not correlate with CBF, NSE level, or clinical outcome. Caval clamping was well tolerated in both patient groups. (+info)