Chronic Active Viral Hepatitis Research Articles

Characterization of neutralizing antibodies reacting with the 213-224 amino-acid segment of human galectin-9.

Extra-cellular galectin-9 (gal-9) is an immuno-modulatory protein with predominant immunosuppressive effects. Inappropriate production of gal-9 has been reported in several human malignancies and viral diseases like nasopharyngeal, pancreatic and renal carcinomas, metastatic melanomas and chronic active viral hepatitis. Therefore therapeutic antibodies neutralizing extra-cellular gal-9 are expected to contribute to immune restoration in these pathological conditions. Two novel monoclonal antibodies targeting gal-9 –Gal-Nab 1 and 2—have been produced and characterized in this study. We report a protective effect of Gal-Nab1 and Gal-Nab2 on the apoptotic cell death induced by gal-9 in primary T cells. In addition, they inhibit late phenotypic changes observed in peripheral T cells that survive gal-9-induced apoptosis. Gal-Nab1 and Gal-Nab2 bind nearly identical, overlapping linear epitopes contained in the 213–224 amino-acid segments of gal-9. Nevertheless, they have some distinct functional characteristics suggesting that their three-dimensional epitopes are distinct. These differences are best demonstrated when gal-9 is applied on Jurkat cells where Gal-Nab1 is less efficient than Gal-Nab2 in the prevention of apoptotic cell death. In addition, Gal-Nab1 stimulates non-lethal phosphatidylserine translocation at the plasma membrane and calcium mobilization triggered by gal-9 in these cells. Both Gal-Nab1 and 2 cross-react with murine gal-9. They bind its natural as well as its recombinant form. This cross-species recognition will be an advantage for their assessment in pre-clinical tumor models.

Delayed anthracycline-induced cardiomyopathy – case report

A 43-year-old man was admitted to the hematology department due to second recurrence of anaplastic lymphoma T-cell ALK+. Lymphoma was diagnosed 28 years earlier. The patient received COP regimen (17 cycles) and CHOP (5 cycles), radiotherapy and underwent splenectomy. He achieved complete remission at that time. Relapse of the disease was diagnosed 8 years later, which was treated with 6 cycles of chemotherapy (cytarabine, mitoxantrone, vepeside and glucocorticoids) and high-dose chemotherapy followed by hematopoietic stem cell transplantation. Second disease recurrence was found in 2013, it was anaplastic lymphoma T-cell ALK+ stage IIA by Ann Arbor. Echocardiography and myocardial perfusion scintigraphy revealed chronic heart failure NYHA class I. Angiotensin receptor antagonist (ramipril) and β-blocker (carvedilol) were recommended. The patient underwent 6 cycles of ESHAP, complete remission was reported after the second cycle. High-dose therapy with autologous stem cell rescue was considered at that time. However, having T-cell ALK+ lymphoma with a relatively good prognosis, previous prolonged complete remissions (respectively – 12 and 8 years), an insufficient yield from the harvest (3,33 × 106/kg CD34+ cells), heart failure and chronic active viral hepatitis B, the high risk intensive chemotherapy followed by hematopoietic stem cells transplantation was discontinued. The chemotherapy was complicated by brachial vein and superficial vein thrombosis of left upper limb and hypogammaglobulinemia. Follow-up echocardiography performed after completion of chemotherapy showed improvement in EF (64%).

Cytokeratin 8 and 18 Expression in Imprint Smears of Chronic Viral Hepatitis, Autoimmune Hepatitis and Hepatocellular Carcinoma

To investigate whether the expression of cytokeratin (CK) 8 and 18 is altered in chronic active viral hepatitis, autoimmune hepatitis and hepatocellular carcinoma.Cytologic imprint smears were obtained from 53 liver core biopsy specimens and were studied immunocytochemically for the expression of CK8 and 18.CK8-positive expression was observed in 45.5% of chronic active hepatitis B (CH-B), 20% of chronic active hepatitis C (CH-C), 90% of autoimmune hepatitis (AIH) and 83.3% of hepatocellular carcinoma (HCC) cases. CK18-positive expression was observed in 36.4% of CH-B, 26.7% of CH-C, 70% of AIH and 83.3% of HCC cases. A statistically significant association was found between CK8- and CK18-positive expression and the diagnosis of AIH and HCC. In contrast, CH-C and CH-B were associated with negative CK8 and CK18 expression. In addition, a negative [CK8(-)/CK18(-)] or imbalanced [CK8(-)/CK18(+), CK8(+)/CK18(-)] expression pattern was found in 100.0% and 81.18% of CH-C and CH-B cases, respectively, while the relative percentages of AIH and HCC cases were significantly lower (30.0% and 16.7%, respectively) (p < 0.0001).Our results indicate that CK8 and 18 expression is maintained in AIH and HCC and altered in CH-B and CH-C. The pathogenetic mechanism of this alteration remains to be clarified.

Exacerbation of Sarcoidosis Following Interferon-alpha Therapy for Chronic Active Hepatitis C

Interferon alpha is an immunomodulator that is used as an antiviral agent to treat chronic active viral hepatitis C. However, interferon can induce or exacerbate sarcoidosis. We report a case of 42-year-old man with an exacerbation of pulmonary sarcoidosis after the cessation of interferon and ribavirin therapy for chronic hepatitis C. The patient's sarcoidosis improved spontaneously and he continues to be monit ored regularly without steroid therapy. (Tuberc Respir Dis 2006; 61: 285-288)

Histopathologic and immunocytochemical changes in the liver in patients with chronic hepatitis C

The presence of lymphocytes within the liver parenchyma is related to immunologically mediated liver damage in chronic hepatitis C. The aim of the study was to make histological, histochemical, and immunocytochemical assessment of liver biopsy specimens in patients with chronic hepatitis C virus (HCV) infection. Biopsy specimens of 20 patients with chronic HCV disease were analyzed, using standard staining procedures to verify histologic liver lesions, as well as immunoenzymatic staining with monoclonal antibodies to detect CD4+ T-lymphocytes, B-lymphocytes, and macrophages. Micromorphologic characteristics of chronic active viral hepatitis C were present in all the patients, differing, however, by the level of their activity. Dominant changes were found within the portal space, consisting of mononuclear lympho-plasmocytic infiltration and macrophages. Immunocytochemical investigation of mononuclear and macrophageal infiltration showed the correlation between micromorphological findings and the degree of the activity. The presence of lymphocytic and macrophageal infiltration within the hepatic tissue directly correlated with the intensity of the liver damage. Analysis of the population of cellular infiltrate in the liver together with the monitoring of viremia level and the level of hepatocyte necrosis, could be useful tools for elucidation of the pathogenesis of chronic hepatitis C.

Chemical modification of glycyrrhizic acid as a route to new bioactive compounds for medicine.

Glycyrrhizic Acid (GL) is the major bioactive triterpene glycoside of licorice root (Glycyrrhiza Radix) extracts possessing a wide range of pharmacological properties (anti-inflammatory, anti-ulcer, anti-allergic, anti-dote, anti-oxidant, anti-tumor, anti-viral etc.). Official sources of GL are Glycyrrhiza glabra L. and Gl. uralensis Fish. (Leguminosae). The content of GL in licorice root is 2-24% of the dry weight. GL is one of the leading natural compounds for clinical trials of chronic active viral hepatitis and HIV infections (preparation Stronger Neo-Minophagen C, SNMC), and its monoammonium salt (glycyram, tussilinar) is used as an anti-inflammatory and anti-allergic remedy. The synthetic transformations of GL on carboxyl and hydroxyl groups were carried out to produce new bioactive derivatives for medicine. GL esters were produced containing fragments of bioactive acids (4-nitrobenzoic, cinnamic, salycilic, acetylsalycilic, nicotinic, isonicotinic). Bioactive amides of GL were synthesized using chloroanhydride technique and N,N'-diciclohexylcarbodiimide (DCC) method. The synthesis of acylthioureids and semicarbazones was carried out via the reaction of triacylisothiocianate of penta-O-acetyl-GL with primary amines and hydrazines. The chain of transformations of trichloranhydride of penta-O-acetyl-GL was made with the introduction of diazoketone groups in the molecule. A new group of GL derivatives to be triterpene glycopeptides was prepared by the activated esters method (N-hydrohysuccinimide-DCC or N-hydroxybenzotriazol-DCC) using alkyl (methyl, ethyl, propyl, butyl, tert-butyl) or benzyl (4-nitrobenzyl) esters of amino acids. The glycyrrhizyl analogs of the known immunostimulator, N-acetyl-muramoyldipeptide (MDP), were synthesized using Reagent Woodward K. A series of ureids and carbamates of GL was synthesized containing 5-amino-5-desoxy-D-xylopyranose units. The synthesis of 4-nitro-4-desoxy-glycosides, modified analogs of GL, was carried out by the oxidative splitting of the carbohydrate part of GL with NaIO(4). Triterpene 2-desoxy-D-glycosides, analogs of GL, were prepared by the glycal method in the presence of iodine-containing promoters or sulfonic acid cation-exchange resin KU-2-8 (H+) and LiBr. New anti-inflammatory and anti-ulcer agents were found among GL derivatives such as esters, amides, ureids, carbamates, thioureids and glycopeptides. GL glycopeptides are of interest as immunomodulators. Some of the chemically modified GL derivatives (salts, amides, glycopeptides) were potent HIV-1 and HIV-2 inhibitors in vitro. Preparation niglizin (penta-O-nicotinate of GL) was studied clinically as an anti-inflammatory agent and is of interest for studies as hepatoprotector and HIV inhibitor.

Liver biopsy findings in 501 patients infected with human immunodeficiency virus (HIV).

Patients infected with human immunodeficiency virus (HIV) are at risk for a variety of liver diseases. We undertook a retrospective study of 501 HIV-seropositive patients to assess the yield of percutaneous liver biopsy. The most common indications for liver biopsy were liver test abnormalities (89.5%), fever for 2 weeks (71.9%), and hepatomegaly (52.0%). The most common biopsy-derived diagnosis was Mycobacterium avium complex (MAC), seen in 87 (17.4%) biopsies. Mycobacterium tuberculosis was found in 13 biopsies (2.6%). In 28 biopsies (5.6%) mycobacteria was seen, but speciation of the organism was not possible. Chronic active viral hepatitis was seen in 60 biopsies (12.0%). Opportunistic hepatic infection from other organisms was found in 14 biopsies (2.8%). The most common neoplasm was lymphoma, which was seen in 12 biopsies (2.4%). MAC infection of the liver was associated with elevated alkaline phosphatase (p = 0.01). Among patients with fever for 2 weeks after an extensive negative workup including bone marrow biopsy, 58.2% had a diagnosis by liver biopsy. Overall, 64.3% of liver biopsies yielded a histopathological diagnosis, 45.7% of which were potentially treatable. We could not evaluate whether liver biopsy had a positive effect on patient outcome and survival, nor did we attempt to prove that liver biopsy resulted in a change in treatment or a change in preprocedure clinical diagnosis. Thus, questions about the efficacy of liver biopsy cannot be answered. Liver biopsy may be a helpful diagnostic tool in HIV-positive patients with fever, liver test abnormalities or hepatomegaly.

Laparoscopic and Histopathologic Features of the Liver in Severe Chronic Active Epstein‐Barr Virus Infection Syndrome: A Case Report

Abstract: A 40‐year‐old man was admitted to our hospital with persistent fever, generalized lymphadenopathy and hepatosplenoamegaly. Immunological examination demonstrated high titers of several anti‐Epstein‐Barr virus (EBV) antibodies, including anti‐viral capsid antigens 1gG‐antibody 1: 20, 480, anti‐early antigens‐DR IgG‐antibody 1: 5, 120, and reduced activity of EBV‐specific cytotoxic T lymphocytes. Laparoscopic features resembled those of chronic active viral hepatitis, including an uneven surface appearance and diffuse hepatic enlargement. Histopathological examination of a liver biopsy specimen showed inflammatory cell infiltration along sinusoidal surfaces (single file appearance) and enlarged portal areas with intralobular punched‐out necrosis. The diagnosis was confirmed by detecting the EB viral genome in serum. Despite treatments with natural alpha‐interferon, adenosine arabinocide and recombinant human interleukin‐2, the patient died of progressive hepatic failure.

Recombinant-α2b-interferon treatment in patients with chronic active hepatitis: effects on peripheral blood mononuclear cells and correlation with response

The purpose of this study was to evaluate the relationship between peripheral blood monocyte and lymphocyte subsets and response to recombinant-α2b-interferon (r-α2b-IFN) in patients with viral chronic active hepatitis (CAH). Peripheral blood mononuclear cell subsets were studied by use of flow cytometry before beginning treatment, after 24 hours, and after 15, 30, and 90 days of treatment with r-α2b-IFN (3 million U thrice weekly) in 16 patients with CAH—11 who tested anti-HCV—positive and five HBsAg-positive/anti-HBe—positive/HBV-DNA—positive (HCV = hepatitis C virus; HBsAg = hepatitis B surface antigen; HBe = hepatitis B e antigen; HBV = hepatitis B virus). r-α2b-IFN acutely decreased the number of peripheral blood B lymphocytes, natural killer (NK) cells, and T-naive cells. It also activated monocytes and T lymphocytes, as indicated by increased expression of surface human leukocyte antigen (HLA)-DR molecules and interleukin-2 receptors, respectively. These effects were no longer evident after 15 days of treatment. The number of NK cells was significantly lower in anti-HCV—positive than in HBsAg-positive patients (CD16+ cells: 277 ± 55/μL vs 450 ± 33/μL, P < 0.03) and was decreased in both groups during the 3 months of therapy. Responders to r-α2b-IFN did not differ from nonresponders except in the number of NK cells, which was higher than in anti-HCV—positive nonresponders 24 hours after the first injection. r-α2b-IFN acutely activates peripheral blood mononuclear cells and decreases the number of circulating NK cells in anti-HCV—positive and HBsAg-positive/anti-HBe—positive/HBV-DNA—positive patients with CAH. These effects did not correlate with treatment response.

Interleukin-8 and Granulocyte-Macrophage Colony-Stimulating Factor Secretion in Hepatocellular Carcinoma and Viral Chronic Active Hepatitis

Interleukin-8 (IL-8) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are important mediators of inflammation and immune response in human disease. To demonstrate their importance in pathophysiological processes in liver disease, we measured the circulating levels of IL-8 and GM-CSF in patients with hepatocellular carcinoma (HCC) and chronic active hepatitis (CAH). IL-8 and GM-CSF levels in serum samples were determined with highly specific and sensitive enzyme-linked immunosorbent assays. IL-8 levels were more elevated in serum samples of patients with HCC and CAH associated with hepatitis C virus infection than HCC and CAH associated with hepatitis B virus infection. However, in all patients with autoimmune CAH and in some patients with HCC and CAH, GM-CSF levels were elevated over the baseline levels measured in all of the normals, but this difference was not statistically significant for any group. We conclude that IL-8 and GM-CSF are increased in some patients with liver diseases, and as such they may play a significant role in host defense and disease.

Comparison of the expression of cytokine-dependent adhesion molecules by the hepatocytes during chronic active viral hepatitis C (CHC) and B (CHB)

Comparison of the expression of cytokine-dependent adhesion molecules by the hepatocytes during chronic active viral hepatitis C (CHC) and B (CHB)

Eosinophilic infiltration of the liver in primary biliary cirrhosis: A morphological study

Eosinophils and their secretory proteins are important in necroinflammatory processes. In this study we surveyed eosinophilic infiltration of the liver in 176 liver biopsy specimens from patients with primary biliary cirrhosis. A considerable number of eosinophils were found in the portal tracts in 51 of these specimens (29%), whereas this finding occurred in only 2 of 50 (4%) specimens from patients with viral chronic active hepatitis. Eosinophilic infiltration of the portal tracts was focal. These eosinophils were immunohistochemically shown to contain the secreted form of eosinophilic cationic protein. Grades of eosinophilic infiltration of the portal tracts were higher in those livers with higher grades of lymphoplasmacytic infiltration, granulomas and florid duct lesion in the portal tracts, and they were lower in those livers with higher grades of bile duct disappearance and orcein-positive granuoles in hepatocytes. In the livers of patients with primary biliary cirrhosis, eosinophils were abundant around the damaged bile ducts, around the portal vein branches and at the marginal regions, and they were scattered in the portal tracts, whereas only the last pattern was seen in viral chronic active hepatitis. Peripheral blood eosinophils tended to be increased in primary biliary cirrhosis patients with higher grades of eosinophilic infiltration of the portal tracts. Eosinophilic infiltration of the portal tracts may play a role in immunological injuries of the interlobular bile ducts in primary biliary cirrhosis. (HEPATOLOGY 1993;17:206–212.)

Eosinophilic infiltration of the liver in primary biliary cirrhosis: A morphological study

Eosinophils and their secretory proteins are important in necroinflammatory processes. In this study we surveyed eosinophilic infiltration of the liver in 176 liver biopsy specimens from patients with primary biliary cirrhosis. A considerable number of eosinophils were found in the portal tracts in 51 of these specimens (29%), whereas this finding occurred in only 2 of 50 (4%) specimens from patients with viral chronic active hepatitis. Eosinophilic infiltration of the portal tracts was focal. These eosinophils were immunohistochemically shown to contain the secreted form of eosinophilic cationic protein. Grades of eosinophilic infiltration of the portal tracts were higher in those livers with higher grades of lymphoplasmacytic infiltration, granulomas and florid duct lesion in the portal tracts, and they were lower in those livers with higher grades of bile duct disappearance and orcein-positive granuoles in hepatocytes. In the livers of patients with primary biliary cirrhosis, eosinophils were abundant around the damaged bile ducts, around the portal vein branches and at the marginal regions, and they were scattered in the portal tracts, whereas only the last pattern was seen in viral chronic active hepatitis. Peripheral blood eosinophils tended to be increased in primary biliary cirrhosis patients with higher grades of eosinophilic infiltration of the portal tracts. Eosinophilic infiltration of the portal tracts may play a role in immunological injuries of the interlobular bile ducts in primary biliary cirrhosis.

Zidovudine plus interferon alfa-2b treatment in patients with HIV and chronic active viral hepatitis.

Results are reported for a small study of 11 patients positive for HIV and with chronic active viral hepatitis. Low dose zidovudine/interferon alfa-2b combined treatment produced a general reduction in alanine aminotransferase activities and increased the CD4 lymphocyte count, hepatitis B e seroconversion, and the loss of HIV p24 antigen. The treatment was well tolerated and progression of HIV disease was not seen.

Therapeutic and antilipoperoxidant effects of silybin-phosphatidylcholine complex in chronic liver disease: Preliminary results

Eight patients (two men and six women; mean age, 54.6 + 5 years) with viral chronic active hepatitis were treated with silipide (IdB1016), a new silybin-phosphatidylcholine complex, for 2 months. After treatment with IdB1016, serum malondialdehyde levels decreased by 36%, and the quantitative liver function evaluation, as expressed by galactose elimination capacity, increased by 15%. A statistically significant reduction ( P < 0.05) of transaminases was also seen. These results suggest that silipide may be effective in improving the biochemical and quantitative indices of hepatic function in patients with chronic active hepatitis.

Expression of a novel activation antigen on intrahepatic CD8 + T lymphocytes in viral chronic active hepatitis

It has been suggested that CD8 + T lymphocytes play an important role in the pathogenesis of liver cell injury in viral chronic active hepatitis. However, the mere presence of T lymphocytes with cytotoxic/ suppressor phenotype in the hepatic inflammatory infiltrate does not necessarily imply that these cells are actively involved in an immune reaction. In the present study, the expression of different activation antigens have been investigated, such as the interleukin-2 and the transferrin receptors and a recently described T-cell activation molecule termed “activation-inducer molecule” on the different lymphocyte subsets of both peripheral blood and liver-infiltrating lymphocytes from patients with virus-induced chronic active hepatitis. Studies of double immunostaining clearly showed that the majority of intrahepatic CD8 + T lymphocytes selectively coexpressed the activation-inducer molecule, whereas no significant expression of this molecule was found on either intrahepatic CD4 + T lymphocytes or peripheral blood lymphocytes of the same patients. Furthermore, lymphocytes from both peripheral blood or liver compartments did not express other activation antigens such as the interleukin-2 and the transferrin-receptor molecules. These results suggest that the CD8 + T-cell subset bearing the activation-inducer molecule may represent the main activated intrahepatic lymphoid cell population in virus-related chronic active hepatitis.

Expression of a novel T cell activation antigen on intrahepatic CD8+ T lymphocytes in viral chronic active hepatitis

Expression of a novel T cell activation antigen on intrahepatic CD8+ T lymphocytes in viral chronic active hepatitis

Detection of anti‐interferon‐α2a antibodies in chronic liver disease

The occurrence of antibodies to interferon‐α2a (anti‐IFN‐α2a) to recombinant human IFN‐α2a was examined in chronic liver disease by a sensitive enzyme‐linked immunosorbent assay (ELISA). Naturally occurring IgG and/or IgM anti‐IFN‐α2a were found in one of 12 cases of chronic persistent hepatitis, four of 18 cases of chronic active hepatitis (CAH), two of 12 cases of liver cirrhosis, six of seven cases of primary biliary cirrhosis, nine of 11 cases of auto‐immune CAH and none of 21 normal control subjects. Fifteen patients with viral CAH were treated with recombinant IFN‐α2a. Two of them were positive prior to receipt of IFN‐α2a and their titres increased after the therapy. Two patients became positive for anti‐IFN‐α2a after the therapy. Absorption experiments revealed that anti‐IFN‐α2a cross‐reacted with native human leucocyte IFN‐α and recombinant IFN‐α2b but not with recombinant IFN‐β and ‐γ. The immunoblotting experiment confirmed the binding of antibodies to IFN. The results of anti‐IFN‐α2a obtained by antiviral, cytopathic effect assay were in good agreement with those of IgG anti‐IFN‐α2a, but not with those of IgM antibodies obtained by the ELISA. The ELISA described in the present study is a simple, sensitive and quantitative assay for anti‐IFN‐α2a. It should be useful in assessing sub‐specificities of anti‐IFN and provide valuable information to predict the effect of IFN therapy and to elucidate the immunological abnormality in liver disease.

Expression of a novel T cell activation antigen on intrahepatic CD8+ T lymphocytes in viral chronic active hepatitis

Expression of a novel T cell activation antigen on intrahepatic CD8+ T lymphocytes in viral chronic active hepatitis

Interferon therapy does not modify elevated serum prolyl-hydroxylase in viral chronic active hepatitis

Interferon therapy does not modify elevated serum prolyl-hydroxylase in viral chronic active hepatitis