Chronic hepatitis C in the advanced adult and elderly subjects.

Aging is associated with a complex remodeling of the immune system. While adaptive immune responses show impairment with aging, innate immune responses tend to improve it. Low numbers of CD3+, CD4+ and CD8 T cells have been observed in aged individuals. B lymphocytes tend to diminish as well. However, an increase in NK cells and effector T lymphocytes (CD28- CD8) can be shown. Effector T lymphocytes are characterized by: 1) expression of markers of cytotoxicity; 2) high levels of NK activity; 3) expression of the same inhibitory receptors as NK cells; 4) no cytokine production. For effector T lymphocyte-mediated cytotoxicity of virus-infected cells to occur, viral epitopes need to be exposed on the cell surface in the absence of MCH class I molecule expression, just as it has been shown with NK cells. Indeed, chronic infection with intracellular parasites is known to hinder MHC class I expression on cell surface. In elderly patients with chronic hepatitis C, infected hepatocytes can be shown to express a wide variety of HCV antigens, reflecting latency or active replication, as opposed to low or absent MHC class I expression. This favors elimination of infected hepatocytes by NK cells and effector T lymphocytes. A negative correlation has been observed between outcome of hepatitis and patients' age. Liver biopsies from elderly patients generally show chronic active hepatitis or cirrhosis, which are far less commonly observed in young patients or young adults. Overproduction of proinflammatory cytokines, namely TNF-alpha, IL-1 and IL-6, is responsible for enhanced immuno-phlogosis and underlies a more extensive damage to liver parenchyma. Since interferon-alpha has been shown to upregulate MHC class I molecule expression on infected hepatocytes, it may turn useful as a tool to inhibit NK cell- and effector T lymphocyte-mediated cytotoxicity. Thus, a rationale exists to recommend interferon-a administration in hepatitis C patients, especially in elderly patients. If the data presented here can contribute to foster research into interferon-a treatment of elderly patients with hepatitis C, our goal will be reached.

[Secondary pulmonary hypertension in the elderly: pathophysiological and clinical aspects from an observed case]. / Ipertensione polmonare secondaria negli anziani: aspetti fisio- patologici e clinici da un caso venuto alla nostra osservazione.

The authors report the case of a 76-year-old woman with severe pulmonary hypertension (80 mmHg). She had been suffering for years from chronic bronchitis and presented tricuspid insufficiency. The case report refers to the association between valvular insufficiency and/or chronic bronchitis and pulmonary hypertension. This condition--if severe--results in progressive disability and death. The treatment of severe pulmonary hypertension has not been taken into account, since it has proven to be ineffective and has side effects. The early detection and the prevention of the underlying causes represent the only available therapy. Sclerotic valvulopathy occurs more frequently in the elderly; it represents the major cause of valvular insufficiency/stenosis, especially if compared to the significant decrease in rheumatic disease in Western countries. Chronic bronchitis is characterized by a slow progression, in patients younger than fifty, by a decay worsened by aging. These data show that symptomatic pulmonary hypertension may often occur in the elderly (age > or =65 years). This paper results from our clinical experience on preventive measures in elderly patients with symptomatic pulmonary hypertension. If the material presented in this work succeeds in promoting new research or possible preventive measures to arrest or to slow down the course of this condition in the elderly, it will hit its target.

Interferon-gamma: biologic functions and HCV terapy (type I/II) (2 of 2 parts).

PURPOSE: To discuss exhaustively: 1) the interferon-gamma in inducing and modulating of immune responses; 2) impairment of IFN-gamma production that plays an important role in the persistence of infection, chronicity of inflammation, evolution in fibrosis; 3) in "vivo" effects of combination treatment with recombinant interferon-gamma and alpha in chronic HCV-infection. DESIGN: We reviewed the most important recent studios on relationship between IFN-gamma and chronic course of hepatitis C. OVERVIEW: IFN-gamma is also a potent activator of macrophages. Exposure to IFN-gamma greatly enhances the microbicidal (and, to a lesser degree, citotoxic) activity of macrophages and induces them to secrete nitric oxide and monokines such as IL-1, IL-6, IL-8, and TFNalpha. It also activates neutrophils, NK cells, and vascular endothelial cells. Although IFN-gamma tends to promote the differentiation of B cells and CD8 T cells into immunologically active effectors, it does not promote lymphocyte proliferation. It enhances the activity of Thl cells, but inhibits the production of Th2 cells. IFN-gamma not only decreases the production of IL-4 by Th2 cells but also potently blocks the effects of IL-4 on B cells, promoting IgG1 production at the expense of IgE production. The inadequate Thl immunity as well as the weak HCV-specific T-cell response at the site of inflammation is associated with failure to clear the virus and a chronic course of disease. The production of IL-12 is critical for induction of Thl immunity, directed towards elimination of intracellular pathogenes and viruses. The core protein of HCV seems to have a suppressive action on IL-12 production at the transcriptional level. The specific Thl cell defect is correlated with insufficient Th and CTL responses, and lower production of type 1 cytokine (IL-2, IFN-gamma, lymphokine-activated killer cells). Taken together, these results are probably responsible for non-eradication of HCV infection. Particularly the effects of interferon-gamma may include inhibition of HCV virion production by an effect on viral RNA and protein synthesis, enhancement of immune lysis of HCV infected cells, inhibition of hepatic fibrosis by an effect on TGF-beta, and an effect on HCV induced carcinogenesis. These data suggest an HCV-related cellular immune defect in patients with hepatitis C that can be restored in most patients by IL-12. CONCLUSIONS: The efficacy of IFN monotherapy in the HCV replicon system has been reported using IFN-alpha, IFN-gamma and IFN-beta. A recent clinical study to treatment chronic HCV involving sequential administration of IFN-alpha followed by IFN-gamma (IFN-alpha2b + IFN-gamma) showed a greater improvement over IFN monotherapy. This type of approach may lead to significant improvements in the therapeutic arsenal against chronic HCV infection.

Interferon-gamma: biologic functions and HCV therapy (type I/II) (1 of 2 parts).

PURPOSE: This review is aimed at exhaustively presenting and discussing the interferon-gamma (IFN-gamma), a cytokine that plays an important role in inducing and modulating an array of immune responses. DESIGN: A review of the most significant and recent clinical trials was performed. OVERVIEW: Although IFN-gamma has some antiviral activity, it is much less active in this regard than type I IFNs. IFN-gamma is involved in the regulation of nearly all phases of the immune and inflammatory responses, including the activation and differentiation of T cells, B cells, NK cells, macrophages, and others. It is therefore best regarded as a distint immunoregulatory cytokine. IFN-gamma secretion is a hallmark of Th1 lymphocytes. It is also secreted by nearly all CD8 T cells, by some Th0 cells, and by NK cells. Each of these cell types secretes IFN-gamma only when activated, usually as part of immune response and especially in response to IL-2 and IL-12. IFN-gamma production is inhibited by IL-4, IL-10, TGFbeta, glucocorticoids, cyclosporin A and FK506. Nearly all cell types express the heterodimeric receptor for IFN-beta and respond to this cytokine by increasing the surface expression of class I MHC proteins. As a result, virtually any cell in the vicinity of an IFN-beta-secreting cell becomes more efficient at presenting endogenous antigens and hence a better target for cytotoxic killing if it harbors an intracellular pathogen. Unlike the type I IFNs, IFN-gamma also increases the expression of class II MHC proteins on professional APCs, and so promotes antigen presentation to helper T cells as well. It also induces de novo expression of class II MHC proteins on venular endothelial cells and on some other epithelial and connective tissue cells that do not otherwise express them, thus enabling these cell types to function as temporary APCs at sites of intense immune reactions. The effector functions of NK cells are to lyse virus-infected cells and to secrete IFN-gamma, which activates macrofages to destroy phagocytosed microbes. The mechanism of NK cell-mediates cytolysis is essentially the same as that of cytolysis by CTLS. NK cells lyse virally infected cells before antigen specific CTLS came become fully active, that is, during the first few days after viral infection. NK cells are expanded and activated by cytokines of innate immunity, such as IL-12 and IL-15, and they kill infected cells, especially those that display reduced levels of class I molecoles. Some tumors, especially those of hematopoietic origin, are targets of NK cells, perlevels or types of class I MHC molecules. Therefore, IFN-gamma serves critical functions in innate immunity and in specific cell-mediated immunity (in addition, IFN activates neutrophilis and stimulates the cytolitic activity of NK cells). Many IFNs-gamma induced effects result in heigtened immune surveillance. CONCLUSIONS: IFN-gamma is a remarkable cytokine that orchestrates many distinct cellular programs through transcriptional control over large numbers of genes. Many IFNs-gamma-induced effects resulting in heightend immune surveillance and immune system function during infection have been discussed in this review. As the pathogens (microorganism with the potential to cause tissue injury or disease) augment local IFN-gamma production, and IFN-gamma augments the immune system response, an important function of IFN-gamma during in vivo infection is suggested. IFN-gamma is primarily secreted by activated T cells and natural killer cells, and can promote macrophage activation, mediate antiviral e antibacterial immunity, enhance antigen presentation, orchestrate activation of the innate immune system, coordinate lymphocyte-endothelium interaction, regulate Th1/Th2 balance, and control cellular proliferation and apoptosis.

Role of hemochromatosis genes in chronic hepatitis C.

PURPOSE: Hereditary hemochromatosis is commonly associated with iron overload and hepatitis C virus (HCV). Association between hemochromatosis C282Y or H63D mutation has been observed, although not uniformly, and iron overload is also commonly found in chronic HCV hepatitis. This study explored the contribution of genetic hemochromatosis to iron accumulation in hepatitis C. DESIGN: Review of current literature. RESULTS: The prevalence of increased serum iron stores in patients with HCV infection is 28% (patients having an elevated ferritin or transferrin saturation). Patients with elevated serum iron markers have more active chronic hepatitis with more liver fibrosis. In the opinion of the experts HFE mutations are not associated with a high hepatic iron content. No relation was detected between hepatic iron stores and HFE gene mutation. Significant iron deposition in the liver was uncommon and overall the quantity of iron that was detectable histologically and biochemically was unrelated to the grade and stage of HCV related liver injury. The mechanism by which liver iron accumulates in patients is unclear. CONCLUSIONS: Carriage of HFE mutations does not have a role in the accumulation of iron or the liver disease in HCV. These findings do not support a role for iron depletion in patients with chronic HCV infection, including these with elevated serum studies.

Progressive liver injury in chronic hepatitis C infection is related to altered cellular immune response and to different citokine profile.

Natural immune responses, both cellular and humoral, are not capable of terminating HCV infection in most patients. The aim of this study was to evaluate: a) the importance of the immune system in the pathogenesis of chronic HCV infection; b) analysis of successful immunoresponses in persons infected with C virus; c) immuno mechanisms in the progression of hepatic damage; d) different cytokine profiles from patients with persistent and self-limited hepatitis C virus infection; e) development of new antiviral strategies when virus is resistant to interferon treatment. The inadequate T helper1 (Th1) immunity as well as the weak HCV-specific T-cell response at the site of inflammation is associated with failure to clear the virus and a chronic course of disease. The production of interleukin 12 (IL-12) is critical for induction of Th1 immunity, directed towards elimination of intracellular pathogenes and viruses. The core protein of HCV seems to have a suppressive action on IL-12 production at the transcriptional level. The specific Th1 cell defect is correlated with insufficient Th and CTL responses, and lower production of type 1 cytokine (IL-2, IFN-gamma, lymphokine-activated killer cells). Taken together, these results are probably responsible for non-eradication of HCV infection. Particularly the effects of interferon-gamma may include inhibition of HCV virion production by an effect on viral RNA and protein synthesis, enhancement of immune lysis of HCV infected cells, inhibition of hepatic fibrosis by an effect on TGF-beta, and an effect on HCV induced carcinogenesis. These data suggest an HCV-related cellular immune defect in patients with hepatitis C that can be restored in most patients by IL-12. New approaches using a combination of nucleoside analogs or other strategies, such as immune intervention (DNA vaccine, stimulation of the Th1 response) or gene therapy (antisense oligonucleotides dominant negative mutants) should therefore be evaluated in animal models to optimize the current antiviral protocols.

The pathogenesis of hepatocellular carcinoma is multifactorial event. Novel immunological treatment in prospect.

PURPOSE: To discuss exhanstively: complex molecular and cellular mechanism in Hepatocellular Carcinoma (HCC); effect of chronic inflammation and cirrhosis, accompained by regenerative process, on the development of HCC; genetic instability of liver cells of regenerating nodules; the relative role of hepatitis C virus (HCV) and hepatitis B virus (HBV) in hepatocarcinogenesis; tumorigenicity of aflatoxin B1 (AFB1); gene expression profiles in HCC; liver tumors and host defense; future perspectives of HCC treatment. DESIGN: We reviewed the most important studies on HCV. RESULTS: HCC is an aggressive malignancy with poor prognosis and is one of the most common tumor in the world. In the majority of cases, HCC is found in conjunction with cirrhosis of the liver. Chronic inflammation and cirrhosis, accompagnied by regenerative process, function as a tumor promoter, providing a common pathway from chronic HBV or HCV infection to HCC. The direct etiologic role of HBV and HCV for HCC is obscure. Tumor progression may be brought about in HCC by mutation of the p53 tumor suppressor gene. The prevalences of p53 mutations is similar in HBV-associated and HCV-associated HCCs. Another mechanisms of host defense are the production of transforming growth factor beta1 (TGFbeta1), and the induction of cytotoxic T lymphocytes; the failure of there mechanisms permits the process of hepatocarcinogenesis. Treatment with alpha interferon of chronic hepatitis is necessary to delary or prevent the progression to liver cirrhosis and development of HCC. Various therapies, such radical operation, intra-arterial chemoembolization, percutaneous intratumoral ethanol injection, radio-frequency ablation, have been employed, but there is still non satisfactory treatment. Recent advances in recombinant and gene delivery thechnologies suggest that gene therapy may be a promising alternative to explore. Furthemore, immunotherapy may become a modality for patients with HCC. Clinical application of vaccine immunotherapy with NY-ESO-1 derived peptides in HLA-A2 positive HCC patients will be possible.

Hepatorenal syndrome.

PURPOSE: Discuss exhaustively the clinical aspects of hepatorenal syndrome (HRS), laboratory data, the progress made in understanding the pathogenesis, and treatment. DESIGN: The work is a result of the research conducted in the framework of the most important studies on HRS. RESULTS AND CONCLUSIONS: Functional renal failure (FRF) is the most severe manifestation of hepatorenal syndrome, and becomes manifest with a decreased renal perfusion along with oliguresis, reduced excretion of sodium, high urinary osmolarity, azotemia and creatinemia. Liver transplantation restores normal renal function in patients affected by HRS; this suggests the functional origin of the disease. Portal hypertension determines systemic arterial vasodilatation (peripheral vasodilatation theory), with non absolute but effective hypovolemia in terms of its ability to release high circulating levels of vasoactive substances (PG vasodilators, endotoxins, nitric oxide, calcitonin-GPP, glucagon and PAF). Following vasodilatation, a number of systems are triggered to restore peripheral resistance, such as the renin-angiotensin-aldosterone system, the sympathetic systems and the antidiuretic hormone. In some subjects, the activation of these hormones is sufficient to restore resistance and fill the dilated vascular bed, with the subsequent inactivation of the systems themselves. Conversely, in a subgroup of cirrhosis patients with severe portal hypertension, the activation of water retention and vasoconstrictive systems is not sufficient to restore an effective volemia. These subjects present hypotension, effective hypovolemia, high renin levels, high norepinephrine levels and high antidiuretic hormone levels. These substances cause in a sequence, at the renal level, water and sodium retention, progressive vasoconstriction, reduction of plasma flow and GF, initially countered by intrarenal defense mechanisms such as PG, prostacyclins and callicreins. The FRF also sets in because the kidney, in its context, produces determinant endogenous ischemia-inducing substances like tromboxanes, endothelines and leukotrienes. Kidney transplantation is the only treatment.

High prevalence of hepatitis C virus infection in a southern Italian rural region. Clinical aspects and evidence of inapparent parenteral exposure.

AIM: Infection by hepatitis C virus (HCV) generally determines an asymptomatic acute hepatitis which becomes chronic in about 90% of cases. In order to contribute data on the prevalence and the transmission of HCV infection and its associated conditions, anti-HCV seropositivity records in a large sample of a population living in a rural area in Southern Italy were collected and examined. METHODS: Data were obtained from the registers of local general practitioners operating in 4 neighbouring countries which make up the region analysed. Information on established or potential risk factors for HCV transmission was obtained by means of a questionnaire. RESULTS: More than half of the entire population of the examined region (19,800 subjects, 60%) had a record for an anti-HCV blood testing. Out of these 19,800 subjects, 2,213 were found to be seropositive, with a resulting overall anti-HCV prevalence higher than that reported for the whole country (11.1% vs 3%). Genotype 1b was the most commonly detected (86%). Anti-HCV prevalence was significantly higher in the 50-59 and 60-69 year age groups than in other age groups. The results of multiple regression analysis showed that blood transfusion, use of glass syringes, surgical interventions, promiscuous use of tooth-brush, promiscuous use of sharp-edged instruments and lowest number of years of schooling were all independent predictors of anti-HCV positive. No association was found with family history of liver disease and alcohol consumption. A total 46.6% of the subjects had chronic hepatitis, 24.4% had cirrhosis, 1.8% had hepatocellular carcinoma and cirrhosis and 27.2% were "asymptomatic" (with normal serum ALT levels and no histological features of chronic hepatitis despite HCV viremia). CONCLUSION: The most striking result of the study was that the high levels of HCV endemicity was not frequently associated with apparent evidence of parenteral exposure, suggesting that HCV spread in the community can even occur mostly through inapparent parenteral routes.