Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Kings College group was the first to describe a clinical syndrome similar to autoimmune hepatitis in children and young adults transplanted for non-immune mediated liver diseases. They coined the term "de novo autoimmune hepatitis". Several other liver transplant centres confirmed this observation. Even though the condition is uncommon, patients with de novo AIH are now seen in most of the major transplant centres. The disease is usually characterized by features of acute hepatitis in otherwise stable transplant recipients. The most characteristic laboratory hallmark is a marked hypergammaglobulinaemia. Autoantibodies are common, mostly ANA. We described also a case of LKM1-positivity in a patients transplanted for Wilson's disease, however this patients did not develop clinical or histological features of AIH. Development of SLA/LP-autoantibodies is also not described. Therefore, serologically de novo AIH appears to correspond to type 1 AIH. Like classical AIH patients respond promptly to treatment with increased doses of prednisolone and azathioprine, while the calcineurin inhibitors cyclosporine or tacrolimus areof very limited value - which is not surprising, as almost all patients develop de novo AIH while receiving these drugs. Despite the good response to treatment, most patients remain a clinical challenge as complete stable remissions are uncommon and flares, relapses and chronic disease activity can often occur. Pathogenetically this syndrome is intriguing. It is not clear, if the immune response is directed against allo-antigens, neo-antigens in the liver, or self-antigens, possibly shared by donor and host cells. It is very likely that the inflammatory milieu due to alloreactive cells in the transplanted organ contribute to the disease process. Either leading to aberrant antigen presentation, or providing co-stimulatory signals leading to the breaking of self-tolerance. The development of this disease in the presence of treatment with calcineurin inhibitors supports the view held by most specialists in autoimmune hepatitis that these drugs, even though effective in acute disease, are not helpful in the long-term management of autoimmune liver diseases.
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PMID:De novo autoimmune hepatitis after liver transplantation. 1793 Dec 3

Liver transplantation is now widely recognised as an effective treatment option for patients with advanced liver disease. Many units now achieve greater than 85% survival at 1 year, with the majority of patients having a high quality of life. The maintenance of a high quality of life requires careful clinical management to ensure that the continued maintenance of excellent liver graft function is not achieved at the expense of immunosuppressive drug complications or morbidity. Acute liver rejection will occur in between 30 to 45% of patients, although with modern immunosuppressive protocols, usually combining one of the calcineurin agents, either cyclosporin or tacrolimus, with both azathioprine and corticosteroids (prednisolone) ensures that relatively few grafts are lost from severe acute rejection. While the incidence and severity of acute rejection may be one factor in raising the risk of chronic rejection, it may not be the principal one in many patients. It is important to recognise that the frequency of rejection also varies with the primary underlying liver disease, with patients with hepatitis B or alcoholic liver disease having relatively low rejection rates, compared with patients with primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC), which range between 20 to 70%. Chronic rejection will account for some 5% of grafts lost in the first 3 to 5 years. Indeed, there is some evidence that the incidence of chronic rejection is actually declining over the past few years. While the reason for this apparent decline is uncertain, and it could relate to better immunosuppression management, or more likely to the growing recognition that chronic graft dysfunction may be due to recurrent liver disease, such as autoimmune hepatitis, PBC, PSC, or recurrent hepatitis C. The differentiation of recurrent primary liver disease from chronic rejection can prove to be very difficult in clinical practice. Thus, the clinician must carefully monitor liver and graft function, evaluate any biochemical changes, and try to reach a clear diagnosis before considering any modification of immunosuppressive schedules.
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PMID:Chronic rejection of the liver: the role of immunosuppression. 1803 74

Autoimmune hepatitis (AIH) is a progressive inflammatory diseases of unknown origin that is characterised by a necro-inflammatory and fibrotic process and may result in liver failure or uncompensated liver cirrhosis. Normally AIH is responsive to immunosuppressive therapy, and treatment aims to alleviate clinical symptoms, and induce biochemical and histological remission. This short review aims to describe standard medical treatment (SMT) and the experience with newer immunosuppressive drugs in patients refractory or intolerant to SMT. In such cases calcineurin inhibitors (i.e, ciclosporine and tacrolimus) might salvage patients from transplantation. Mycophenolate mofetil may also improve liver tests and reduce the requirement for corticosteroids. Besides, sirolimus is effective for treatment of de novo autoimmune hepatitis that sometimes develops after liver transplantation. Initial experience with the sirolimus analog everolimus in non-grafted patients with severe AIH complicated by renal dysfunction seems promising. As the experience with these newer therapeutic agents have only been studied in small numbers of patients, larger and controlled clinical trials are clearly needed to ensure that such therapeutic possibilities are expanding without overlook serious side effects.
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PMID:Treatment of patients with severe autoimmune hepatitis. 1829 68

During coronavirus replication, viral proteins induce the formation of endoplasmic reticulum (ER)-derived double-membrane vesicles for RNA synthesis, and viral structural proteins assemble virions at the ER-Golgi intermediate compartment. We hypothesized that the association and intense utilization of the ER during viral replication would induce the cellular unfolded protein response (UPR), a signal transduction cascade that acts to modulate translation, membrane biosynthesis, and the levels of ER chaperones. Here, we report that infection by the murine coronavirus mouse hepatitis virus (MHV) triggers the proximal UPR transducers, as revealed by monitoring the IRE1-mediated splicing of XBP-1 mRNA and the cleavage of ATF6alpha. However, we detected minimal downstream induction of UPR target genes, including ERdj4, ER degradation-enhancing alpha-mannosidase-like protein, and p58(IPK), or expression of UPR reporter constructs. Translation initiation factor eIF2alpha is highly phosphorylated during MHV infection, and translation of cellular mRNAs is attenuated. Furthermore, we found that the critical homeostasis regulator GADD34, which recruits protein phosphatase 1 to dephosphorylate eIF2alpha during the recovery phase of the UPR, is not expressed during MHV infection. These results suggest that MHV modifies the UPR by impeding the induction of UPR-responsive genes, thereby favoring a sustained shutdown of the synthesis of host cell proteins while the translation of viral proteins escalates. The role of this modified response and its potential relevance to viral mechanisms for the evasion of innate defense signaling pathways during coronavirus replication are discussed.
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PMID:Coronavirus infection modulates the unfolded protein response and mediates sustained translational repression. 1830 36

Liver disorders with a likely autoimmune pathogenesis in childhood include autoimmune hepatitis (AIH), autoimmune sclerosing cholangitis (ASC), and de novo AIH after liver transplantation. AIH is divided into two subtypes according to seropositivity for smooth muscle and/or antinuclear antibody (SMA/ANA, type 1) or liver kidney microsomal antibody (LKM1, type 2). There is a female predominance in both. LKM1 positive patients tend to present more acutely, at a younger age, and commonly have partial IgA deficiency, while duration of symptoms before diagnosis, clinical signs, family history of autoimmunity, presence of associated autoimmune disorders, response to treatment, and long-term prognosis are similar in both groups. The most common type of paediatric sclerosing cholangitis is ASC. The clinical, biochemical, immunological, and histological presentation of ASC is often indistinguishable from that of AIH type 1. In both, there are high IgG, non-organ specific autoantibodies, and interface hepatitis. Diagnosis is made by cholangiography. Children with ASC respond to immunosuppression satisfactorily and similarly to AIH in respect to remission and relapse rates, times to normalization of biochemical parameters, and decreased inflammatory activity on follow up liver biopsies. However, the cholangiopathy can progress. There may be evolution from AIH to ASC over the years, despite treatment. De novo AIH after liver transplantation affects patients not transplanted for autoimmune disorders and is strikingly reminiscent of classical AIH, including elevated titres of serum antibodies, hypergammaglobulinaemia, and histological findings of interface hepatitis, bridging fibrosis, and collapse. Like classical AIH, it responds to treatment with prednisolone and azathioprine. De novo AIH post liver transplantation may derive from interference by calcineurin inhibitors with the intrathymic physiological mechanisms of T-cell maturation and selection. Whether this condition is a distinct entity or a form of atypical rejection in individuals susceptible to the development of autoimmune phenomena is unclear. Whatever its etiology, the recognition of this potentially life-threatening syndrome is important since its management differs from that of standard anti-rejection therapy.
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PMID:Autoimmune paediatric liver disease. 1852 33

We previously demonstrated the immunosuppressive activity of anti-histone H1 autoantibody induced in experimental and clinical liver allograft tolerance. This study aimed to explore the immunological aspects of anti-histone H1 autoantibody in liver injury induced by concanavalin A (Con A). To establish a Con A-hepatitis model, 20 mg/kg Con A was intravenously injected into rats, after which liver function and histopathological analyses were performed. In this model, anti-histone H1 autoantibody was transiently induced in the sera during the natural recovery stage, 3-7 days after Con A injection. To evaluate the therapeutic significance of anti-histone H1 autoantibody, a polyclonal antibody against histone H1 was intraperitoneally injected immediately after Con A injection. We found that injection of anti-histone H1 antibody could reduce Con A-induced liver damage. Further mechanical analyses revealed that anti-histone H1 antibody altered the intracellular activation of mitogen-activated protein kinase, nuclear factor-kappaB and calcineurin via T-cell receptor signalling, suggesting that anti-histone H1 antibody may protect the liver from Con A-induced injury by inhibiting activation of effector T cells. These findings suggest that anti-histone H1 autoantibody may be a natural immune regulatory factor that protects inflamed livers suffering from autoimmune hepatitis and may lead to T-cell unresponsiveness through the selective regulation of mitogen-activated protein kinase/nuclear factor-kappaB and calcineurin signalling.
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PMID:Immunological aspects and therapeutic significance of an autoantibody against histone H1 in a rat model of concanavalin A-induced hepatitis. 2010 16

Treatment decisions in autoimmune hepatitis are complicated by the diversity of its clinical presentations, uncertainties about its natural history, evolving opinions regarding treatment end points, varied nature of refractory disease, and plethora of alternative immunosuppressive agents. The goals of this article are to review the difficult treatment decisions and to provide the bases for making sound therapeutic judgments. The English literature on the treatment problems in autoimmune hepatitis were identified by Medline search up to October 2009 and 32 years of personal experience. Autoimmune hepatitis may have an acute severe presentation, mild inflammatory activity, lack autoantibodies, exhibit atypical histological changes (centrilobular zone 3 necrosis or bile duct injury), or have variant features reminiscent of another disease (overlap syndrome). Corticosteroid therapy must be instituted early, applied despite the absence of symptoms, or modified in an individualized fashion. Pursuit of normal liver tests and tissue is the ideal treatment end point, but this objective must be tempered against the risk of side effects. Relapse after treatment withdrawal requires long-term maintenance therapy, preferably with azathioprine. Treatment failure or an incomplete response warrants salvage therapy that can include conventional medications in modified dose or empirical therapies with calcineurin inhibitors or mycophenolate mofetil. Liver transplantation supersedes empirical drug therapy in decompensated patients. Elderly and pregnant patients warrant treatment modifications. Difficult treatment decisions in autoimmune hepatitis can be simplified by recognizing its diverse manifestations and individualizing treatment, pursuing realistic goals, applying appropriate salvage regimens, and identifying problematic patients early.
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PMID:Difficult treatment decisions in autoimmune hepatitis. 2018 Feb 31

There is in vitro proof that mTOR proteins play a role in protecting HCV infected cells from apoptosis. The aim of this cohort study was to evaluate the effect of sirolimus as an mTOR inhibitor on hepatitis C recurrence in liver transplant recipients. Hepatitis C virus positive patients were followed prospectively regarding transaminases, immunosuppressive target levels, HCV RNA and influence of donor and recipient factors on viral recurrence and survival. Viral recurrence was defined as elevated liver enzymes combined with active hepatitis diagnosed on the basis of increasing viral load and/or biopsy-proven HCV relapse in the transplanted organ. Sixty-seven HCV positive patients were included: 39 received a regimen including sirolimus; 28 patients received calcineurin inhibitors. Sirolimus patients showed a significant decrease in the HCV PCR levels (p<0.05). Survival of the sirolimus patients was significantly higher (p<0.03) than in the other patient cohort. Sirolimus has been shown to be a potent immunosuppressive agent after liver transplantation, though nothing is known about its effect on HCV. This analysis suggests that sirolimus has potential to suppress viral recurrence in HCV positive liver transplant candidates.
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PMID:Sirolimus has a potential to influent viral recurrence in HCV positive liver transplant candidates. 2048 86

Survivin (BIRC5) relationship with tumor is presented in several papers. However, how the molecular network and interpretation concerning BIRC5 cell cycle between no-tumor hepatitis/cirrhosis and hepatocellular carcinoma (HCC) remains to be elucidated. Here, we constructed and analyzed significant higher expression gene BIRC5 activated and inhibited cell cycle network from HCC versus no-tumor hepatitis/cirrhosis patients (viral infection HCV or HBV) in GEO Dataset by combination of gene regulatory network inference method based on linear programming and decomposition procedure with the CapitalBio MAS 3.0 software based on the integration of public databases including Gene Ontology, KEGG, BioCarta, GenMapp, Intact, UniGene, OMIM, etc. Compared the same and different activated and inhibited BIRC5 network with GO analysis between no-tumor hepatitis/cirrhosis and HCC, our result showed BIRC5 cell cycle network weaker transcription factor activity in both no-tumor hepatitis/cirrhosis and HCC (1); stronger nucleus protein binding but weaker cytoplasm protein binding in no-tumor hepatitis/cirrhosis (2); stronger cytoplasm protein phosphatase binding but weaker ubiquitin-protein ligase activity in HCC (3). Therefore, we inferred BIRC5 cell cycle module less transcription from RNA polymerase II promoter in both no-tumor hepatitis/cirrhosis and HCC (4). We deduced BIRC5 cell cycle module different from more mitosis but less complex-dependent proteasomal ubiquitin-dependent protein catabolism as a result increasing cell division and cell numbers in no-tumor hepatitis/cirrhosis to more protein amino acid autophosphorylation but less negative regulation of ubiquitin ligase activity during mitotic cell cycle as a result increasing growth and cell volume in HCC (5).
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PMID:Survivin (BIRC5) cell cycle computational network in human no-tumor hepatitis/cirrhosis and hepatocellular carcinoma transformation. 2131 34

Every liver transplant (LT) center has had patients who either self-discontinue immunosuppressive (IS) therapy or are deliberately withdrawn due to a research protocol or clinical concern (ie, lymphoproliferative disorder [LPD], overwhelming infection). This is understandable because maintenance IS therapy, particularly calcineurin inhibitors (CNI), is associated with significant cost, side effects, and considerable long-term morbidity and mortality. Detrimental effects of IS therapy include increased risk of cardiovascular disease, metabolic syndrome, bone loss, opportunistic and community-acquired infections, and malignancy. In fact, LT recipients have among the highest rates of chronic kidney disease and associated mortality among all nonkidney solid organ recipients. This mortality is only ameliorated by undergoing a curative kidney transplant, usurping costs and valuable organ resources. The search for improved treatment algorithms includes trial and error CNI dose minimization, the use of alternative IS agents (antimetabolites, mammalian target of rapamycin [mTOR] inhibitors), or even complete CNI withdrawal. Yet those who are successful in achieving such operational tolerance (no immunosuppression and normal allograft function) are considered lucky. The vast majority of recipients will fail this approach, develop acute rejection or immune-mediated hepatitis, and require resumption of IS therapy. As such, withdrawal of IS following LT is not standard-of-care, leaving clinicians to currently maintain transplant patients on IS therapy for life. Nonetheless, the long-term complications of all IS therapies highlight the need for strategies to promote immunologic or operational tolerance. Clinically applicable biomarker assays signifying the potential for tolerance as well as tolerogenic IS conditioning are invariably needed if systematic, controlled rather than "hit or miss" approaches to withdrawal are considered. This review will provide an overview of the basic mechanisms of tolerance, particularly in relation to LT, data from previous IS withdrawal protocols and biomarker studies in tolerant recipients, and a discussion on the prospect of increasing the clinical feasibility and success of withdrawal.
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PMID:Operational tolerance: past lessons and future prospects. 2138 4


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