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 immune response to foreign or self antigens mediates liver damage during viral or autoimmune hepatitis. However, it now appears that also specific antigen-independent liver diseases, where liver damage has been attributed to occur from oxygen radical formation, seem to be mediated by cells of the innate and adaptive immune response. These liver disorders include alcoholic liver disease, non-alcoholic fatty liver disease or non-alcoholic steatohepatitis, and ischemia/reperfusion injury that impairs the function of liver grafts. Here it seems that breakdown of the gastrointestinal barrier might increase the concentration of bacterial toxins in the portal blood, which then activate cells of the innate immune system, e. g., Kupffer cells, but, depending on the nature of the toxin, probably also conventional T cells. Invariant NKT cells which specifically recognize glycolipid antigens were supposed to become activated during metabolic disorders related to obesity. However, both steatohepatitis as well as ischemia/reperfusion injury are associated with a Th1 cytokine response characterized by IFNgamma and TNFalpha elevation, that might reflect an NKT cell response on the one hand, but also conventional T lymphocytes, in particular CD4 (+) T cells, are critical for the pathophysiology of these disorders. In 1992 we described a model of T cell-dependent liver injury inducible by the T cell-mitogenic lectin concanavalin A. This model of immune-mediated liver injury was intensively used to study pathophysiological immune effector mechanisms as well as cytokine signaling important for hepatocellular apoptosis, inhibition of apoptosis and regeneration. Recently it became evident that the inflammatory response in this model is regulated by specific cytokine signals as well as by immune regulator cells. The immune-regulatory functions of the liver are of particular interest with respect to the scavenger function of this organ, being continuously exposed to foreign antigenic material from the gut which should be eliminated without causing chronic disease.
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PMID:Cellular and cytokine-mediated mechanisms of inflammation and its modulation in immune-mediated liver injury. 1723 22

Several autoimmune diseases are thought to be mediated in part by interleukin (IL)-18. Many are those with associated increased interferon-gamma (IFNgamma) levels such as systemic lupus erythematosus, macrophage activation syndrome, rheumatoid arthritis, Crohn's disease, psoriasis, and graft-versus-host disease. In addition, ischemia, including acute renal failure in human beings, appears to involve IL-18. Animal studies also support the concept that IL-18 is a key player in models of lupus erythematosus, atherosclerosis, graft-versus-host disease, and hepatitis. Unexpectedly, IL-18 plays a role in appetite control and the development of obesity. IL-18 is a member of the IL-1 family; IL-1beta and IL-18 are related closely, and both require the intracellular cysteine protease caspase-1 for biological activity. The IL-18 binding protein, a naturally occurring and specific inhibitor of IL-18, neutralizes IL-18 activities and has been shown to be safe in patients. Other options for reducing IL-18 activities are inhibitors of caspase-1, human monoclonal antibodies to IL-18, soluble IL-18 receptors, and anti-IL-18 receptor monoclonal antibodies.
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PMID:Interleukin-18 and the pathogenesis of inflammatory diseases. 1733 92

Posttransplant de novo autoimmune hepatitis (d-AIH) is increasingly described as a long-term complication after pediatric liver transplantation (LT). d-AIH is characterized by graft dysfunction, the development of autoimmune antibodies and histologic evidence of hepatitis in liver transplant recipients without previous history of autoimmune liver disease. This study is a matched case-control, univariate analysis aimed at identifying risk factors for the development of d-AIH and evaluating response to treatment. From 1984 to 2003, 619 children received 788 LTs at a single center. Forty-one patients developed d-AIH and were matched with controls for year of LT, age at time of LT and diagnosis. The following variables were insignificant in the development of d-AIH: age, gender, race, initial diagnosis, ischemia time, graft type, Epstein-Barr virus and cytomegalovirus status, HLA typing and primary immunosuppression. Compared to controls, d-AIH patients were less likely to be on monotherapy immunosuppression or weaned off prednisone at the time of diagnosis. The d-AIH group relative to the controls had statistically significant greater numbers of rejection episodes. d-AIH was treated with prednisone and/or MMF in 39 of 41 patients and lead to significant improvements in liver function tests. Thirty-nine patients are alive at a mean of 4.0 years follow-up after diagnosis. Three have required retransplantation.
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PMID:Rejection and steroid dependence: unique risk factors in the development of pediatric posttransplant de novo autoimmune hepatitis. 1739 Nov 35

Acute cellular graft-vs.-host disease (GVHD) following liver transplantation has an incidence of 1 to 2% and a mortality rate of 85%. Our aim was to identify a patient population at high risk for developing GVHD using a large clinical database to study both recipient and donor factors. We compared our liver transplant patients who developed GVHD to those that did not for recipient and donor factors and combinations of factors. For 2003-2004 we had 205 first-time liver transplant patients surviving >30 days. From this group, 4 (1.9%) developed GVHD. Compared to the control group, there were no significant differences in recipient age, recipient gender, donor age, donor gender, total ischemia time, donor-recipient human leukocyte antigen (HLA) mismatch, or donor-recipient age difference. Percentages of liver disease etiologies among the patients who developed GVHD were as follows: 16% (1/6) autoimmune hepatitis (AIH) (P = 0.003), 5.6% (3/54) alcoholic liver disease (ALD) (P = 0.057), and 7.1% (3/42) hepatocellular carcinoma (HCC) (P = 0.026). The incidence of GVHD in patients with glucose intolerance (either Type I or Type II diabetes mellitus [DM]) was significant (P = 0.022). Focusing on patients only with high-risk factors for GVHD during the years 2003-2005, we had 19 such patients. Four of these high-risk patients developed GVHD. Three of these 4 patients had received a donor liver with steatosis of degree >or=mild compared to only 2 of the 15 high-risk patients who did not develop GVHD (P = 0.037). In conclusion, we have identified liver transplant patients with AIH or the combination of ALD, HCC, and glucose intolerance who receive a steatotic donor liver as being at high risk for developing GVHD.
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PMID:Recipient and donor factors influence the incidence of graft-vs.-host disease in liver transplant patients. 1739 49

Recent studies have implicated dysregulation of the endocannabinoid system in various liver diseases and their complications (e.g., hepatitis, fibrosis, cirrhosis, cirrhotic cardiomyopathy, and ischemia-reperfusion), and demonstrated that its modulation by either cannabinoid 2 (CB(2)) receptor agonists or CB(1) antagonists may be of significant therapeutic benefits. This review is aimed to focus on the triggers and sources of endocannabinoids during liver inflammation and on the novel role of CB(2) receptors in the interplay between the activated endothelium and various inflammatory cells (leukocytes, lymphocytes, etc.), which play pivotal role in the early development and progression of inflammatory and other liver diseases.
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PMID:Endocannabinoids and liver disease. III. Endocannabinoid effects on immune cells: implications for inflammatory liver diseases. 1823 59

Polyarteritis nodosa (PAN) is a necrotizing, focal segmental vasculitis that affects predominantly medium-sized arteries in many different organ systems. It is associated with hepatitis B virus (HBV) in about 7% of cases, a decline from about 30% before the mandatory testing of blood products and the widespread vaccination programs. HBV PAN is an early postinfectious process. The hepatitis is silent in most cases, with mild transaminase level increases in 50% of patients. Gastrointestinal involvement occurs in 14% to 65% of patients with PAN. Postprandial abdominal pain from ischemia is the most common symptom. When transmural ischemia develops, there may be necrosis of the bowel wall with perforation, associated with a poor prognosis. Liver involvement occurs in 16% to 56% of patients, although clinical manifestations related to liver disease are quite rare. Acalculous gangrenous cholecystitis may develop owing to arteritis involving the wall of the gallbladder. Microaneurysms on arteriography or computed tomography angiography are characteristic of PAN, but are seen in other conditions. Tissue biopsy may confirm the diagnosis, although involvement is segmental. Corticosteroids are used for non-HBV PAN with cyclophosphamide added for severe disease. For PAN related to HBV, a 2-week course of corticosteroids is begun, with plasma exchanges and an antiviral agent. Corticosteroids and cyclophosphamide have improved patient outcome so that the 1-year survival rate is now about 85%.
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PMID:Gastrointestinal involvement in polyarteritis nodosa. 1858 77

Our center has attempted to minimize corticosteroid (CS) use in all of our orthotopic liver transplantation (OLT) recipients. Because patients with autoimmune hepatitis (AIH) typically require CSs after transplantation, we reviewed our experience in this cohort of patients to determine (1) patient outcomes including recurrent disease and (2) long-term requirements for CS use in AIH patients. From 1988 to 2006, 1102 OLTs were performed in 1032 adult patients at the University of Colorado, of whom 66 (6%) with AIH received 68 allografts. Recurrence was defined by a clinically worsening examination and histological evidence from biopsy. Bivariate and multivariate analyses were used to evaluate predictors of CS withdrawal. Twelve potential predictors of CS discontinuation were considered: age, gender, presence of inflammatory bowel disease (IBD), type of graft (cadaver or living donor), recurrence of AIH, warm ischemia time, follow-up time (time since transplant), and immunosuppressants (cyclosporine, tacrolimus, sirolimus, azathioprine, and mycophenolate mofetil). Overall survival at 5 years was 91%. The 1- and 5-year recurrence-free survival was 88% and 59%, respectively. Risk (incidence) of recurrent AIH at 1, 3, and 5 years was 12%, 26%, and 36%, respectively. Disease recurred in 23 of 66 patients or 34.8%. Of the 23 patients who developed recurrent disease, none received a second transplant because of recurrent disease. CSs were withdrawn in 50% of patients at the time of review. Only 2 factors on multivariate analysis were strongly associated negatively with CS withdrawal: (1) an increasing dose of the immunosuppressant and (2) the presence of IBD. Controlling for these other factors, we found that recurrent disease did not strongly influence CS withdrawal. In conclusion, outcomes in AIH patients were quite favorable, and none of the patients required retransplantation for recurrent AIH. With a CS minimization approach, one-half of the patients were able to remain CS-free.
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PMID:Liver transplantation for autoimmune hepatitis and the success of aggressive corticosteroid withdrawal. 1875 54

1. In hepatitis C virus (HCV)-infected patients undergoing liver transplantation (LT), the virus infects the liver graft immediately after transplantation. The main source of HCV infection is circulating virions. Nevertheless, some data suggest that HCV present in extrahepatic compartments may contribute to HCV infection in some cases of hepatitis C recurrence. 2. Studies on early kinetics have shown that HCV replication starts a few hours after transplantation and that HCV-RNA concentrations increase a few hours or days after the procedure, suggesting that HCV has an enormous ability to adapt to the new environment. 3. The quasispecies population may change significantly after transplantation, most likely because of the need to adapt to a new environment. There are no conclusive data supporting the role of HCV quasispecies composition and disease outcomes. 4. Persistence of HCV infection is the rule after transplantation. This is due to immunosuppression and to the immune exhaustion of the previously exposed immune system. 5. In general, HCV is not thought to be directly cytopathic. Thus, it is believed that the immune response against HCV causes liver damage. However, understanding the mechanisms of liver damage in HCV-infected LT recipients is extremely complex because of the existence of a human leukocyte antigen-mismatched organ, the preexisting virus-specific T cells that may be dysfunctional and/or tolerized, and the immunosuppression. 6. Despite the possible effect of immune-mediated liver damage, it is clear that strong immunosuppression is associated with severe forms of hepatitis C recurrence (cholestatic hepatitis, fibrosing cholestatic hepatitis, and accelerated fibrosis progression). Thus, in the absence of a strong anti-HCV immune response, HCV is able to directly (HCV proteins) or indirectly (cytokines) produce liver damage. 7. The activation of stellate cells and accelerated deposition of fibrosis are the final consequences of HCV infection in the graft. There are several mechanisms that may act synergistically to activate and perpetuate stellate cell activation in the setting of LT: ischemia-reperfusion damage, old donor age, HCV proteins, cholestasis, rejection, infection with other viruses (cytomegalovirus), and immune-mediated injury.
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PMID:Virology and pathogenesis of hepatitis C virus recurrence. 1882 23

The factors that influence the long-term histological outcome of transplanted liver allografts in children are not yet fully understood, and the role of surveillance biopsies in patients with normal graft function remains controversial. The aims of this study were to describe the long-term graft histology of pediatric liver transplant recipients surviving at least 3 years and to analyze factors correlating with long-term histological outcome. Histological slides of 63 long-term liver transplant recipients were assessed for inflammation and fibrosis. The histological findings were correlated with clinical, biochemical, serological, and radiological findings. A significant proportion of biopsies from these patients showed some type of histological abnormalities, with fibrosis being observed in 61 (97%) patients. Duration of transplantation of >6 years and > or =grade 2 inflammation were significantly associated with advanced fibrosis. We could not identify any correlation between > or =stage 3 fibrosis and donor age, cold and warm ischemia time, history of de novo autoimmune hepatitis, hepatic artery thrombosis, chronic rejection, or alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase values. In conclusion, liver fibrosis appears to be a common finding in long-term pediatric liver transplant survivors. The cause of this fibrosis is uncertain, and normal alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase levels do not exclude the presence of significant fibrosis.
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PMID:Graft histology characteristics in long-term survivors of pediatric liver transplantation. 1897 86

Clinicopathologic features of 45 patients with fulminant hepatic failure due to massive or submassive hepatic necrosis were studied. Both percutaneous biopsies and liver explants were available in 23 patients, whole livers only in 11 cases, and biopsies only in 11 cases. An etiologic diagnosis was established in 16 cases (36%). A further 3 cases (7%) were associated with aplastic anemia. Established etiologies included drug reactions (n = 7); autoimmune hepatitis, type 2 (n = 3); halothane hepatitis (n = 1); ischemia/hypotension (n = 1); mushroom poisoning (n = 1); mitochondrial disorder (n = 1); hemophagocytic lymphohistiocytosis (n = 1); and adenoviral hepatitis (n = 1). The extent of necrosis on liver biopsy correlated poorly with that in liver explants (mean difference, 32% +/- 23.8%). Almost all cases could be classified into one of 2 broad patterns of necrosis, namely, (1) zonal coagulative necrosis or (2) panlobular (nonzonal) necrosis. These patterns differed significantly with respect to several clinical parameters including sex ratio, peripheral blood white cell count, serum aspartate transaminase and alanine transaminase, conjugated bilirubin, and alkaline phosphatase levels. Livers with panlobular necrosis showed a spectrum of histopathologic findings that included central venulitis (76%), lymphocytic infiltration of large duct/gallbladder epithelium (54%), and syncytial giant cell transformation (18%). These features were not seen in livers with zonal coagulative necrosis which frequently showed prominent steatosis (91%). Both patterns of necrosis frequently showed ductular proliferation (100%) and cholangiolitis (80%). The diagnostic yield of ancillary studies (histochemistry, immunohistochemistry, and electron microscopy) was very low (<1%). The small proportion of cases with etiologic diagnoses precluded correlation of clinical and histopathological parameters with specific etiologies. In summary, this study describes the spectrum of changes seen in massive and submassive necrosis in children and identifies clinical features that might differentiate between 2 broad patterns of necrosis.
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PMID:Clinicopathologic spectrum of massive and submassive hepatic necrosis in infants and children. 1912 48


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