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 aim of this study was to compare major histocompatibility complex (MHC) class II susceptibility to type 1 autoimmune hepatitis (AH) between children and adults of the same ethnic group. HLA-DRB1, HLA-DRB3, HLA-DQA1, and HLA-DQB1 gene subtypes were examined by high resolution oligonucleotide typing in 122 pediatric (PAH) and 84 adult (AAH) patients and in 208 controls. In children, HLA-DRB1*1301 was the primary susceptibility allele (66.4% patients vs. 10.6% controls, relative risk [RR] = 16.3, Pc < 10(-24)) whereas HLA-DRB1*1302, which differs from HLA-DRB1*1301 by only 1 amino acid, appeared to be protective. The exclusion of individuals with HLA-DRB1*1301 from control and pediatric patients allowed us to find a secondary association of PAH with HLA-DRB1*0301. Possession of HLA-DRB1*1301, however, was associated with a lower therapeutic response rate. Analysis of peptide binding pocket residues indicated that Tyr 10, Ser 11, Ser 13, and Val 86 in the class II beta chain were present in 85% of patients compared with 37% of controls, suggesting that a high proportion of AH susceptibility is attributable to these residues (etiologic fraction [EF] = 76%). In contrast to the class II associations in children, AAH was associated with HLA-DRB1*0405 (RR = 10.4, Pc <.005) but not with HLA-DRB1*1301 or HLA-DRB1*0301. In addition, HLA-DR4 with the class I gene, HLA-A11, appeared synergistic in predisposing AAH patients to develop extra-hepatic autoimmune (AI) manifestations (odds ratio [OR] = 104.9, Pc < 10(-4)). Concomitant differences in autoantibody profiles were also observed in PAH versus AAH: smooth muscle antibodies (SMA) were most prevalent in PAH but antinuclear antibodies were most prevalent in AAH (P =.003). This study therefore reveals that different HLA-DRB1 allotypes confer susceptibility to AH in children and adults and raises the possibility that PAH and AAH may be triggered by different factors.
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PMID:Pediatric and adult forms of type I autoimmune hepatitis in Argentina: evidence for differential genetic predisposition. 1057 14

The effect of segmental transcatheter arterial chemoembolization (TAE) on serum amino acid levels and liver function were studied in 23 patients with HCC associated with hepatitis virus C (22 patients) or alcoholism (1 patient), with compensated liver cirrhosis (Child A 18 patients, Child B 5 patients). Serum levels of branched-chain amino acids (BCAA), tyrosine, branched-chain amino acids to tyrosine ratio (BTR), ammonia, total bilirubin and albumin, and prothrombin times were measured before and after TAE (24 h, 7 and 14 days). The BTR was increased significantly 24 h after TAE (p<0.001) and gradually decreased to pre-TAE levels. Serum tyrosine levels decreased at 24 h after TAE (p<0.005) and later increased. Serum BCAA levels increased slightly at 7days after TAE and were decreased at 14 days after TAE. This results indicated that the increased BTR was due primarily to the decreased tyrosine level at 24 h after TAE. Serum ammonia levels gradually decreased after TAE and the prothrombin time and serum levels of total bilirubin and albumin were not significantly changed. In this study, segmental TAE had little influence on liver function, and the BTR unexpectedly increased at 24 h after TAE. These results suggest that segmental TAE has minimal side effects and may have a beneficial effect on amino acid metabolism.
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PMID:Effect of segmental transcatheter arterial chemoembolization on branched chain amino acids and tyrosine ratio in patients with hepatocellular carcinoma. 1102 1

Treatment of chronic hepatitis B is directed at interrupting the natural history and clinical outcomes of the disease. It needs to take into account the virology and replication cycle of the hepatitis B virus (HBV), and the host immune response to HBV. Long term follow-up of patients treated with interferon supports the paradigm that a sustained, major suppression of HBV replication, particularly that associated with hepatitis B e antigen (HBeAg) seroconversion, interrupts the natural history of hepatitis B. The availability of potent but well tolerated and orally available HBV antivirals, of which lamivudine is the prototype, has allowed clearer treatment objectives to be formulated. These are: temporary or permanent reduction of hepatitis (necroinflammatory) activity, arrest of fibrotic progression, prevention of cirrhosis and liver failure, and prevention of recurrent HBV infection after liver transplantation. Lamivudine has good medium term efficacy in achieving each of these objectives. The only significant problem for the longer term is emergence of antiviral resistance conferred by mutations in the YMDD (tyrosine-methionine-aspartic acid-aspartic acid) motif of the HBV reverse transcriptase. As a result, contentious issues remain about defining when antiviral therapy is indicated, whether to treat for a defined interval or indefinitely, and when to stop treatment if HBeAg seroconversion is not achieved. Some personal views are expressed in this review. Among newer HBV antivirals in clinical studies, adefovir dipivoxil, entecavir and emtricitabine appear to be at least as potent as lamivudine in suppressing HBV replication. Famciclovir appears less potent. In vitro studies show that YMDD mutations confer cross-resistance between lamivudine, emtricitabine and beta-L-Fd4C (L-2',3'-didehydro-dideoxy-5-fluorocytidine). However, adefovir dipivoxil, lobucavir, entecavir, DAPD (beta-D-2,6-diaminopurine dioxolane) and possibly clevudine (L-FMAU) suppress replication of YMDD mutant HBV, as well as wildtype. Preliminary studies indicate clinical efficacy of adefovir dipivoxil once resistance to lamivudine has developed. Immunomodulatory approaches to treatment of chronic hepatitis B are conceptually attractive, but newer agents used to date (thymalfasin, interleukin-12, therapeutic vaccines) have not demonstrated sufficient efficacy for widespread use. The next challenge for HBV treatment is to use antivirals in combination and/or in cyclical therapy to reduce the emergence of drug resistance and increase efficacy, particularly to achieve sustainable post-treatment suppression of hepatitis B.
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PMID:Clinical potential of emerging new agents in hepatitis B. 1108 96

We present a case of infection with lamivudine-resistant mutant hepatitis B virus (HBV) that fatally exacerbated hepatitis following the emergence of HBV with mutations in the tyrosine-methionine-aspartate-aspartate (YMDD) motif in an immunocompetent patient who was receiving long-term lamivudine therapy. Restriction fragment length polymorphism analysis showed that the YMDD-motif mutant was the predominant form of circulating HBV at the time of the fatal exacerbation, and a necropsy specimen of the liver revealed submassive hepatic necrosis without steatosis.
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PMID:Fatal submassive hepatic necrosis associated with tyrosine-methionine-aspartate-aspartate-motif mutation of hepatitis B virus after long-term lamivudine therapy. 1143 12

Western blot experiments showed that sera from mice infected with the mouse hepatitis virus strain A59 (MHV-A59) contained autoantibodies (autoAb) that bound to a 40-kDa protein present in liver and kidney extracts. No reaction was observed with extracts of the heart, muscles, spleen, brain and lung. The Ab cross-reacted with a 40-kDa protein from human, rat and sheep liver, but not with liver extracts from the silver side fish (Odontesthes bonariensis). No correlation was found between the development of the hypergammaglobulinemia that followed the viral infection and the occurrence of the autoAb. Reactive immunoglobulins pertained to the IgG1, IgG2a and IgG2b subclasses, recognized cryptic epitopes and were detected from 10 days up to 8 weeks after MHV-infection. The 40-kDa protein was purified from mouse liver extracts by ion-exchange chromatography, gel filtration and SDS-PAGE. Because the N-terminal was blocked, we digested the protein in-gel with trypsin and sequenced various peptides. Results indicated a 100% homology of sequence between the protein recognized by the autoAb and liver fumarylacetoacetate hydrolase (FAH), the enzyme that mediates the last step of tyrosine catabolism. Additionally, a second protein recognized by the autoAb was detected during FAH purification steps and was identified as liver alcohol dehydrogenase.
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PMID:Identification of two liver proteins recognized by autoantibodies elicited in mice infected with mouse hepatitis virus A59. 1146 1

Five patients of cholestatic jaundice and multiple hyperaminoacidemias were uncovered during neonatal mass screening for homocystinuria. All five patients had increased plasma levels of methionine, citrulline, tyrosine, threonine, phenylalanine, lysine and arginine. Compared with those of age-matched cholestatic disease controls, idiopathic neonatal hepatitis (n=9) and biliary atresia (n=14), plasma levels of three amino acids, citrulline, methionine, and threonine, were significantly greater, respectively (P<0.01). Liver biopsies examined in four patients uniformly showed diffuse hepatic fatty liver with micro- and macrovesicular droplets without giant cell transformation. Administration of fat-soluble vitamins and formula milk containing middle-chain triglyceride resulted in normalization of amino acid profiles by 6 weeks after the treatment. All liver function tests normalized by 17 months of age.
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PMID:An undescribed subset of neonatal intrahepatic cholestasis associated with multiple hyperaminoacidemia. 1147 Jun 24

Lamivudine (Zeffix, Epivir, GlaxoSmithKline) is the most important recent advance in the treatment of chronic hepatitis B in both adults and children. It is the only available oral treatment and has an excellent safety profile, which makes it even more attractive. It increases the rate of hepatitis B e antigen (HBeAg) loss and seroconversion in compensated chronic HBeAg-positive carriers, with subsequent improvement of histology at a similar rate as IFN-alpha. Lamivudine is mostly active in patients with elevated transaminases and is not effective in compensated patients with quiescent disease. Long-term follow-up studies are still required to evaluate long-term benefits, including those on hepatitis B surface antigen (HBsAg) seroconversion rate and disease evolution control. In decompensated patients, the drug can stabilise and improve liver function, allowing the patient to wait safely for transplantation. Patients may improve to such an extent that transplantation can be postponed. Combined with hepatitis B immunoglobulin (HBIG), lamivudine considerably decreases the risk of graft re-infection after transplantation. It is also active in chronic HBeAg-negative hepatitis patients, for whom IFN is less efficient. The major drawback is the emergence of the tyrosine-methionine-aspartate-aspartate (YMDD) mutation, which prevents further efficacy of the drug and may lead to flares of hepatitis. Due to the questions the YMDD mutation raises and because hepatitis B is a complex disease, indications for treatment must be established with care and only by physicians with expert knowledge of the disease, the drug and YMDD mutation-related issues.
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PMID:Lamivudine for the treatment of chronic hepatitis B. 1186 82

Natural killer (NK) cells are major contributors to early defense against infections. Their effector functions are controlled by a balance between activating and inhibiting signals. To date, however, the involvement of NK cell activating receptors and signaling pathways in the defense against pathogens has not been extensively investigated. In mice, several NK cell activating receptors are coexpressed with and function through the immunoreceptor tyrosine-based activation motif (ITAM)-bearing molecule KARAP/DAP12. Here, we have analyzed the role of KARAP/DAP12 in the early antiviral response to murine cytomegalovirus (MCMV). In KARAP/DAP12 mutant mice bearing a nonfunctional ITAM, we found a considerable increase in viral titers in the spleen (30-40-fold) and in the liver (2-5-fold). These effects were attributed to NK cells. The formation of hepatic inflammatory foci appeared similar in wild-type and mutant mice, but the latter more frequently developed severe hepatitis with large areas of focal necrosis. Moreover, the percentage of hepatic NK cells producing interferon gamma was reduced by 56 +/- 22% in the absence of a functional KARAP/DAP12. This is the first study that shows a crucial role for a particular activating signaling pathway, in this case the one induced through KARAP/DAP12, in the NK cell-mediated resistance to an infection. Our results are discussed in relation to recent reports demonstrating that innate resistance to MCMV requires the presence of NK cells expressing the KARAP/DAP12-associated receptor Ly49H.
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PMID:Pivotal role of KARAP/DAP12 adaptor molecule in the natural killer cell-mediated resistance to murine cytomegalovirus infection. 1192 27

The signal transducer and activator of transcription (STAT) family proteins are transcription factors critical in mediating cytokine signaling. Among them, STAT3 is often constitutively phosphorylated and activated in human cancers and in transformed cell lines and is implicated in tumorigenesis. However, cause of the persistent activation of STAT3 in human tumor cells is largely unknown. The hepatitis C virus (HCV) is a major etiological agent of non-A and non-B hepatitis, and chronic infection by HCV is associated with development of liver cirrhosis and hepatocellular carcinoma. HCV core protein is proposed to be responsible for the virus-induced transformation. We now report that HCV core protein directly interacts with and activates STAT3 through phosphorylation of the critical tyrosine residue. Activation of STAT3 by the HCV core in NIH-3T3 cells resulted in rapid proliferation and up-regulation of Bcl-XL and cyclin-D1. Additional expression of STAT3 in HCV core-expressing cells resulted in anchorage-independent growth and tumorigenesis. We propose that the HCV core protein cooperates with STAT3, which leads to cellular transformation.
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PMID:Activation of STAT3 by the hepatitis C virus core protein leads to cellular transformation. 1220 79

Better understanding of hepatitis B virus (HBV) replication, natural history and the immunopathogenesis of chronic hepatitis B, together with the introduction of effective agents with different mechanisms of action are the basis for better therapeutic strategies against chronic hepatitis B. Among currently available drugs, interferon-alpha and thymosin-alpha1 have only modest efficacy (approximately 40% vs 9-20% in controls). In the past decade, lamivudine has dominated in the treatment of chronic HBV infection because it is easy to use, safe, and is effective in terms of hepatitis B e antigen and/or HBV-DNA loss, ALT normalization, and improvement in histology. The response rate increases with increasing pretherapy alanine aminotransferase (ALT) levels, suggesting that patients with stronger endogenous immune response against HBV have a better response to direct antiviral agents. Lamivudine is also beneficial in decompensated cirrhotics with HBV replication. Hepatitic flares may occur after stopping lamivudine therapy in nonresponders and also in responders. Therefore, prolonged therapy is usually required. However, tyrosine-methionine-aspartate-aspartate (YMDD) mutations conferring resistance to lamivudine start to emerge after 6-9 months of therapy, and hepatitis flare, even decompensation, may develop after viral breakthrough. Thus the benefits of long-term lamivudine therapy must be balanced against the concern about YMDD mutations and the durability of treatment response. Adefovir dipivoxil, entecavir, emtricitabine, clevudine and other nucleoside/ nucleotide analogues have shown encouraging results and some agents appear effective in patients with YMDD mutants. Further development of new drugs and new strategies may help to improve treatment in the new century.
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PMID:Therapy of chronic hepatitis B: current challenges and opportunities. 1243 Dec


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