PubMed Health⌕ Search

Biomedical subjects

M P Manns

Publications and source records attributed to M P Manns.

At least 19 recordsLinked to original sources
PubMed1997

Long-term outcome of hepatitis C virus infection after liver transplantation.

We analyzed the long-term clinical course of 71 patients with RNA-positive hepatitis C virus (HCV) infection after liver transplantation. Patients with reinfection after transplantation for HCV-related liver disease, or de novo infection at transplantation were followed for up to 12 years. Cumulative survival for patients with HCV infection at 2, 5, and 10 years after transplantation was 67%, 62%, and 62%, respectively. It was not significantly different from that in patients transplanted for other nonmalignant diseases without HCV infection. The main factor determining long-term survival was the presence or absence of hepatocellular carcinoma (HCC) at transplantation. The 5-year survival rate for HCV patients with or without HCC was 35% versus 73%, respectively (P < .05). No deaths because of viral hepatitis of the graft were observed. Deaths in the first year after transplantation were caused by infectious complications, cardiovascular problems, or rejection; deaths after more than 12 months were exclusively because of recurrence of HCC. Biochemical and histological evidence of hepatitis was found in the majority of the patients, only 16% had normal alanine aminotransferase (ALT) values throughout. Twenty-two percent of patients complained of symptoms, with hepatitis C being the cause in 82% of these. Two patients lost their HCV-RNA for prolonged, ongoing periods of time. The severity of the posttransplantation hepatitis was unrelated to age, sex, severity of liver disease before transplantation, cold ischemic time of the graft, duration of the operation, transfusions, the number of rejection episodes, or the long-term immunosuppressive regime. Only initial short-term therapy with interleukin 2 (IL2) receptor antibodies adversely influenced inflammatory activity. Viral genotype did not influence the course of the graft hepatitis in our series. Histology showed inflammation in 88% of the biopsies and signs of fibrosis in 24%. Mean ALT values correlated with inflammation but not with fibrosis in the biopsies. Porto-portal bridging was observed in six patients, one patient developed cirrhosis within 2 years after orthotopic liver transplantation (OLT). We conclude that chronic hepatitis develops in the majority of patients with HCV infection after liver transplantation. Carrier states without significant laboratory abnormalities are observed in approximately 16%, biochemical abnormalities without symptoms are seen in 60%, and symptomatic disease develops in a quarter of the patients. The disease course closely resembles that seen in nontransplanted hepatitis C patients. It is generally mild but little over 10% of patients develop signs of fibrosis of the graft during the first decade.

Adolescent↗
PubMed1997

Differences in the regulation of cytochrome P450 family members during liver regeneration.

BACKGROUND/AIMS: Cytochrome P450 enzymes (P450s) metabolise endogenous substances and a vast variety of drugs. Little is known about the regulation of P450s during pathophysiological conditions in the liver. Therefore we studied the regulation of P450 1A1, 1A2, 2E1 and 3A during liver regeneration after two-thirds hepatectomy. METHODS: Partial hepatectomy or sham surgery was performed in Sprague-Dawley rats. At different time points after surgery, microsomal proteins were isolated and the RNA was prepared. Northern blot analysis, Western blot analysis and enzyme assays for the different P450s were performed. RESULTS: Northern blot analysis showed a transient downregulation of cytochromes P450 1A2 and 2E1 after hepatectomy, while the expression of cytochrome P450 3A remained unaffected. Western blot analysis of microsomal proteins showed that changes of the mRNA levels are not reflected in the protein level, most likely because the half-life of the P450 proteins in hepatocytes is long, and thus a transient mRNA downregulation has little impact on the total amount of protein detected. Differences in the regulation of the enzymatic activities were found for P450 1A2 and 2E1. Interestingly, the metabolic activity of cytochrome P450 2E1 decreased dramatically post-hepatectomy, while the P450 2A1 activity remained unchanged. CONCLUSIONS: Regulatory mechanisms were found on the RNA level and by post-translational mechanisms which downregulate P450 expression and activity during liver regeneration. These results indicate prolonged half-life of drugs during hepatocyte proliferation, and thus also have important implications for therapy in humans.

Animals↗
PubMed1997

Frequency and significance of antibodies to P450IID6 protein in Japanese patients with chronic hepatitis C.

BACKGROUND/AIMS: The aims of the current study were to assess the frequency and the significance of antibodies to cytochrome P450IID6 protein (anti-P450IID6) in various diseases among Japanese patients. METHODS: Sera from 541 patients were tested by indirect immunofluorescence, and the specificity of anti-P450IID6 was ascertained by either enzyme immunoassay (ELISA) or Western blot using recombinant antigen or rat liver microsomes. RESULTS: Anti-P450IID6 was found in only 6 of 235 patients (2.6%) with chronic active hepatitis (CAH) positive for hepatitis C virus (HCV) antibody and quantitative HCV-RNA with genotypes II and IV. The predominant epitopes on immunoblots were 66 and 50KD, a 10KD band being the newly underfined microsomal antigen. Even in the patients negative for autoantibodies to nuclear antigens (ANA) by routine indirect immunofluorescence test, various ANA were detected by the newly developed recombinant ELISA. These patients were younger, with lower gamma-globulin and IgG levels than patients with autoimmune hepatitis. Three of five patients with anti-P450IID6 responded well to interferon therapy and one received prednisone when interferon was ineffective. Interestingly, only this patient was diagnosed as definite autoimmune hepatitis according to the criteria proposed by the International Autoimmune Hepatitis Group (IAHG). The other five patients who did not satisfy the IAHG criteria might be considered as CAH-C with autoimmune features. No autoimmune hepatitis patients positive for anti-P450IID6 were identified in the current study, indicating that the variant is very rare in Japan. CONCLUSIONS: Anti-P450IID6 in CAH-C patients in Japan is not as rare as expected. Anti-P450IID6 among Japanese patients has uncertain significance and precludes further characterization of CAH-C with autoimmune features, which might require interferon therapy.

Adult↗
PubMed1997

Treatment of hepatitis B-related polyarteritis nodosa with famciclovir and interferon alfa-2b.

BACKGROUND: The association between polyarteritis nodosa and viral hepatitis B infection is well established and still remains a therapeutic challenge. Famciclovir--a new nucleoside analog--has a broad spectrum of antiviral activity against herpes viruses and the human hepatitis B virus. CASE REPORT: A 56-year-old man with hepatitis B-related polyarteritis nodosa presented with symptoms correlating to high levels of HBV DNA. The patient did not respond to treatment with steroids (prednisolone started with 100 mg daily) and two courses of interferon alfa-2b (5 x 10(6) units 3 times per week for 6 months). Therefore, a combination therapy of interferon alfa-2b (5 x 10(6) units 3 times per week) and famciclovir (500 mg tid, orally) was started; 5 mg daily prednisolone was given at this time. Under this regimen HBV DNA rapidly declined, with a reduction of 79% after the first week (HBV DNA 53 pg/ml), and 88% after the second week (29 pg/ml), accompanied by a significant improvement in clinical symptoms. After 1 year of famciclovir treatment, HBeAg-anti-HBe seroconversion was noted; HBsAg still remained positive. Long-term famciclovir therapy has been continued at a reduced dose of 125 mg tid for 3 years now. HBV DNA values have been stable below 100 pg/ml, transaminases have normalized and clinical symptoms of polyarteritis nodosa have disappeared. CONCLUSIONS: Famciclovir has been successfully administered to a patient with hepatitis B-related polyarteritis nodosa. A reduction in viral replication and an improvement of symptoms were noted within 4 weeks of starting famciclovir. The oral nucleoside analog famciclovir is effective and well tolerated, even in long-term therapy, and might offer new treatment options in immunosuppressed patients for whom hepatitis B replication is critical for the disease process.

2-Aminopurine↗
PubMed1997

Quantification of inflammatory mediators in stool samples of patients with inflammatory bowel disorders and controls.

Previous studies indicated that eosinophils and mast cells accumulate and become activated in inflammatory bowel disorders. The aim of the study was to examine the presence of eosinophil and mast cell mediators in human stool samples of patients with inflammatory bowel disorders. We measured eosinophil cationic protein (ECP), eosinophil protein X (EPX), methylhistamine, and alpha 1-antitrypsin in fecal samples of 136 patients (62 Crohn's disease, 24 ulcerative colitis, 15 intestinal food allergy, 35 other gastrointestinal diseases) and 8 healthy controls. We found strongly elevated levels of ECP (median: 29, range: 0.4-1783 ng/g feces) and EPX (803, 10-33,225 ng/g) in all patients groups compared to controls (ECP: 1.5, 0.5-55 ng/g; EPX: 235, 12-746 ng/g). Similar results, albeit less pronounced, were obtained for methylhistamine and alpha 1-antitrypsin. Particularly high concentrations of ECP and EPX were found in patients with active mucosal inflammation. In conclusion, the study presents an easy and reliable method for the detection of fecal ECP, EPX, and methylhistamine and may provide a tool to gain insight into the pathogenesis of inflammatory bowel diseases and have potential as diagnostic test.

Adolescent↗
PubMed1997

Hepatotropic viruses and autoimmunity 1997.

Autoimmune hepatitis is a disease of unknown cause. Apart from genetic markers such as HLA DR3 and HLA DR4, female predominance, hypergammaglobulinaemia and characteristic autoantibodies are diagnostic hallmarks. Several viruses have been discussed to induce autoimmune hepatitis, among them all major hepatotropic viruses, Epstein-Barr virus and herpes simplex virus. It seems that herpes viruses may be responsible in at least some cases of patients with autoimmune hepatitis type 2. Furthermore, hepatotropic viruses like hepatitis C and hepatitis D virus may cause autoimmune phenomena which are similar to those in idiopathic autoimmune hepatitis. LKM-1 antibodies in hepatitis C and LKM-3 antibodies in hepatitis D may cause diagnostic problems. LKM-1 antibodies in hepatitis C are directed either against cytochrome P450 2D6 or other yet unidentified microsomal antigens. As in hepatitis C the antimicrosomal autoantibody response in hepatitis D is more heterogeneous. These LKM-3 antibodies react with several epitopes on proteins of family 1 and 2 UDP-glucuronosyltransferases (UGT). Additional autoantibodies are seen in hepatitis D virus infection. Liver diseases are models to study autoimmune disease, drug-induced and virus-induced autoimmunity in humans.

Autoantigens↗
PubMed1997

CREB controls LAP/C/EBP beta transcription.

LAP/C/EBP beta is a member of the C/EBP family of transcription factors and is involved in hepatocyte-specific gene expression. Recently we showed that, besides its posttranscriptional regulation, LAP/C/EBP beta mRNA is modulated during liver regeneration. Therefore, in this study we investigated mechanisms which control LAP/C/EBP beta gene transcription. Deletion analysis of the 5'-flanking region, located upstream of the start site of transcription in the LAP/C/EBP beta gene, demonstrated that a small region in close proximity to the TATA box is important in maintaining a high level of transcription of the luciferase reporter gene constructs. In gel shift experiments two sites were identified which are important for specific complex formation within this region. Further analysis by cross-linking, super shift, and competition experiments was performed with liver cell nuclear extracts, hepatoma cell nuclear extracts, or recombinant CREB protein. These experiments conclusively demonstrated that CREB binds to both sites in the LAP/C/EBP beta promoter with an affinity similar to that with the CREB consensus sequence. Transfection experiments with promoter constructs where the CREB sites were mutated showed that these sites are important to maintain both basal promoter activity and LAP/C/EBP beta inducibility through CREB. Northern blot analysis and runoff transcription assays demonstrated that the protein kinase A pathway not only stimulated the activity of the luciferase reporter construct but also the transcription of the endogenous LAP/C/EBP beta gene in different cell types. Western blot analysis of rat liver cell nuclear extracts and runoff transcription assays of rat liver cell nuclei after two-thirds hepatectomy showed a functional link between the induction of CREB phosphorylation and LAP/C/EBP beta mRNA transcription during liver regeneration. These results demonstrate that the two CREB sites are important to control LAP/C/EBP beta transcription in vivo. As several pathways control CREB phosphorylation, our results provide evidence for the transcriptional regulation of LAP/C/EBP beta via CREB under different physiological conditions.

Animals↗
PubMed1997

Cytochrome P450 1A2 is a hepatic autoantigen in autoimmune polyglandular syndrome type 1.

Autoantibodies directed against proteins of the adrenal cortex and the liver were studied in 88 subjects of Sardinian descent, namely six patients with autoimmune polyendocrine syndrome type 1 (APS1), 22 relatives of APS1 patients, 40 controls with other autoimmune diseases, and 20 healthy controls. Indirect immunofluorescence, using tissue sections of the adrenal cortex, revealed a cytoplasmatic staining pattern in 4 of 6 patients with APS1. Western blotting with adrenal mitochondria identified autoantigens of 54 kDa and 57 kDa, Western blotting with placental mitochondria revealed a 54-kDa autoantigen. The 54-kDa protein was recognized by 4 of 6 patients with APS1 both in placental and adrenal tissue, whereas the 57-kDa protein was detected only by one serum. Using recombinant preparations of cytochrome P450 proteins, the autoantigens were identified as P450 scc and P450 c17. One of six APS1 patients suffered from chronic hepatitis. In this patient, immunofluorescence revealed a centrolobular liver and a proximal renal tubule staining pattern. Western blots using microsomal preparations of human liver revealed a protein band of 52 kDa. The autoantigen was identified as cytochrome P450 1A2 by use of recombinant protein preparations. P450 1A2 represents the first hepatic autoantigen reported in APS1. P450 1A2 usually is not detected by sera of patients with isolated autoimmune liver disease and might be a hepatic marker autoantigen for patients with APS1.

Adolescent↗
PubMed1997

Accidental intoxication with methylene dianiline p,p'-diaminodiphenylmethane: acute liver damage after presumed ecstasy consumption.

BACKGROUND: MDA is the abbreviation for methylene dianiline (p,p' diaminodiphenylmethane; 4,4'-methylenedianiline; CAS 101-77-9); and for methylendioxyamphetamine (MDMA, N, alpha-dimethyl-1,3-benzodioxole-5-ethanamine; CAS 42542-10-9). While the former is used for the production of polyurethane foams, the latter is a psychometric drug, which is becoming increasingly popular in the techno scene. METHODS: We report six participants of a technoparty (1 female, 5 males, ages 17-25) who were admitted to the hospital with severe colicky abdominal pain and subsequently developed symptoms of hepatotoxicity. They had ingested an alcoholic beverage that had been spiked with a powdery substance they dubbed MDA. RESULTS: All patients showed similar clinical symptoms, with an identical time course. Acute jaundice developed within 2 days after ingestion. Enzymes indicating cholestasis increased steadily over 7 days and reached peak values of 800 U/L (AP) and 380 U/L (GGT), whereas transaminases remained moderately elevated. Between days 5 and 7, all patients became febrile for one day, their body temperatures rising up to 40 degrees C. There was no evidence for hemolysis or an infectious hepatitis. Toxicological analysis revealed the presence of p,p'-diaminodiphenylmethane (4,4'-methylenedianiline) at a concentration of 130 mg/L in one of two urine extracts examined. CONCLUSIONS: The analytical data indicate that the participants of the technoparty assumed the aniline-derivative, the cause of Epping Jaundice, was methylendioxyamphetamine because the same abbreviation, MDA, is used for both compounds. An overview of the acute liver toxicity of aniline derivatives is given and the possibility of amphetamine-induced liver damage is discussed.

3,4-Methylenedioxyamphetamine↗
PubMed1997

[Chronic hepatitis].

Explore the source record for details and available documents.

Diagnosis, Differential↗
PubMed1996

Association between fulminant hepatic failure and a strain of GBV virus C.

BACKGROUND: The GB virus C (GBV-C) and the hepatitis G virus (HGV) have been detected in patients with acute indeterminant hepatitis and post-transfusion hepatitis. However, the role of the new hepatitis viruses in the aetiology of fulminant hepatitis is little understood. We investigated the presence of GBV-C/HGV in patients with fulminant hepatic failure. METHODS: Serum samples from 22 German patients with fulminant hepatic failure and 106 symptom-free blood donors (controls) were studied for presence of GBV-C RNA by seminested reverse transcriptase PCR. Primer sequences were derived from the published gene sequences of the conserved NS3 region of the GBV-C prototype and the published isolates. Nucleotide and amino acid sequences of GBV-C-positive isolates, the control RNA, and the published HGV and GBV-C prototype sequences were compared by multiple sequence alignment. We also compared the GBV-C sequences of virus-positive patients who had fulminant hepatic failure with those of 19 patients with chronic hepatitis from our centre. In addition, we searched databases and published papers for further GBV-C helicase sequences in patients with non-fulminant hepatitis. FINDINGS: GBV-C RNA was detected in 11 (50%) of the 22 patients with fulminant hepatic failure and in five (4.7%) of 106 control-group blood donors. Among the patients with fulminant hepatic failure, six of seven with fulminant hepatitis B and five of ten with fulminant non-A-E hepatitis were positive for GBV-C RNA. Analysis of nucleic acid sequences showed six mutations at defined positions in all 11 patients with fulminant hepatic failure who were positive for GBV-C. None of these mutations were found in the five GBV-C-positive control-group blood donors. Of the six nucleotide changes, four caused no amino acid changes, whereas two mutations at position 100 (G to T) and 102 (T to C) led to an alanine to serine change in the predicted translation product. However, comparison with GBV-C sequences of patients with non-fulminant hepatitis showed that this amino acid mutation was not specific for fulminant hepatic failure. The sequence-motif containing the six nucleotide mutations detected in all patients with fulminant hepatic failure was found in only two of 19 German patients with chronic hepatitis from our centre, and in only one of 88 GBV-C sequences from non-fulminant patients reported by others. INTERPRETATION: The frequency of GBV-C RNA is higher in fulminant hepatic failure than in any other group of patients with hepatitis, particularly in patients with fulminant hepatitis B or fulminant non-A-E hepatitis. A specific strain of GBV-C may occur in serum of German patients with fulminant hepatic failure.

Adult↗
PubMed1996

The long-term course of hepatitis C after kidney transplantation.

Patients with chronic hepatitis run the risk of developing progressive liver disease during immunosuppressive therapy after kidney transplantation. To determine the impact of chronic hepatitis C on morbidity and mortality we analyzed 162 anti-HCV positive of 1241 renal-grafted patients (prevalence 13.1%; 84.9% HCV RNA positive) regularly surveyed in our outpatient clinic between 1992 and 1994. The mean age at transplantation was 44.5 (6-69) years, and follow-up after grafting was 7.4 (0.1-23.9) years. The immunosuppressive regimen and frequency of rejection episodes in HCV-infected patients were comparable to the total population. Only 4.3% (5/117) of the anti-HCV positive, HBV negative patients living with functioning grafts developed a markedly compromised liver function. Fifteen (9.3%) of the HCV-infected patients died, but none suffered from posthepatitic cirrhosis. An additional retrospective analysis of causes of death after transplantation prior to 1992 revealed that liver disease had only been responsible for 2% of the deaths (7 of 324) in the HBsAg negative population (n= 1901). In contrast, the predominant cause of death in the HBsAg positive population (n=76) was posthepatitic cirrhosis in 58% (15 of 26). Thus, kidney transplantation in patients with replicative hepatitis C and normal liver function appears to be justified because of low early and late morbidity and mortality due to chronic liver disease. HBV infection and hemosiderosis substantially increase the risk of chronic liver disease in renal transplant recipients with hepatitis C.

Adolescent↗
PubMed1996

C/EBP-beta/LAP controls down-regulation of albumin gene transcription during liver regeneration.

Expression of the albumin gene in the liver is controlled by several liver-enriched transcription factors. However, the mechanisms which contribute to its regulation during pathophysiological states, such as liver regeneration, are still little understood. In the present study we found that during liver regeneration down-regulation of albumin mRNA expression is transcriptionally controlled through a minimal element (nucleotide -170 to +22) of the albumin promoter and is observed mainly during the G1 phase of the cell cycle, while high levels of albumin expression are preserved at later time points. Decreased albumin mRNA levels correlate with a dramatic increase in nuclear expression of C/EBP-beta/LAP, a protein known to bind to the D site of the albumin promoter and also to be involved in cell cycle control. In contrast, nuclear expression of other factors such as HNF-1 or C/EBP-alpha, which also have been shown to transcriptionally control albumin expression, is either unchanged or slightly decreased. We show that pre- and post-translational mechanisms are involved in the higher nuclear expression of C/EBP-beta/LAP as early as 1 h after hepatectomy, which also leads to its increased binding toward the D site of the albumin promoter. Finally, in vitro transcription assays with liver nuclear extracts and recombinant C/EBP-beta/LAP demonstrate that C/EBP-beta/LAP can directly down-regulate transcription mediated by the minimal element of the albumin promoter. Additionally the inhibitory role of C/EBP-beta/LAP on the albumin minimal promoter could be confirmed by transfection experiments in hepatoma cells. These results indicate that C/EBP-beta/LAP, while enhancing transcription of cell cycle-related genes and controlling G1/S phase checkpoint, down-regulates a major liver function, i.e. albumin synthesis, to prepare the hepatocyte for entry into the cell cycle.

Albumins↗