W Stremmel

Universität Heidelberg, Heidelburg, Baden-Württemberg, Germany

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Publications (417)1410.57 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Pharmacokinetic monitoring of calcineurin inhibitors (CNIs) is unsatisfactory because, at comparable blood concentrations, side effects vary considerably. We recently confirmed the applicability of a pharmacodynamic (PD) assay that measures the suppression of CNI target genes, specifically the suppression of nuclear factor of activated T cells (NFAT)-regulated genes in liver transplant (LT) recipients. The aim of this prospective study was to prove the clinical reliability of this assay. Therefore, we quantified the residual gene expression (RGE) of NFAT-regulated genes and evaluated the association between the RGE of NFAT-regulated genes and the incidence of cytomegalovirus (CMV) infection. In 20 LT recipients, 10 patients on cyclosporine (CsA) and 10 patients on tacrolimus (Tac) therapy, who presented with CMV infection, the RGEs of interleukin-2, interferon-γ (IFNγ), and granulocyte-monocyte colony-stimulating factor were measured and compared with the RGEs of these cytokines in 40 healthy dose-matched LT controls. CsA-treated CMV patients demonstrated a lower RGE of all NFAT-regulated genes compared with controls (30 ± 17 vs. 44 ± 20, P = 0.067). For IFNγ, the level of significance was reached (26 ± 17 vs. 43 ± 17, P = 0.0125). Daily CsA dosage, CsA baseline (C0 ) and 2 h (C2 ) concentrations were comparable (CsA dosage 169 mg/day vs. 165 mg/day; CsA C0 94 μg/L vs. 85 μg/L; CsA C2 389 μg/L vs. 381 μg/L). In addition, Tac-treated CMV patients demonstrated a lower RGE of all NFAT-regulated genes compared with controls (68 ± 25 vs. 84 ± 22, P = 0.0769). Analogous to CsA-treated CMV patients, the level of significance was reached for IFNγ (61 ± 24 vs. 88 ± 29, P = 0.0154). Daily Tac dosage and Tac 1.5 h concentrations (C1.5 ) were comparable in both groups (Tac dosage 4 mg/day vs. 4 mg/day; Tac C1.5 8 μg/L vs. 10 μg/L), whereas Tac C0 concentrations were significantly higher in controls (Tac C0 4 μg/L vs. 6 μg/L, P = 0.0276). Measuring the RGE of NFAT-regulated genes is appropriate to assess the risk of infections in LT recipients. Measuring the RGE of IFNγ is particularly suitable to assess the risk of CMV infection. PD monitoring of CNIs in LT recipients is an approach to individualize immunosuppression, which may help to reduce infectious complications.
    Transplant Infectious Disease 03/2014; · 1.98 Impact Factor
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    ABSTRACT: A recent genome-wide association study identified the FUT2 secretor status and genotype defined by the single-nucleotide polymorphism rs601338 as potential genetic risk factor in primary sclerosing cholangitis (PSC), which significantly influences biliary bacterial composition. To determine the impact of the rs601338-FUT2 genotype on frequency of biliary infections, development of dominant stenosis and liver-transplantation-free survival in patients with PSC. Cohort study of 215 patients with PSC treated at our tertiary care centre with respect to their rs601338-FUT2 genotype. Results of endoscopic retrograde cholangiography and bile culture were analysed; 639 biliary samples were obtained, cultured and subjected to microbial analysis. Clinical and laboratory data were analysed using chart reviews. For the rs601338-FUT2 genotype, 69 patients (32.1%) were found to be wildtype (GG), 97 (45.1%) patients were heterozygous (AG) and 49 patients (22.8%) were homozygous-mutated (AA). In addition to alterations in the bacterial pattern, especially in heterozygous carriers, patients with mutated alleles had a marked increase in the frequency of biliary Candida infections (P = 0.025). Further, patients with mutated alleles showed an increased frequency of episodes of cholangitis (P = 0.0025), development of dominant stenosis (P < 0.002) and a reduced actuarial transplantation-free survival (P = 0.044). Levels of biliary Ca19-9 were significantly elevated in the homozygous-mutated patients. The rs601338-FUT2 genotype is strongly associated with episodes of cholangitis, fungobilia and the incidence of dominant stenosis, which are three clinical hallmarks of PSC; FUT2 is thus an important genetic risk factor for host-microbial diversity and disease progression in PSC.
    Alimentary Pharmacology & Therapeutics 02/2014; · 4.55 Impact Factor
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    ABSTRACT: Tuberculosis (TB) infection is a major concern in patients with chronic autoimmune conditions under immunosuppressive therapy. Gastrointestinal tuberculosis can be misdiagnosed as Crohn's disease with detrimental consequences for the patient. We report on a 40-year old ethnic Turkish patient with HLA-B27 positive spondyloarthritis who developed gastrointestinal symptoms under immunosuppressive treatment with infliximab. Crohn's disease was diagnosed at a primary care hospital and immunosuppressive treatment was escalated. Initial diagnostic tests for tuberculosis were negative. When the clinical condition deteriorated, the patient was transferred to our intensive care unit for further diagnosis and treatment. Tuberculosis was suspected due to clinical presentation and radiological signs and anti-tuberculous treatment was initiated. After the onset of treatment, first microbiological results confirmed the diagnosis of miliary TB with Mycobacterium bovis. As an infection route we assume primary gastrointestinal infection with M. bovis during the patient's annual holidays in Turkey with a rapid development of miliary TB under infliximab and escalated immunosuppressive therapy. This case report demonstrates the difficulties in differentiating intestinal TB from other granulomatous conditions such as Crohn's disease. The diagnostic tools for gastrointestinal tuberculosis are discussed in detail regarding their sensitivity, specificity as well as positive and negative predictive values.
    Zeitschrift für Gastroenterologie 10/2013; 51(10):1177-1183. · 1.41 Impact Factor
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    ABSTRACT: Background and Aim: The clinical presentation of Wilson disease (WD) is highly variable. The aim of this study was to evaluate the disease presentation in siblings of index patients in order to reveal possible genotype-phenotype correlations. Patients and Methods: 165 affected siblings of 1077 index patients (mostly from Central and Eastern Europe) identified by genetic testing were studied with complete data available in 137. Age and symptoms at onset, serum ceruloplasmin, presence of Kayser- Fleischer rings and if available, results of liver biopsy were analyzed. H1069Q was assayed by PCR. H1069Q compound heterozygotes and H1069Q negative patients were further examined by denaturating gel HPLC using exon specific primers. Mutations were identified by direct sequencing on an ABI Prism 310 Genetic Analyzer (Perkin Elmer, Norwalk, USA). Results: 131 of the 137 siblings were brothers or sisters, 5 were children and 1 a second degree relative of an index case. 73 index patients had liver disease (age: 17.2±8.9; 41 female, including 6 cases of fulminant WD and 2 with hemolytic anemia) and 54 neurologic disease (age: 21.0+7.5 years, 28 female). 92 siblings (67%, 47 female) were asymptomatic, 44 had symptoms which were discordant in seven. Ceruloplasmin was normal in 9. 81 had no KF-rings. In 93 and 33 siblings, mutations on both (including 46 H1069Q homozygotes) or one chromosome/s were identified, respectively. At diagnosis, 37 siblings were older and 99 younger than the index patients, one pair were monozygous twins. 52 siblings of patients with hepatic WD were asymptomatic, 24 had liver disease. During follow up, 2 siblings not taking the prescribed medication developed neurologic symptoms. 40 siblings of patients with neurologic WD were asymptomatic (17 of them had no KF-rings, 4 normal CPL), 13 had neurologic symptoms, 5 had liver disease (including the homozygous twin) and one hemolytic anemia. Conclusion: Of the symptomatic siblings of patients with WD, only a minority (15%) had discordant symptoms, including the monozygous twin sister of a patient with severe neurologic disease. Nevertheless the discordant cases indicate that genetic factors other than ATP7B mutations apparently modify the phenotypic presentation of WD.
    Journal of Hepatology 01/2013; 58(Suppl 1):s559. · 9.86 Impact Factor
  • J Seessle, W Stremmel, F Ebinger, U Merle
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    ABSTRACT: A 26-year-old female patient presented with the clinical picture of an acute ileus. Since childhood the patient has been diagnosed as having a MELAS syndrome, a mitochondriopathy. A subtotal colectomy was performed some years ago because of a similar ileus episode. The further diagnostic work-up revealed an expanded small intestine in abdominal radiography. Laboratory analysis showed increased levels of serum lactate with a consecutive respiratory compensated metabolic acidosis. A conservative treatment regime with nasogastric tube, fluid therapy, parental nutrition via peripheral veins and peristalsis inducing drugs was initiated, but did not resolve ileus symptoms. Under the hypothesis that in MELAS syndrome the ileus-related catabolic state aggravates the ileus symptoms in terms of a circulus vitiosus, we started high-caloric parenteral nutrition by using a central venous catheter. A few hours after this intervention, a clear clinical improvement could be observed. Since this initial presentation, the patient was admitted to our hospital several times with the same ileus symptoms. Each of the episodes was successfully and rapidly treated by this high-caloric parenteral nutrition therapy. The reproducible rapid clinical improvement after starting parenteral nutrition supports the hypothesis that an optimal energy supply is the key therapy not only for cerebral but also for gastrointestinal symptoms in patients with MELAS syndrome.
    Zeitschrift für Gastroenterologie 11/2012; 50(11):1161-1165. · 1.41 Impact Factor
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    ABSTRACT: In the present study we prospectively evaluated the safety and efficacy of temporary fully covered, self-expandable metal stents (fcSEMS) to treat biliary strictures (n = 9), leaks (n = 9), and combined lesions (n = 1) occurring after liver transplantation, when standard endoscopic attempts had failed. Placement of fcSEMS and their removal in scheduled patients were successful and without complications. Resolution of the biliary lesion was confirmed in 15 of 19 patients (79 %). Treatment was not successful in two patients and not evaluable in 2 other patients. Complications occurred in 9 /19 patients (47 %): stent migration in 6, stent occlusion in 1, and de novo stricture after successful treatment of a biliary leak in 2. After a median follow-up of 12 months, one recurrent anastomotic stricture was noted. Temporary placement of fcSEMS in biliary strictures and leaks after liver transplantation provides satisfactory results even in patients who have undergone multiple previous conventional endoscopic attempts, and offers an alternative approach to surgical intervention.
    Endoscopy 02/2012; 44(5):536-8. · 5.74 Impact Factor
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    ABSTRACT: Lentiviral vectors are vectors of choice for many gene therapy applications. Recently, efficient targeting of lentiviral vectors pseudotyped with the Measles virus (MV) glycoproteins has been reported. However, MV antibodies in patients might limit the clinical use of these vectors. We demonstrate here that lentiviral vectors can also be pseudotyped with the glycoproteins of Tupaia paramyxovirus (TPMV), the hemagglutinin (H) and fusion (F) protein. As this animal paramyxovirus has no known close relatives in humans, we do not expect TPMV antibodies in patients. Because TPMV normally does not infect human cells, 'detargeting' from natural receptors is unnecessary. Similar to the MV system, TPMV glycoproteins can mediate targeted cell entry by displaying different single-chain antibodies (scAb) directed against surface molecules on target cells on the viral hemagglutinin. We generated a panel of H and F proteins with truncated cytoplasmic tails and determined the variants that efficiently pseudotyped lentiviral vectors. The B-cell marker CD20 was used as a model antigen, and CD20-targeted TPMV vectors selectively transduced CD20-positive cells, including quiescent primary human B-cells. Lentiviral vectors pseudotyped with targeted TPMV envelope proteins might be a valuable vector choice when systemic application of targeted lentiviral vectors in humans is required.Gene Therapy advance online publication, 5 January 2012; doi:10.1038/gt.2011.209.
    Gene therapy 01/2012; · 4.75 Impact Factor
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    ABSTRACT: To establish a score to predict 30-day mortality and graft loss retrospectively and to validate the score prospectively. Retrospectively in 296 liver transplant recipients, a score was developed that included the peak aspartate aminotransferase concentration within the first week and γ-glutamyltransferase and bilirubin concentrations at day 7 to predict graft loss or patient death within 30 days. The score was then prospectively validated in 86 patients undergoing liver transplantation. From the retrospective training cohort, cut-off values for prediction of adverse outcomes were determined using receiver operating characteristic curve analysis for peak aspartate aminotransferase (>1870 IU/mL), γ-glutamyltransferase (<214 IU/mL), and bilirubin (>5.75 mg/dL). Sensitivity and specificity of the score to predict an end point from the retrospective cohort were excellently reproduced in the prospective cohort. Overall, fulfillment of at least 2 criteria predicted graft loss or death within 30 days with sensitivity of 0.70 and specificity of 0.78. No patients with values that remained below all 3 thresholds experienced graft loss or death within 30 days. This simple score calculated from standard laboratory values within the first week after liver transplantation enables prediction of graft loss and patient death within 30 days after transplantation. Early identification of patients at risk may help to improve outcomes by observing these patients more closely and allocating resources for them.
    Transplantation Proceedings 06/2011; 43(5):1747-50. · 0.95 Impact Factor
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    ABSTRACT: A female patient receiving pantoprazole during a corticosteroid therapy for encephalomyelitis disseminata developed severe acute hepatitis one month after initiation of pantoprazole treatment. Other causes of hepatic dysfunction including viral hepatitis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, haemochromatosis or Wilson's disease were excluded. Liver biopsy showed severe hepatic lesions with extensive necroses of the parenchyma. One week after discontinuation of pantoprazole the liver function began to improve and gradually the patient fully recovered. One year earlier the patient had been treated with pantoprazole before and had developed a milder form of hepatitis then. This case argues for an idiosyncratic hepatocellular damage caused by pantoprazole.
    Zeitschrift für Gastroenterologie 02/2011; 49(2):207-10. · 1.41 Impact Factor
  • Journal of Hepatology - J HEPATOL. 01/2011; 54.
  • Journal of Hepatology - J HEPATOL. 01/2011; 54.
  • Journal of Hepatology - J HEPATOL. 01/2011; 54.
  • Journal of Hepatology - J HEPATOL. 01/2011; 54.
  • Journal of Hepatology - J HEPATOL. 01/2011; 54.
  • Journal of Hepatology - J HEPATOL. 01/2011; 54.
  • Journal of Hepatology - J HEPATOL. 01/2011; 54.
  • Journal of Hepatology - J HEPATOL. 01/2011; 54.
  • DMW - Deutsche Medizinische Wochenschrift 11/2010; 135(47):2333. · 0.65 Impact Factor
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    ABSTRACT: The importance of disease-related topics can vary widely between patients and doctors. Patient organisations such as the German Verein Morbus Wilson e. V. can overcome this discrepancy. The goal of the present cooperative study was the collection of topics important to Wilson patients by asking patients to generate paintings about their disease. Patients with Wilson disease were asked by mail to draw paintings about their disease and to donate them to the Verein Morbus Wilson e. V. 32 paintings from 27 patients were donated. The majority of the patients added written comments to their art work. Disease-related topics included in the paintings were as follows: psychological work-up of the disease 33 % (n = 11), presentation of affected organs (liver/brain) 22 % (n = 6), therapy 19 % (n = 5), diagnostic path 15 % (n = 4), inheritance 15 % (n = 4), copper-related diet 11 % (n = 3). 33 % (n = 11) of the paintings were composed of two parts reflecting before and after the disease or presenting the individual time course of the disease. Psychological aspects of disease acceptance are the prominent topic in the paintings. The timepoint of diagnosis is experienced as major change in life. The paintings enable both the patient organisation and the caretakers to put more focus on the psychological aspects of the disease. Asking for paintings opens a new channel for patient-physician contacts and produces a feeling of interest and competence in patients.
    Zeitschrift für Gastroenterologie 10/2010; 48(10):1189-99. · 1.41 Impact Factor
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    ABSTRACT: Combined liver-kidney transplantations (CLKT) and kidney after liver transplantations (KALT) are established treatments for patients with end-stage hepatic and renal disease and the number of transplantations has continuously increased over the past few years. The most frequent indications for CLKT in adults are polycystic kidney disease with severe liver involvement and liver cirrhosis of different origins with concomitant chronic kidney failure due to chronic glomerulonephritis or diabetic nephropathy. In children, CLKT is most frequently required due to primary oxalosis type I. At present the main indication for KALT still is calcineurin inhibitor-induced chronic nephrotoxicity, emphasizing the need for a nephron-sparing long-term immunosuppression in liver transplant recipients. Compared to KALT, the indications for CLKT are not as well defined and the decision must therefore be made on a case-by-case basis by a multidisciplinary team of experienced clinicians to avoid unnecessary transplantations of both organs in patients with reversible kidney failure, given the scarcity of organs for transplantation worldwide. In hepatorenal syndrome CLKT should only be considered if the GFR is lower than 20 ml/min for more than three months or if the patient has been on renal replacement treatment for more than one month. In CLKT, there appears to be a certain immunological protection for the kidney transplant by the liver transplant.
    DMW - Deutsche Medizinische Wochenschrift 10/2010; 135(40):1973-8. · 0.65 Impact Factor

Publication Stats

8k Citations
1,410.57 Total Impact Points

Institutions

  • 1995–2014
    • Universität Heidelberg
      • • General pediatrics, pediatric neurology, metabolism, gastroenterology, nephrology
      • • University Hospital of Internal Medicine
      Heidelburg, Baden-Württemberg, Germany
    • Institute for Pathology, Cologne
      Köln, North Rhine-Westphalia, Germany
  • 2008
    • Universität Ulm
      • Department of Internal Medicine
      Ulm, Baden-Wuerttemberg, Germany
  • 1995–2004
    • German Cancer Research Center
      • Division of Immunogenetics
      Heidelburg, Baden-Württemberg, Germany
  • 2002
    • Bologna Center
      Bolonia, Emilia-Romagna, Italy
  • 2001
    • Washington University in St. Louis
      San Luis, Missouri, United States
  • 1999
    • Stanford University
      Palo Alto, California, United States
  • 1984–1996
    • Heinrich-Heine-Universität Düsseldorf
      • • Medizinische Fakultät
      • • Nuklearmedizinische Klinik
      Düsseldorf, North Rhine-Westphalia, Germany
  • 1988–1995
    • Universitätsklinikum Düsseldorf
      Düsseldorf, North Rhine-Westphalia, Germany
    • Herz- und Diabeteszentrum Nordrhein-Westfalen
      Bad Oeyhausen, North Rhine-Westphalia, Germany
  • 1991–1994
    • Ruhr-Universität Bochum
      Bochum, North Rhine-Westphalia, Germany
  • 1992–1993
    • Medizinische Laboratorien Düsseldorf
      Düsseldorf, North Rhine-Westphalia, Germany
  • 1987
    • CUNY Graduate Center
      New York City, New York, United States
  • 1983
    • Icahn School of Medicine at Mount Sinai
      • Department of Medicine
      Manhattan, New York, United States