[Show abstract][Hide abstract] ABSTRACT: Currently, limited data of the outcome of inflammatory bowel disease (IBD) in patients after solid organ transplantation (SOT) are available. We aimed to analyze effects of SOT on the IBD course in a large IBD patient cohort.
Clinical data from 1537 IBD patients were analyzed for patients who underwent SOT (n = 31) between July 2002 and May 2014. Sub-analyses included SOT outcome parameters, IBD activity before and after SOT, and efficacy of IBD treatment.
4.74% of patients with ulcerative colitis (UC) and 0.84% of patients with Crohn's disease (CD) underwent SOT (p = 2.69 x 10-6, UC vs. CD). 77.4% of patients with SOT underwent liver transplantation (LTx) with tacrolimus-based immunosuppressive therapy after SOT. All LTx were due to primary sclerosing cholangitis (PSC) or PSC overlap syndromes. Six patients (19.4%) required renal transplantation and one patient (3.2%) heart transplantation. A survival rate of 83.9% after a median follow-up period of 103 months was observed. Before SOT, 65.0% of patients were in clinical remission and 5 patients received immunosuppressive therapy (16.1%). After SOT, 61.0% of patients were in remission (p = 1.00 vs. before SOT) and 29.0% required IBD-specific immunosuppressive or anti-TNF therapy (p = 0.54 vs. before SOT). 42.9% of patients with worsening of IBD after SOT were at higher risk of needing steroid therapy for increased IBD activity (p = 0.03; relative risk (RR): 10.29; 95% CI 1.26-84.06). Four patients (13.0%) needed anti-TNF therapy after SOT (response rate 75%).
SOT was more common in UC patients due to the higher prevalence of PSC-related liver cirrhosis in UC. Despite mainly tacrolimus-based immunosuppressive regimens, outcome of SOT and IBD was excellent in this cohort. In this SOT cohort, concomitant immunosuppressive therapy due to IBD was well tolerated.
PLoS ONE 08/2015; 10(8):e0135807. DOI:10.1371/journal.pone.0135807 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Miliary brain metastases are a rare condition but associated with an exceedingly poor prognosis. We present the case of a patient suffering from malignant melanoma with an acute progressively worsening of neurological symptoms up to the loss of consciousness. The magnetic resonance imaging (MRI) demonstrated a new onset of disseminated, miliary spread of central nervous system metastases from a malignant melanoma within 4 days.
We report on a 57-year-old woman suffering from metastatic malignant melanoma positive for BRAF-V600E mutation who developed an acute onset of neurological symptoms. The patient received vemurafenib and dacarbacin as chemotherapeutic regime for treatment of malignant melanoma. After admission to our hospital due to progressive disturbance of memory and speech difficulty a magnetic resonance tomography (MRI) was performed. This showed no evidence of cerebral tumour manifestation. The symptoms progressed until a loss of consciousness occurred on day five after admission and the patient was admitted to our intensive care unit for orotracheal intubation. No evidence for infectious, metabolic or autoimmune cerebral disorders was found. Due to the inexplicable acute worsening of the neurological symptoms a second MRI was performed on day five. This revealed a new onset of innumerable contrast-enhancing miliary lesions, especially in the grey matter which was proven as metastases from malignant melanoma on histopathology.
This case describes an unique hyperacute onset of tumour progression correlating with an acute deterioration of neurological symptoms in a patient suffering from miliary brain metastasis from BRAF positive malignant melanoma.
[Show abstract][Hide abstract] ABSTRACT: The transcription factor T-bet regulates the production of interferon-γ and cytotoxic molecules in effector CD8 T cells, and its expression correlates with improved control of chronic viral infections. However, the role of T-bet in infections with differential outcome remains poorly defined. Here, we report that high expression of T-bet in virus-specific CD8 T cells during acute hepatitis B virus (HBV) and hepatitis C virus (HCV) infection was associated with spontaneous resolution, whereas T-bet deficiency was more characteristic of chronic evolving infection. T-bet strongly correlated with interferon-γ production and proliferation of virus-specific CD8 T cells, and its induction by antigen and IL-2 stimulation partially restored functionality in previously dysfunctional T-bet-deficient CD8 T cells. However, restoration of a strong interferon-γ response required additional stimulation with IL-12, which selectively induced the phosphorylation of STAT4 in T-bet(+) CD8 T cells. The observation that T-bet expression rendered CD8 T cells responsive to IL-12 suggests a stepwise mechanism of T cell activation in which T-bet facilitates the recruitment of additional transcription factors in the presence of key cytokines. These findings support a critical role of T-bet for viral clearance and suggest T-bet deficiency as an important mechanism behind chronic infection.
Journal of Experimental Medicine 09/2014; 211(10). DOI:10.1084/jem.20131333 · 12.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
T-cell exhaustion seems to play a critical role in CD8+ T-cell dysfunction during chronic viral infections. However, up to now little is known about the mechanisms underlying CD4+ T-cell dysfunction during chronic hepatitis B virus (CHB) infection and the role of inhibitory molecules such as programmed death 1 (PD-1) for CD4+ T-cell failure.
The expression of multiple inhibitory molecules such as PD-1, CTLA-4, TIM-3, CD244, KLRG1 and markers defining the grade of T-cell differentiation as CCR7, CD45RA, CD57 and CD127 were analyzed on virus-specific CD4+ T-cells from peripheral blood using a newly established DRB1*01-restricted MHC class II Tetramer. Effects of in vitro PD-L1/2 blockade were defined by investigating changes in CD4+ T-cell proliferation and cytokine production.
CD4+ T-cell responses during chronic HBV infection was characterized by reduced Tetramer+CD4+ T-cell frequencies, effector memory phenotype, sustained PD-1 but low levels of CTLA-4, TIM-3, KLRG1 and CD244 expression. PD-1 blockade revealed individualized patterns of in vitro responsiveness with partly increased IFN-γ, IL-2 and TNF-α secretion as well as enhanced CD4+ T-cell expansion almost in treated patients with viral control.
HBV-specific CD4+ T-cells are reliably detectable during different courses of HBV infection by MHC class II Tetramer technology. CD4+ T-cell dysfunction during chronic HBV is basically linked to strong PD-1 upregulation but absent coregulation of multiple inhibitory receptors. PD-L1/2 neutralization partly leads to enhanced CD4+ T-cell functionality with heterogeneous patterns of CD4+ T-cell rejunivation.
PLoS ONE 08/2014; 9(8):e105703. DOI:10.1371/journal.pone.0105703 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hepatic apoptosis is involved in the pathogenesis of immune-mediated liver diseases such as autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). The aim of our study was to quantify distinct markers of apoptosis in sera of patients with AIH, PBC, and PSC, and to evaluate correlation with markers of disease activity and prognosis.
Sera of patients with AIH, PBC, and PSC, and of healthy controls were collected and distinct cell death markers were quantified using a bead-based multiplex enzyme linked immunosorbent assay (sICAM, MIF, sFas, PAI-1) or single enzyme linked immunosorbent assays (DNAse, M30, M65).
In comparison with healthy controls the apoptotic markers sFas, sICAM (only in PSC patients), M30, and the cell death marker M65 were substantially elevated in sera of patients with immune-mediated liver diseases, whereas DNAse activity was reduced. Interestingly, patients with advanced PSC presented with higher levels of sICAM, M30, and M65 than patients with mild PSC. Regression analysis revealed correlations between serum levels of sICAM, M30, and M65 with the Mayo Risk Score for PSC, and of M65 with the Mayo Risk Score for PBC.
Concentrations of the serum markers of apoptosis sFas and M30 and of the marker of total cell death M65 are elevated in patients with immune-mediated liver diseases, whereas activity of DNAse is reduced. In patients with PSC sICAM, M30, and M65 may serve as indicators for disease activity and prognosis.
Hepatology Research 01/2014; 44(13). DOI:10.1111/hepr.12304 · 2.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hydrophobic bile salts such as glycochenodeoxycholate (GCDC) accumulate in cholestatic liver disease and induce hepatocellular apoptosis, promoting pro-fibrotic signalling. The tissue microenvironment is an integral player in cellular pathophysiology, but it is not routinely incorporated into laboratory studies. Tissue oxygen partial pressure (pO2 ) may be an underestimated component of the microenvironment: in the liver, a pO2 of 30-45mmHg (approximately 6%O2 ) is physiologic, due to predominantly portal blood supply. It was the aim of this project to investigate the impact of physiologic hypoxia (i.e., 6%O2 ) on hepatocellular function, namely, bile salt-induced apoptosis.
Human hepatoma cells (HepG2-Ntcp) and primary rat hepatocytes were cultured at standard laboratory (hyperoxic) conditions (21%O2 ) and at physiologic hypoxia (6%O2 ) in parallel for 1-8 days to study hepatocellular apoptosis and activation of signalling pathways. Standard laboratory analyses were applied for bile salt uptake, caspase-3/-7 activity, western blotting and gene-array analysis.
Culturing at physiologic hypoxia protected both human and rat hepatocytes against GCDC-induced apoptosis: caspase-3/-7 activation was diminished by 3.1±0.5-fold in human HepG2-Ntcp and completely abolished in primary rat hepatocytes. Bile salt uptake was unaffected. Induction of hypoxia-inducible factor-1α indicated adaption to physiologic hypoxia. The MEK/ERK cascade was activated and anti-apoptotic mediators were induced: N-Myc down-regulated gene, gelsolin and carbonic anhydrase IX were upregulated 12.4-, 6.5- and 5.2-fold, respectively. We conclude from these data that (i) physiologic hypoxia protects hepatocytes from bile salt-induced apoptosis, (ii) tissue pO2 is a crucial, underestimated component of the microenvironment and should (iii) be considered when studying hepatocellular physiology in vitro. This article is protected by copyright. All rights reserved.
Liver international: official journal of the International Association for the Study of the Liver 10/2013; 34(8). DOI:10.1111/liv.12368 · 4.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: β-Muricholic acid (βMCA) is a trihydroxylated bile acid that constitutes the major bile acid in rat and mouse. βMCA is more hydrophilic than ursodeoxycholic acid and has been evaluated for dissolution of cholesterol gallstones. Since it is unknown if βMCA has beneficial effects on hepatocyte cell death we determined the effect of tauro-βMCA (TβMCA) on apoptosis in vitro.
Human Ntcp-transfected HepG2 cells and primary hepatocytes from rat and mouse were incubated with the proapoptotic glycochenodeoxycholic acid (GCDCA) as well as the free fatty acid palmitate in the absence and presence of TβMCA. Apoptosis was quantified using caspase 3/7-assays and after Hoechst 33342 staining. The mitochondrial membrane potential (MMP) was measured fluorometrically using JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-benzimidazol-carbocyaniniodide). Immunoblotting was performed against the proapoptotic Bcl-2-protein Bax.
In Ntcp-HepG2 cells, GCDCA markedly increased apoptosis after 4h. Co-incubation with TβMCA reduced apoptosis to 49% (p<0.01 vs. GCDCA, each; n=6). While GCDCA (100μmol/L) reduced the MMP to 34% after 6h, combination treatment with TβMCA restored the MMP to control levels at all time points (n=4). TβMCA also restored breakdown of the MMP induced by palmitate. GCDCA induced a translocation of Bax from the cytosol to mitochondria that was inhibited by simultaneous treatment with TβMCA in eqimolar concentrations.
TβMCA restricts hepatocellular apoptosis induced by low micromolar concentrations of GCDCA or palmitate via inhibition of Bax translocation to mitochondria and preservation of the MMP. Thus, further studies are warranted to evaluate a potential use of TβMCA in ameliorating liver injury in cholestasis.
Biochemical and Biophysical Research Communications 07/2012; 424(4):758-64. DOI:10.1016/j.bbrc.2012.07.029 · 2.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The chromosome 4q27 region harboring IL2 and IL21 is an established risk locus for ulcerative colitis (UC) and various other autoimmune diseases. Considering the strong coincidence of primary sclerosing cholangitis (PSC) with UC and the increased frequency of other autoimmune disorders in patients with primary biliary cirrhosis (PBC), we investigated whether genetic variation in the IL2/IL21 region may also modulate the susceptibility to these two rare cholestatic liver diseases.
Four strongly UC-associated single nucleotide polymorphisms (SNPs) within the KIAA1109/TENR/IL2/IL21 linkage disequilibrium block were genotyped in 124 PBC and 41 PSC patients. Control allele frequencies from 1,487 healthy, unrelated Caucasians were available from a previous UC association study.
The minor alleles of all four markers were associated with a decreased susceptibility to PSC (rs13151961: p = 0.013, odds ratio (OR) 0.34; rs13119723: p = 0.023, OR 0.40; rs6822844: p = 0.031, OR 0.41; rs6840978: p = 0.043, OR 0.46). Moreover, a haplotype consisting of the four minor alleles also had a protective effect on PSC susceptibility (p = 0.0084, OR 0.28). A haplotype of the four major alleles was independently associated with PSC when excluding the patients with concomitant inflammatory bowel disease (p = 0.033, OR 4.18).
The IL2/IL21 region may be one of the highly suggestive but so far rarely identified shared susceptibility loci for PSC and UC.
[Show abstract][Hide abstract] ABSTRACT: The ATP-binding cassette transporter A1 (ABCA1) is a membrane-bound protein that is abundant in macrophages and is essential for the first step of reverse cholesterol transport and maintenance of homeostasis of high-density lipoprotein (HDL)-bound cholesterol. Low serum HDL levels are associated with increased risk for cardiovascular disease. Homozygous and heterozygous mutations in the ABCA1 gene may be associated with increased atherosclerosis. Here we report about two heterozygous mutations c.5398A>C and c.2369G>A in the ABCA1 gene associated with HDL cholesterol deficiency in serum.
[Show abstract][Hide abstract] ABSTRACT: Bei jungen Patienten mit rezidivierenden Gallenkoliken trotz Cholezystektomie und begleitender Leberwerterhöhung stellt das
„low phospholipid associated cholelithiasis“ (LPAC-) Syndrom eine wichtige Differenzialdiagnose dar. Hinweisend für ein LPAC-Syndrom
ist ein Symptomenkomplex aus Beschwerderekurrenz nach Cholezystektomie, echoreichen intrahepatischen Foki in der Abdomensonographie,
Auftreten einer intrahepatischen Schwangerschaftscholestase bzw. das Auftreten einer Cholestase unter hormoneller Antikonzeption
sowie familiär gehäuften Gallensteinen. Bei rechtzeitiger Diagnose ist die Erkrankung mit Ursodeoxycholsäure gut zu therapieren.
“Low phospholipid associated cholelithiasis” (LPAC) syndrome is an important differential diagnosis in younger patients with
biliary symptoms after cholecystectomy and concomitant elevated serum liver tests. Typical symptoms include recurrence of
biliary colics after cholecystectomy, echogenic material in the intrahepatic bile ducts, intrahepatic cholestasis of pregnancy
or cholestasis under hormonal contraception and a family history of gallstone disease. Patients with LPAC syndrome can be
successfully treated with ursodeoxycholic acid.
KeywordsGenetics–Hepatopathy–Intrahepatic cholelithiasis–LPAC syndrome–Ursodeoxycholic acid
Der Internist 01/2011; 52(10):1234-1237. DOI:10.1007/s00108-010-2775-2 · 0.31 Impact Factor