Effect of mycophenolic acid on inosine monophosphate dehydrogenase (IMPDH) activity in liver transplant patients.

BACKGROUND: Due to the development of immunosuppressants, the focus in transplanted patients has shifted from short-term to long-term survival as well as a better adjustment of these drugs in order to prevent over- and under-immunosuppression. Mycophenolic acid (MPA) is a noncompetitive inhibitor of inosine monophosphate dehydrogenase (IMPDH) and approved for prophylaxis of acute rejection after kidney, heart, and liver transplantation, where it has become a part of the standard therapy. Targeting inosine monophosphate IMPDH activity as a surrogate pharmacodynamic marker of MPA-induced immunosuppression may allow a more accurate assessment of efficacy and aid in limiting toxicity in liver transplanted patients. AIM: Assess IMPDH-inhibition in liver transplant recipients and its impact on biliary/infectious complications, acute cellular rejection (ACR) and liver dependent survival. METHODS: This observational cohort study comprises 117 liver transplanted patients that were treated with mycophenolate mofetil (MMF) for at least 3 months. Blood samples (BS) were collected and MPA serum level and IMPDH activity were measured before (t(0)), 30minutes (t(30)) and 2h after (t(120)) MMF morning dose administration. Regarding MPA, we assessed the area under the curve (AUC). Patients were prospectively followed up for one year and assessed for infectious and biliary complications, episodes of ACR and liver dependent survival. RESULTS: The MPA levels showed a broad interindividual variability at t(0) (2.0±1.8ng/ml), t(30) (12.7±9.0ng/ml) and t(120) (7.5±4.3ng/ml). Corresponding IMPDH activity was at t(o) (23.2±9.5 nmol/h/mg), at t(30) (16.3±8.8 nmol/h/mg) and t(120) (18.2±8.7 nmol/h/mg). With regard to MPA level we found no correlation with infectious or biliary complications within the follow-up period. Patients with baseline IMPDH(a) below the median had significant more viral infections (6 (10.2%) vs. 17 (29.3%); P=0.009) with especially more cytomegalovirus (CMV) infections (1 (3.4%) vs. 6 (21.4%); P=0.03)). Furthermore, patients with baseline IMPDH(a) above the median developed more often non-anastomotic biliary strictures (8 (13.6%) vs. 1 (1.7%), P=0.03). We found the group reaching the combined clinical endpoint of death and re-transplantation showing significantly lower MPA baseline values (t(0) 0.9±0.7 vs. 2.1±1.8µg/ml Mann-Whitney-U: P=0.02). We calculated a simplified MPA(AUC) with the MPA level at baseline, 30 and 120minutes after MPA administration. Whereas we found no differences with regard to baseline characteristics at entry into the study patients with MPA (AUC) below the median experienced significantly more often the combined clinical endpoint (12.1% (7/58) vs. 0.0% (0/57); P=0.002) and had a reduced actuarial re-transplantation-free survival (1.0 year vs. 0.58 years; Log-rank: P=0.007) during the prospective one-year follow-up period. In univariate and multivariate analysis including gender, age, BMI, ACR, MPA (AUC) and IMPDH(a) only BMI, MPA (AUC) and IMPDH(a) were independently associated with reduced actuarial re-transplantation-free survival. CONCLUSION: MPA-levels and IMPDH-activity in liver transplanted patients allows individual risk assessment. Patients with higher IMPDH inhibition acquire more often viral infections. Insufficient IMPDH inhibition is associated with development of non-anastomotic bile duct strictures and reduced re-transplantation-free survival.

Cardiac volume overload and pulmonary hypertension in long-term follow-up of patients with a transjugular intrahepatic portosystemic shunt.

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPSS) cause haemodynamic changes in patients with cirrhosis, yet little is known about long-term cardiopulmonary outcomes. AIM: To evaluate the long-term cardiopulmonary outcome after TIPSS. METHODS: We evaluated cardiopulmonary parameters including echocardiography during long-term follow-up after TIPSS. Results at 1-5 years after TIPSS were compared to those of cirrhotic controls. Pulmonary hypertension (PH) diagnoses rates were included. Endothelin 1, thromboxane B2 and serotonin were measured. RESULTS: We found significant differences 1-5 years after TIPSS compared to pre-implantation values: median left atrial diameter (LAD) increased from 37 mm [interquartile range (IQR): 33-43] to 40 mm (IQR: 37-47, P = 0.001), left ventricular end-diastolic diameter (LV-EDD) increased from 45 mm (range: 41-49) to 48 mm (IQR: 45-52, P < 0.001), pulmonary artery systolic pressure (PASP) increased from 25 mmHg (IQR: 22-33) to 30 mmHg (IQR: 25-36, P = 0.038). Comparing results 1-5 years post-implantation to the comparison cohort revealed significantly higher (P < 0.05) LAD, LV-EDD and PASP values in TIPSS patients. PH prevalence was higher in the shunt group (4.43%) compared to controls (0.91%, P = 0.150). Thromboxane B2 levels correlated with PASP in the TIPSS cohort (P = 0.033). There was no transhepatic gradient observed for the vasoactive substances analysed. CONCLUSIONS: TIPSS placement is accompanied by long-term cardiovascular changes, including cardiac volume overload, and is associated with an increased rate of pulmonary hypertension. The need for regular cardiac follow-up after TIPSS requires further evaluation.

Reduction in alkaline phosphatase is associated with longer survival in primary sclerosing cholangitis, independent of dominant stenosis.

BACKGROUND: Alkaline phosphatase (ALP) is an important serum marker in primary sclerosing cholangitis (PSC). Patients with obstruction of the large bile ducts due to dominant strictures (DS) are a special, clinically important phenotype. AIM: To determine the impact of ALP reduction on liver transplantation-free survival in PSC patients with DS. METHODS: Prospective cohort study in 215 PSC patients. We performed subgroup analysis for patients without DS (no DS, n = 84), DS at first presentation (DS early, n = 72) and development of DS during the course of the study (DS late, n = 59). We evaluated two scores of ALP reduction. ALP reduction 1 was defined as ALP normalisation, 50% reduction compared with baseline values, or reduction below 1.5 times of upper limit of normal (ULN) within 6 months. ALP reduction 2 was defined as ALP reduction below 1.5 times of ULN within 12 months. RESULTS: Of the patients, 59.5% reached an ALP reduction 1 and 56.7% according to ALP reduction 2. Achievement of each score was associated with longer transplantation-free survival in all three groups (ALP reduction 1: no DS P = 0.001; DS early P < 0.001; DS late P = 0.022; ALP reduction 2: no DS P = 0.014; DS early P = 0.001; DS late P = 0.002). Cox-regression analysis revealed each score as an independent predictor for improved transplantation-free survival (ALP reduction 1 and 2 P < 0.001 each). We further analysed previously published scores of ALP improvement in PSC showing also improved survival in patients with ALP normalisation or a reduction below 1.5 times of ULN (P = 0.003, P = 0.001, respectively), whereas the score determined by 40% reduction did not show significant differences in survival (P = 0.55). CONCLUSIONS: Reduction in alkaline phosphatase values within the first year is associated with improved transplantation-free survival in patients with primary sclerosing cholangitis independent of the presence of dominant strictures. Alkaline phosphatase might be an adequate surrogate marker for outcome assessment in clinical studies both for patients with and without dominant strictures.

Reduced residual gene expression of nuclear factor of activated T cells-regulated genes correlates with the risk of cytomegalovirus infection after liver transplantation.

BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Fut2 genotype is a risk factor for dominant stenosis and biliary candida infections in primary sclerosing cholangitis.

BACKGROUND: 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. AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Development of miliary tuberculosis under infliximab in a patient with spondyloarthritis and suspected Crohn's disease.

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.

[Mucosal protection by phosphatidylcholine as new therapeutic concept in ulcerative colitis]. / Mukosaschutz durch Phosphatidylcholin als neues therapeutisches Prinzip bei der Colitis ulcerosa.

The colonic mucus serves a first barrier towards invasion of commensal bacteria in stool. One essential component of intestinal mucus is phosphatidylcholine (PC) which represents more than 90 % of the phospholipids in mucus indicative for a selective transport of PC into this compartment. It is arranged in lamellar structures as surfactant-like particles which provide a hydrophobic surface on top of the hydrated mucus gel to prevent invasion of bacteria from the intestinal lumen. In ulcerative colitis (UC) the mucus PC content is reduced by 70 % irrespective of the state of inflammation. Thus, it could represent an intrinsic primary pathogenetic condition predisposing to bacterial invasion and precipitation of inflammation. Since PC was shown to be mainly secreted by the ileal mucosa from where it is assumed to move distally to the colon, the PC content along the colonic wall towards the rectum gradually thins out with lowest PC content in the rectum. It explains the start of the clinical manifestation of UC in the rectum and expansion from there to the upper parts of the colon. When the lacking mucus PC in the UC was supplemented by an oral, delayed released PC preparation, it was shown in three clinical trials that the inflammation improved and even resolved. The data indicate the essential role of the mucus phosphatidylcholine content for protection against inflammation in colon. This can be the basis for the development of an innovative therapy for ulcerative colitis using orally available delayed released phosphatidylcholine.

Targeted lentiviral vectors pseudotyped with the Tupaia paramyxovirus glycoproteins.

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.

An unusual case of paralytic ileus.

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.

Temporary placement of fully covered self-expandable metal stents in biliary complications after liver transplantation.

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.

Prospective validation of a simple laboratory score to predict outcome after orthotopic liver transplantation.

OBJECTIVE: To establish a score to predict 30-day mortality and graft loss retrospectively and to validate the score prospectively. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Algorithm for detection of small-bowel metastasis in malignant melanoma of the skin.

BACKGROUND AND STUDY AIM: The aim of this study was to develop an algorithm to detect small-bowel metastasis (SBM) of melanoma by sequential laboratory parameters and pan-intestinal endoscopy (PIE) including video capsule endoscopy (VCE). PATIENTS AND METHODS: A total of 390 melanoma patients (AJCC stage I/II/III/IV, 140/80/121/49) were screened for signs of intestinal blood loss (fecal occult blood test [FOBT] or overt bleeding) in an open, multicenter, prospective study, and those who were positive underwent PIE. Independent of the presence of intestinal bleeding, all stage IV patients were offered PIE. Follow-up was obtained in 357 patients (91.5 %) for a median of 16 months. We undertook to identify possible associations between SBM and clinical and laboratory data. Survival data were analyzed with regard to clinical and laboratory data and small-bowel findings. RESULTS: Intestinal blood loss was suspected in 49 of 390 patients (12.6 %), 38 of whom (77.6 %) agreed to undergo endoscopy. In 10 patients, SBM was detected by VCE (intention-to-diagnose, 20.4 %; AJCC III, n = 2; AJCC IV, n = 8). The SBM was resected in five patients. Total detection rates of SBM were 14 of 49 patients in stage IV (28.6 %, intention-to-diagnose), 2 of 121 in stage III (1.7 %), and 0 in stage I/II. In FOBT-positive patients, SBM detection rates were 72.7 %, 14.3 %, and 0 % in tumor stages IV, III, and I/II, respectively. Positive FOBT proved to be an independent negative prognostic factor for total survival in stage III and IV melanoma. CONCLUSIONS: SBMs are frequent in advanced melanoma. In stage III patients, screening for intestinal blood loss by PIE may help to identify SBMs. In stage IV, indication for PIE should depend on the individual consequences of detecting SBM, but not on bleeding symptoms alone.

Lipopolysaccharide binding protein, interleukin-6 and C-reactive protein in acute gastrointestinal infections: value as biomarkers to reduce unnecessary antibiotic therapy.

AIM: Several new biomarkers, such as lipopolysaccharide binding protein (LBP) and interleukin-6 (IL-6), have the potential to determine the severity and outcome of infectious diseases. LBP and IL-6 serum levels have not been reported in patients with gastrointestinal infections. The aim of this study was to compare established markers of infection with new markers, such as LBP and IL-6, in patients with acute gastrointestinal infections METHOD: LBP, C-reactive protein (CRP), white blood cell count (WBC) and IL-6 serum levels were determined in patients with acute viral or bacterial (positive stool cultures) gastroenteritis. The final diagnosis and empiric antibiotic use were recorded. In total, medical data on 88 patients with acute gastroenteritis (22 bacterial, 66 viral or nonspecific) were analyzed. RESULTS: LBP and CRP levels were significantly increased in patients with acute bacterial gastroenteritis [28.5 ± 16.5 vs. 15.2 ± 11.5 µg/mL (p < 0.05) and 10.4 ± 9.6 vs. 3.8 ± 5.5 mg/dL (p < 0.001), respectively]. LBP at a cut-off value of 14.6 µg/mL and CRP at a cut-off value of 1.7 mg/dL distinguished between bacterial and non-bacterial gastrointestinal infection (receiver operator characteristic analysis). Empiric antibiotic therapy was initiated in 82% of patients with bacterial gastroenteritis and in 27% of patients with viral gastroenteritis. CONCLUSION: The use of the cut-off values for LBP and CRP determined here would have avoided unnecessary antibiotic therapy in 14 and 11%, of patients respectively. CRP and LBP appear to be superior to IL-6 and WBC as diagnostic markers of bacterial gastrointestinal infection. Cut-off values may be a useful tool to support clinical decision-making on whether or not to initiate empiric antibiotic therapy.

Pantoprazole induces severe acute hepatitis.

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.

[Wilson disease--evaluation of disease-related topics through the eyes of patients by patient-generated paintings--a cooperative study with the German patient organisation Verein morbus Wilson e. V]. / Morbus Wilson--künstlerische Darstellung der Erkrankung durch Patienten zur Evaluation subjektiv bedeutender krankheitsassoziierter Themen--eine Gemeinschaftsstudie mit der Patientenorganisation Verein Morbus Wilson e. V.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

[Combined liver-kidney and kidney after liver transplantation: indications and experiences from a nephrological perspective at a single center]. / Die kombinierte und sequentielle Leber-Nieren-Transplantation: Indikationen und Zentrumserfahrungen aus Sicht des Nephrologen.

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.

Cytomegalovirus infection after liver transplantation incidence, risks, and benefits of prophylaxis.

BACKGROUND: Cytomegalovirus (CMV) infection and related disease is a feared complication after liver transplantation. Antiviral prophylaxis is recommended in clinical practice guidelines depending on the CMV status of both donor and recipient as well as the individual risk profile. METHODS: We retrospectively analyzed 211 liver transplant recipients with respect to the incidence of CMV infection after transplantation, the influence of donor and recipient CMV status, and the effect of antiviral prophylaxis. In addition, the underlying liver disease and immunosuppressive regimen were compared with the incidence of CMV infection. Patients were divided into 4 groups according to CMV donor/recipient (D/R) profile: group A (D-/R-) 28 patients (13.3%), group B (D-/R+) 64 patients (30.3%), group C (D+/R+) 79 patients (37.4%), and group D (D+/R-) 40 patients (19.0%). RESULTS: CMV infection was observed in 17.9%, 29.7%, 24.1%, and 22.5% of the patients, respectively, with no significant difference in infection rates between the groups. CMV infection occurred in 5 patients (17.9%) in the presumed low-risk profile (group A), despite an antiviral prophylaxis in 4 out of these 5 patients. In contrast, CMV infection occurred in only 9/40 patients (22.5%) in the presumed high-risk profile (group D). The most frequent infection rates were found in groups B and C (R+ groups). After successful treatment of CMV infection, no recurrence was detected. Underlying liver disease or immunosuppressive protocol had no influence on CMV infection. CONCLUSION: Approximately one fourth of patients will acquire CMV infection after liver transplantation independent of donor/recipient status. Surprisingly, antiviral prophylaxis does not seem to be sufficient to reduce this proportion of patients, either in presumed high-risk or in presumed low-risk situations.

An early increase in gamma glutamyltranspeptidase and low aspartate aminotransferase peak values are associated with superior outcomes after orthotopic liver transplantation.

BACKGROUND: Prediction of prognosis after liver transplantation (OLT) remains difficult. The present study determines if standard laboratory parameters measured within the first week after OLT correlate with outcome. PATIENTS AND METHODS: Laboratory parameters measured within the first weak after OLT of 328 patients were grouped either graft loss or death within 90 days after (group 1: graft loss; group 2: death; group 3: neither graft loss nor death within 90 days). RESULTS: Peak AST and ALT were significantly lower in group 3 (1867 and 1252 U/L) than in group 1 (4474 and 2077 U/L) or 2 (3121 and 1865 U/L). Bilirubin was significantly lower and gamma-GT significantly higher in group 3 compared to groups 1 and 2. In multivariate analysis, high AST peaks were independently associated with death or graft loss within 90 days. An increase in gamma-GT and low bilirubin early after transplantation were found to be independently associated with superior outcome. DISCUSSION: Unexpectedly, a disproportionate rise in gamma-GT was associated with graft and patient survival of more than 90 days. This might be explained by regeneration phenomena in the liver indicative of a well functioning graft.

Fatal varicella in an immunocompromised adult associated with a European genotype E2 variant of varicella zoster virus.

Varicella zoster virus (VZV) seronegative patients under immunosuppressive therapy are at risk for severe life-threatening varicella. A 25-year-old male patient presented with rash and hepatitis. He had been known to suffer from Crohn's disease and received immunosuppressive treatment with azathioprine. The patient showed dyspnoea, and presented with a generalized rash with vesicular lesions typical for herpesvirus infections. He was started immediately on acyclovir therapy. Varicella infection was determined in this VZV seronegative patient in rash vesicles, blood and tracheal secretions and a high VZV viral load was detected in these specimens. The causative agent was genotyped by sequencing of several genes as a variant of the European genotype E2 containing several unique single nucleotide polymorphisms. Despite all measures, there was progressive septic shock, and the patient died due to multi-organ failure. Immunocompromised adults without varicella history are at high risk to develop life-threatening complications of varicella. Antiviral therapy with acyclovir can only be successful when administered as early as possible on suspicion of varicella infection in this group of patients. The most effective method to prevent severe varicella in immunocompromised patients is active immunization prior to immunosuppressive therapy.

Is stenting necessary after balloon dilation of post-transplantation biliary strictures? Results of a prospective comparative study.

BACKGROUND AND STUDY AIMS: Biliary strictures are a major cause of morbidity following liver transplantation. In the present prospective comparative trial, we evaluated balloon dilation vs. balloon dilation plus stenting with regard to technical and clinical efficacy as well as complications. PATIENTS AND METHODS: A total of 32 patients with symptomatic biliary strictures after liver transplantation were assigned to balloon dilation (n = 17) or balloon dilation plus plastic stent placement (n = 15). The main outcome parameter was sustained clinical success defined as an interval of at least 3 months without further endoscopic intervention. Additional outcome parameters were assisted clinical success and treatment failure, as well as procedure-related complications. RESULTS: The initial technical success and primary clinical success rates in the dilation group were both 100%; in the stent group, the corresponding rates were 100% and 93% (n. s.). The sustained clinical success was 71% vs. 73%, respectively (n. s.). The time interval to reach sustained clinical success was 6.1 and 5.1 months, respectively (n. s.). No significant differences were found in assisted clinical success or in treatment failure. Complications were observed in 4.3% in the dilation group and 13.6% in the stent group (P < 0.05). Independent of the treatment group, a sustained clinical success in anastomotic strictures was achieved in 100%, whereas the success rate of strictures of the donor hepatic duct was 50% and of strictures involving the hilum, only 14% (P < 0.05). CONCLUSIONS: In patients with biliary strictures after liver transplantation, endoscopic balloon dilation alone was as effective as dilation plus stent placement. Stent placement was associated with a significantly higher complication rate. Endoscopic treatment of strictures of the biliary anastomosis is highly effective, whereas attempts to treat more complex strictures are less promising.