Spleen transient elastography predicts actuarial survival after liver transplantation.

Background: Splenic transient elastography (TE) correlates with increased portal pressure. Little data are available in the post liver transplantation (LTx) setting. Methods: Three months after LTx, we performed splenic TE in 125 LTx recipients. Results: Mean splenic TE values were 29.4 (±6.3; range, 21.6-49.2) kPa. Splenic TE correlated with reduced time to development until persistent ascites (30 events, OR =1.082, 95% CI: 1.034-1.133; P=0.001), hepatorenal syndrome (8 events, OR =1.109, 95% CI: 1.015-1.211; P=0.022) and hepatic encephalopathy (16 events, OR =1.136, 95% CI: 1.066-1.211; P=0.000). In Cox univariate analysis, splenic TE served as a predictor of actuarial survival free of liver (OR =1.114, 95% CI: 1.050-1.182; P<0.001) and remained an independent risk factor associated with reduced actuarial survival free of LTx in multivariate analysis (OR =1.103, 95% CI: 1.026-1.186; P=0.008). Conclusions: Splenic TE measurement at 3 months after LTx serves as a robust predictor of survival in LTx recipients.

Routine Liver Elastography Could Predict Actuarial Survival after Liver Transplantation.

BACKGROUND AND AIMS: Transient elastography (TE) has routinely been implemented in the diagnosis and assessment of chronic liver disease. Little data are available in the post liver transplant (LTx) setting. METHODS: Three months after LTx, we performed TE in 137 liver transplant recipients and investigated its predictive value upon further clinical outcome. The mean follow-up time for clinical outcome was 24 months. RESULTS: Mean TE value was 10.6 kPa (± 6.3 kPa; range 2.8 - 29.9 kPa). There was a significant correlation between TE and aspartate aminotransferase (AST) (p=0.004), gamma-glutamyl transferase (GGT) (p=0.031) and bilirubin (p<0.001) serum levels. In Cox univariate analysis, TE served as a predictor of actuarial survival free of liver transplantation (OR=1.111, 95%CI: 1.051-1.174; p<0.001). In multivariate analysis, TE remained an independent risk factor associated with reduced actuarial survival free of liver transplantation (OR=1.080, 95%CI: 1.001-1.166; p=0.047), along with thrombocytes (OR=0.992, 95%CI: 0.986-0.999; p=0.020) and metabolic co-disease (OR = 0.250, 95%CI: 0.070-0.895; p=0.033). CONCLUSION: Transient elastography measurement at three months after LTx seems a robust predictor of survival in liver transplant recipients.

Multidrug-Resistant Bacteria and Disease Progression in Patients with End-Stage Liver Disease and after Liver Transplantation.

BACKGROUND: Multidrug-resistant (MDR) pathogens represent an emerging challenge in end-stage liver disease and in liver transplant recipients. METHODS: We evaluated the impact of MDR bacteria upon clinical outcomes in patients with end-stage liver disease (n = 777) at the time of enrollment on the liver transplant (LTx) waiting list, after first LTx (n = 645), and after second LTx (n = 128). RESULTS: Colonization/infection with MDR bacteria was present in 72/777 patients on the waiting list, in 98/645 patients at first LTx, and in 46/128 patients at second LTx. While on the LTx waiting list, the time until first hydropic decompensation (p = 0.021), hepatic encephalopathy (p < 0.001) and hepatorenal syndrome (p < 0.001) was reduced in the presence of MDR bacteria, which remained an independent risk factor of poor survival in multivariate analysis (p < 0.001). Following first and second liver transplant, MDR bacteria were associated with an increased risk of infection-related deaths (first LTx: p < 0.001; second LTx: p = 0.037) and reduced actuarial survival (first LTx: p < 0.001; second LTx: p = 0.046). CONCLUSIONS: We showed that MDR pathogens are associated with poor outcomes before, after first and after recurrent LTx.

Serum miRNA-122 is an independent biomarker of survival in patients with primary sclerosing cholangitis.

BACKGROUND AND AIMS: The disease course of primary sclerosing cholangitis (PSC) is variable and difficult to predict. MicroRNA-122 (miR-122) is associated with various liver diseases. We investigated the value of miR-122 as a biomarker for the disease course of PSC. METHODS: We determined serum miR-122 levels in a long-term, prospective cohort of 114 PSC patients and a second validation cohort. RESULTS: Based on miR-122 levels, PSC patients were assigned to low or high level miR-122 groups. Kaplan-Meier analysis showed significantly impaired actuarial transplant-free survival for PSC patients in the low miR-122 group (mean: 46.1 +/- 4.1 months; 95% confidence intervals [CI]: 38.1-54.2) compared to the high miR-122 group (mean: 95.2 +/- 7.9 months; 95% CI: 79.5-110.8; p = 0.034). Using a multivariate Cox's proportional hazards model approach, Mayo-Risk score (odds ratio [OR]: 1.47; 95% CI: 1.13‒1.92; p = 0.004), the presence of dominant strictures (OR: 2.62; 95% CI: 1.00‒5.55; p = 0.004), and serum miR-122 levels (OR: 1.19; 95% CI: 1.00‒1.43; p = 0.045) were independent risk factors associated with reduced actuarial transplant-free survival. We were able to confirm this finding in a second, independent cohort of PSC patients (low miR-122 group: mean survival: 13.1 +/- 5.2 months; 95% CI: 2.8-23.4; high miR-122 group: mean: 28.62 +/- 4.2 months; 95% CI: 20.3-37.0; p = 0.018). CONCLUSIONS: We identified miR-122 as a novel, independent prognostic biomarker associated with improved survival in PSC patients. It is unknown whether exogenous miR-122 might influence the disease course of PSC patients. .

Impact of age at diagnosis on disease progression in patients with primary sclerosing cholangitis.

BACKGROUND: The median age of diagnosis of primary sclerosing cholangitis (PSC) is ∼30-40 years. OBJECTIVE: We aimed to analyse disease progression and liver-dependent survival in patients diagnosed with PSC after 50 years of age. METHODS: Patients with PSC were analysed with regard to their age at diagnosis. Patients with a first diagnosis of PSC after the age of 50 years were considered as the late-onset group. RESULTS: A total of 32/215 (14.9%) patients were diagnosed with PSC after 50 years of age. The proportion of females was significantly higher among patients with late-onset PSC (48.4 vs. 27.3%; p = 0.02). Patients with later diagnosis required dilatation therapy more often due to dominant stenosis (84.2 vs. 53.1%; p = 0.01) and suffered from recurrent cholangitis more often (48.3 vs. 21.0%; p = 0.003). Patients with late-onset PSC had reduced transplantation-free survival (10.5 ± 0.6 years vs. 20.8 ± 1.7 years, p < 0.0001), with progredient liver failure and cholangiocarcinoma as the leading causes of death. CONCLUSIONS: Patients with later age at diagnosis of PSC displayed a different clinical phenotype with a different sex ratio, immune status and an increased risk for progressive liver failure and biliary malignancies.

Von Willebrand factor and alkaline phosphatase predict re-transplantation-free survival after the first liver transplantation.

BACKGROUND: After liver transplantation (LT), there are liver-related, infectious and cardiovascular complications that contribute to reduced graft survival. These conditions are associated with an increase in the Von Willebrand factor antigen (VWF-Ag), which was previously correlated with survival in cirrhotic patients. OBJECTIVE: Evaluate VWF-Ag as a predictive marker of re-transplantation-free survival in patients after LT. METHODS: We measured VWF-Ag in patients after first LT and then followed them prospectively with regard to the primary endpoint, namely re-transplantation-free survival. RESULTS: There were 6 out of 80 patients who died or received re-LT during follow-up. In these patients, the median VWF-Ag was 510.6%, which was significantly higher (p = 0.001) than in the patients who were alive at the end of follow-up (with a median VWF-Ag = 186.8%). At a cut-off of 286.8%, VWF-Ag was significantly correlated with re-transplantation-free survival (p < 0.001). VWF-Ag was independently associated with re-transplantation-free survival in a multivariate analysis; as was alkaline phosphatase (ALP), but not the model of end-stage liver disease (MELD) score, donor age, nor cold ischemia time. A score combining VWF-Ag and ALP showed an impressive capability in the receiver operating characteristic (ROC) analysis (with area under the curve (AUC) = 0.958) to distinguish between patients with regard to the primary endpoint. CONCLUSIONS: VWF-Ag is a non-invasive marker that can predict outcome in patients after LT. Its diagnostic performance increased when combined with ALP in a newly developed scoring system.

Carcinoembryonic Antigen Level in Primary Sclerosing Cholangitis Is Not Influenced by Dominant Strictures or Bacterial Cholangitis.

BACKGROUND: Carcinoembryonic antigen (CEA) can be used to screen for biliary tract cancer in patients with primary sclerosing cholangitis (PSC). AIM: To study the influence of benign dominant strictures (DS), superimposed bacterial cholangitis (SBC), smoking status, and inflammatory bowel disease on CEA serum levels. METHODS: A retrospective analysis of CEA values in cancer-free PSC patients was performed. We included the maximal CEA value obtained during follow-up and information on the presence of DS and SBC at that time, and we analyzed the CEA values in the presence and absence of DS and SBC. Results are reported as medians with the interquartile range (IQR). RESULTS: The median maximal CEA level, which was 1.8 ng/mL (IQR 1.2-2.9) in the final 270 PSC patients included in the study, was not influenced by the presence of either DS or SBC (P = 0.320). Moreover, in 49 patients, the first CEA value available at the time of DS (1.5 ng/mL; IQR 1.2-2.1) and that at a time without DS (1.6 ng/mL; IQR 1.1-2.3) did not differ significantly (P = 0.397). Lastly, in 24 patients, the median CEA values at a time without SBC (1.8 ng/mL; IQR 1.2-2.5) and at the time of SBC (1.8 ng/mL; IQR 1.0-3.0) were comparable (P = 0.305). Smoking did not influence CEA-based cancer screening. CONCLUSIONS: Serum CEA level is not influenced by the presence of DS or SBC and might therefore serve as a favorable parameter for improving cancer screening in PSC patients.

Control of diabetic hyperglycaemia and insulin resistance through TSC22D4.

Obesity-related insulin resistance represents the core component of the metabolic syndrome, promoting glucose intolerance, pancreatic beta cell failure and type 2 diabetes. Efficient and safe insulin sensitization and glucose control remain critical therapeutic aims to prevent diabetic late complications Here, we identify transforming growth factor beta-like stimulated clone (TSC) 22 D4 as a molecular determinant of insulin signalling and glucose handling. Hepatic TSC22D4 inhibition both prevents and reverses hyperglycaemia, glucose intolerance and insulin resistance in diabetes mouse models. TSC22D4 exerts its effects on systemic glucose homeostasis-at least in part-through the direct transcriptional regulation of the small secretory protein lipocalin 13 (LCN13). Human diabetic patients display elevated hepatic TSC22D4 expression, which correlates with decreased insulin sensitivity, hyperglycaemia and LCN13 serum levels. Our results establish TSC22D4 as a checkpoint in systemic glucose metabolism in both mice and humans, and propose TSC22D4 inhibition as an insulin sensitizing option in diabetes therapy.

CD14 is associated with biliary stricture formation.

UNLABELLED: The pathogenesis of intrahepatic biliary stricture formation in patients with primary sclerosing cholangitis (PSC) or after liver transplantation (LTx) remains elusive. CD14 receptor signaling is a key mediator of the innate immune system; its common genetic variant is associated with alcoholic liver disease. PSC and LTx cohort patients and primary biliary cirrhosis (PBC) control patients were genotyped for the CD14 -260C>T (rs2569190) polymorphism, and genotypes were correlated with long-term clinical outcome. Biliary tissue, bile, and whole blood of PSC patients and healthy controls were screened for markers of the innate immune system and bacterial infection. In 121 PSC patients, the CD14 -260C>T genotype was associated with development of dominant bile duct strictures (P = 0.02). In 365 LTx patients, TT carriers (4.1%) were protected against the formation of nonanastomotic biliary strictures versus CC/CT patients (12.6%; P = 0.01). Chemokine ligand 8 (P = 0.04) and chemokine receptor 6 (P = 0.004) were up-regulated in biliary tissue of PSC patients with the TT versus the CC/CT genotype. Lipopolysaccharide whole-blood stimulation resulted in a significant change in interleukin (IL)-8 (P = 0.05) and IL-12p40 levels (P = 0.04) in healthy control subjects carrying the TT genotype. TT PSC patients were protected against Gram-negative bacterial biliary infection (TT: 0% vs. CC/CT: 22.5%; P = 0.02). Serum-soluble CD14 levels correlated with the CD14 -260C>T genotype (P = 0.02), representing an independent risk indicator of survival in PSC patients (hazard ratio, 0.40; 95% confidence interval, 0.19-0.86; P =0.01). CONCLUSIONS: The function of the innate immune response by CD14 is crucial during biliary infection and stricture formation. The benefits of CD14 signaling modification should be addressed in future studies. (Hepatology 2016;64:843-852).

A common genetic variant of fucosyltransferase 2 correlates with serum carcinoembryonic antigen levels and affects cancer screening in patients with primary sclerosing cholangitis.

BACKGROUND: Primary sclerosing cholangitis (PSC) patients are at increased risk of biliary tract cancer, and carcinoembryonic antigen (CEA) serum levels might be used for screening. OBJECTIVE: To examine cancer screening with CEA in PSC patients and analyse how serum CEA levels are affected by genetic variants of fucosyltransferase (FUT) 2 and 3. METHODS: In a retrospective cohort analysis we evaluated CEA levels in 226 PSC patients, including 19 with biliary malignancy, and investigated how FUT2 and FUT3 SNPs affected CEA levels. Receiver-operating-characteristic (ROC) analysis was performed and cut-off values were determined based on Youden's index. A control cohort contained 240 patients, including 28 with biliary malignancy. RESULTS: Median CEA concentration was lower in cancer-free patients (1.4 ng/mL) than in cancer patients (2.0 ng/mL, P = 0.014). ROC analysis revealed an area under the curve (AUC) of 0.671, the optimal cut-off was 3.2 ng/mL. The FUT2 variant rs601338 (G428A) correlated with CEA levels, and the effect was most prominent in a subgroup of patients genetically incapable of expressing CA19-9. The AUC improved if ROC analysis was performed separately for wild-type (AUC: 0.731) and homozygous mutant (AUC: 0.816) G428A. The influence of FUT2 on CEA was confirmed in the control cohort. CONCLUSIONS: CEA is interesting for biliary-malignancy screening in PSC patients, especially in patients who do not express CA19-9. This is the first study to show that the combined use of CEA measurement and FUT genotyping is clinically beneficial and that it might enhance the early detection of biliary malignancy in clinical practice. This approach could also be effective when screening for other common gastrointestinal malignancies.

Coffee consumption protects against progression in liver cirrhosis and increases long-term survival after liver transplantation.

BACKGROUND: Therapeutic options to treat progression of end-stage liver disease (ESLD) or improve long-term survival after liver transplantation remain scarce. We investigated the impact of coffee consumption under these conditions. METHODS: We recorded coffee consumption habits of 379 patients with ESLD awaiting liver transplantation and 260 patients after liver transplantation. Survival was analyzed based on coffee intake. RESULTS: One hundred ninety-five patients with ESLD consumed coffee on a daily basis, while 184 patients did not. Actuarial survival was impaired (P = 0.041) in non-coffee drinkers (40.4 ± 4.3 months, 95% confidence interval [CI]: 32.0-48.9) compared with coffee drinkers (54.9 ± 5.5 months, 95% CI: 44.0-65.7). In subgroup analysis, the survival of patients with alcoholic liver disease (ALD; P = 0.020) and primary sclerosing cholangitis (PSC; P = 0.017) was increased with coffee intake while unaffected in patients with chronic viral hepatitis (P = 0.517) or other liver disease entities (P = 0.652). Multivariate analysis showed that coffee consumption of PSC and ALD patients retained as an independent risk factor (odds ratio [OR]: 1.94; 95% CI: 1.15-3.28; P = 0.013) along with MELD score (OR: 1.13; 95% CI: 1.09-1.17; P = 0.000). Following liver transplantation, long-term survival was longer in coffee drinkers (coffee: 61.8 ± 2.0 months, 95% CI: 57.9-65.8) than non-drinkers (52.3 ± 3.5 months, 95% CI: 45.4-59.3; P = 0.001). CONCLUSIONS: Coffee consumption delayed disease progression in ALD and PSC patients with ESLD and increased long-term survival after liver transplantation. We conclude that regular coffee intake might be recommended for these patients.

Microbiology and resistance in first episodes of spontaneous bacterial peritonitis: implications for management and prognosis.

PURPOSE: International guidelines for antibiotic treatment of spontaneous bacterial peritonitis (SBP) are based on studies conducted decades ago and do not reflect regional differences of bacterial epidemiology. METHODS: We retrospectively analyzed epidemiology of agents, antibiotic resistance patterns, and survival in liver cirrhosis patients with their first episode of SBP during the years 2007-2013. RESULTS: Of the 311 patients included, 114 patients had a positive ascites culture, and 197 had an ascitic neutrophil count >250 µL. Gram-positive bacteria (47.8%) were more frequently found than Gram-negatives (44.9%), fungi in 7.2%. Enterobacter spp. (40.6%), Enterococcus spp. (26.1%), and Staphylcoccus spp. (13.8%) were the most frequently isolated agents. Third-generation cephalosporins covered 70.2% of non-nosocomial and 56.3% of nosocomial-acquired SBP cases.When SBP was diagnosed by a positive ascitic culture, survival was highly significantly reduced (mean: 13.9 ± 2.9 months; 95% confidence interval [CI]: 8.1-19.8) compared with culture-negative SBP patients (mean: 44.1 ± 5.4 months; 95% CI: 33.4-54.9; P = 0.000). Along with model of end-stage liver disease score and intensive care unit contact, a positive ascites culture remained an independent risk factor associated with poor survival (odds ratio: 1.49; 95% CI: 1.09-2.03) in multivariate analysis; piperacillin/tazobactam proved to be an adequate antibiotic for nosocomial and non-nosocomial SBP in 85.1% and 92.5%, respectively. SBP infection with Enterococcus spp. was associated with poor patient survival (P = 0.048). CONCLUSIONS: Third-generation cephalosporins have poor microbial coverage for treatment of SBP. Current guidelines need to adapt for the emerging number of Gram-positive infectious agents in SBP patients.

Association of serum zinc levels with liver function and survival in patients awaiting liver transplantation.

PURPOSE: Zinc is an important trace element with catalytic and defensive functions. We assessed the impact of zinc deficiency in patients with end-stage liver disease awaiting liver transplantation. METHODS: Serum zinc levels were measured at the time of evaluation for liver transplantation (n = 368). Patients were dichotomized in two groups based on low and normal zinc serum levels. RESULTS: Serum zinc levels are tightly associated with liver function as patients with low zinc levels (n = 226) had a higher Model for End-Stage Liver Disease (MELD) score (15.0 [5.0-40.0]) than patients with normal zinc (n = 142) levels (9.0 [6.0-34.0]; p < 0.00). Multivariate analysis demonstrated that serum zinc levels function as an independent predictor of hepatic decompensation (hydropic decompensation: odds ratio [OR] 0.82; 95% confidence interval [CI] 0.70-0.96; p = 0.015; hepatic encephalopathy: OR 0.80; 95% CI 0.71-0.90; p = 0.000; spontaneous bacterial peritonitis: OR 0.85; 95% CI 0.72-1.00; p = 0.047; hepatorenal syndrome: OR 0.83; 95% CI 0.72-0.95; p = 0.011). Actuarial survival free of liver transplantation was reduced for low-zinc patients (26.7 ± 4.0 months; 95% CI 18.8-34.6) compared to patients with normal zinc levels (30.9 ± 3.0 months; 95% CI 24.9-36.9; p = 0.008). Reduction of zinc levels for patients on the transplantation list resulted in a 28.3-fold increased risk of death/liver transplantation (95% CI 3.2-244.8, p < 0.001). CONCLUSIONS: Serum zinc levels are associated with reduced survival in end-stage liver disease patients. Whether or not zinc supplementation might be beneficial for patients on a liver transplantation list requires further study.

Inflammation But Not Biliary Obstruction Is Associated With Carbohydrate Antigen 19-9 Levels in Patients With Primary Sclerosing Cholangitis.

BACKGROUND & AIMS: Assays that measure the serum level of carbohydrate antigen 19-9 (CA19-9) are used to screen patients with primary sclerosing cholangitis (PSC) for malignancies. However, in patients with PSC, cholestasis, and bacterial cholangitis, the CA19-9 level can be affected by variants in the fucosyltransferases 2 and 3 genes (FUT2 and FUT3), which regulate the production of CA19-9. We investigated how these genotypes affect cancer screening in these patients. METHODS: We performed a retrospective analysis of data from 209 patients with PSC (19 patients with biliary malignancy, 23 patients with cholestasis and bacterial cholangitis) treated at the University Hospital Heidelberg from 1987 through 2014. We collected data on the maximum serum level of CA19-9; laboratory measures of cholestasis or inflammation; the presence of dominant stenosis, cholestasis, and bacterial cholangitis; and FUT2 and FUT3 genotypes. Patients were assigned to intermediate (n = 161) or high (n = 48) CA19-9 biosynthesis groups, based on FUT2 and FUT3 genotypes. Patients incapable of CA19-9 biosynthesis, based on genetic features, were excluded. RESULTS: The median level of CA19-9 was 31.1 U/mL in cancer-free patients. The CA19-9 level correlated with the level of C-reactive protein (P < .001); high CA19-9 biosynthesis correlated with high leukocyte counts (P = .037), but not intermediate CA19-9 biosynthesis. There was no correlation between the level of CA19-9 and laboratory markers of cholestasis. The level of CA19-9 was the lowest in patients without biliary obstruction, cholestasis, or bacterial cholangitis (7.8 U/mL), followed by patients with only obstruction (28.0 U/mL), and then patients with cholestasis and bacterial cholangitis (77.0 U/mL and 205.4 U/mL in patients without or with concomitant obstruction, respectively). The greatest increase in CA19-9 as a result of cholestasis and bacterial cholangitis was observed in patients in the high CA19-9 biosynthesis group. CONCLUSIONS: In patients with PSC, cholestasis has little effect on the level of CA19-9, but cholestasis and bacterial cholangitis increase the level. Their effects on CA19-9 level depend on the FUT2 and FUT3 genotype. These findings support the analysis of FUT2 and FUT3 genotype during follow-up evaluation of patients with PSC.

Survival in patients with colorectal cancer diagnosed by screening colonoscopy.

BACKGROUND: In Germany, screening colonoscopy was first established in 2002 as part of the national cancer screening program. OBJECTIVE: To evaluate whether colorectal cancer (CRC) survival differs when CRC is diagnosed by screening colonoscopy (S-CRC) versus diagnostic colonoscopy (D-CRC). DESIGN: Long-term, retrospective, multicenter, observational study. SETTING: Study centers: 10 private gastroenterology practices in Germany. PATIENTS: A total of 60 patients diagnosed with CRC during screening colonoscopy and 252 patients during diagnostic colonoscopy in 2002, 2003, and 2004. INTERVENTIONS: Colonoscopy. MAIN OUTCOME MEASUREMENTS: Survival of patients up to December 2013. RESULTS: Mean (± standard deviation [SD]) follow-up time was 81.0 (± 40.1) months. Union Internationale Contre le Cancer (UICC) stages I and II were found more often in S-CRC (81.6%) compared with D-CRC (59.9%; P < .002). Kaplan-Meier analysis showed significantly reduced overall survival for patients with D-CRC (mean [± SD] 86.9 [± 3.0] months; 95% confidence interval [CI], 81.0-92.8) compared with S-CRC (mean [± SD] 107.1 [± 4.9] months; 95% CI, 97.4-116.9; P = .003). When deaths not related to CRC were excluded, survival was still shorter for D-CRC patients (mean [± SD] 89.4 [± 3.0] months; 95% CI, 83.5-95.4) compared with S-CRC (mean [± SD] 109.6 [± 4.7] months; 95% CI, 100.2-119.0; P = .004). LIMITATIONS: Retrospective study design. CONCLUSION: In this long-term, retrospective study, patients with CRC diagnosed during screening colonoscopy lived significantly longer when compared with patients with CRC diagnosed during diagnostic colonoscopy.

Effects of increased von Willebrand factor levels on primary hemostasis in thrombocytopenic patients with liver cirrhosis.

In patients with liver cirrhosis procoagulant and anticoagulant changes occur simultaneously. During primary hemostasis, platelets adhere to subendothelial structures, via von Willebrand factor (vWF). We aimed to investigate the influence of vWF on primary hemostasis in patients with liver cirrhosis. Therefore we assessed in-vitro bleeding time as marker of primary hemostasis in cirrhotic patients, measuring the Platelet Function Analyzer (PFA-100) closure times with collagen and epinephrine (Col-Epi, upper limit of normal ≤ 165 s) or collagen and ADP (Col-ADP, upper limit of normal ≤ 118 s). If Col-Epi and Col-ADP were prolonged, the PFA-100 was considered to be pathological. Effects of vWF on primary hemostasis in thrombocytopenic patients were analyzed and plasma vWF levels were modified by adding recombinant vWF or anti-vWF antibody. Of the 72 included cirrhotic patients, 32 (44.4%) showed a pathological result for the PFA-100. They had mean closure times (± SD) of 180 ± 62 s with Col-Epi and 160 ± 70 s with Col-ADP. Multivariate analysis revealed that hematocrit (P = 0.027) and vWF-antigen levels (P = 0.010) are the predictors of a pathological PFA-100 test in cirrhotic patients. In 21.4% of cirrhotic patients with platelet count ≥ 150/nL and hematocrit ≥ 27.0%, pathological PFA-100 results were found. In thrombocytopenic (< 150/nL) patients with cirrhosis, normal PFA-100 results were associated with higher vWF-antigen levels (462.3 ± 235.9% vs. 338.7 ± 151.6%, P = 0.021). These results were confirmed by multivariate analysis in these patients as well as by adding recombinant vWF or polyclonal anti-vWF antibody that significantly shortened or prolonged closure times, respectively. In conclusion, primary hemostasis is impaired in cirrhotic patients. The effect of reduced platelet count in cirrhotic patients can at least be partly compensated by increased vWF levels. Recombinant vWF could be an alternative to platelet transfusions in the future.

Risk factors and outcome in patients with primary sclerosing cholangitis with persistent biliary candidiasis.

BACKGROUND: Candidiasis is commonly observed in patients with primary sclerosing cholangitis (PSC), but the clinical risk factors associated with its presence have not been fully investigated. In this study, we aimed to analyse the incidence, risk factors, and transplantation-free survival in primary sclerosing cholangitis (PSC) patients with persistent biliary candidiasis. METHODS: We retrospectively analysed patients diagnosed with PSC who were admitted to our department during 2002 to 2012. One-hundred fifty patients whose bile cultures were tested for fungal species were selected, and their clinical and laboratory parameters were investigated. The results of endoscopic retrograde cholangiography (ERC) and bile cultures were analysed using chart reviews. The cases of biliary candidiasis were sub-classified as transient or persistent. RESULTS: Thirty out of 150 (20.0%) patients had biliary candidiasis. Although all patients demonstrated comparable baseline characteristics, those with biliary candidiasis showed significantly reduced transplantation-free survival (p < 0.0001) along with a markedly elevated frequency of cholangiocarcinoma (CCA) (p = 0.04). The patients were further sub-classified according to the transient (15/30) or persistent (15/30) nature of their biliary candidiasis. A subgroup analysis showed reduced survival with a greater necessity for orthotopic liver transplantation (OLT) only in patients with persistence of Candida (p = 0.007). The survival in the patients with transient biliary candidiasis was comparable to that in candidiasis-free patients. In a multivariate regression analysis that included Mayo risk score (MRS), sex, age, dominant stenosis, inflammatory bowel disease, autoimmune hepatitis overlap syndrome, and number of times ERC was performed, biliary candidiasis was an independent risk factor for reduced survival (p = 0.008). Risk factors associated with acquisition of biliary candidiasis were age at PSC diagnosis and number of ERCs. CONCLUSIONS: The persistence of biliary candidiasis is associated with markedly reduced transplantation-free survival in PSC patients. By contrast, actuarial survival in patients with transient biliary candidiasis approaches that for patients without any evidence of biliary candidiasis. Further studies on the treatment of persistent biliary candidiasis in patients with PSC are warranted.

Respiratory complications in outpatient endoscopy with endoscopist-directed sedation.

BACKGROUND AND AIMS: Respiratory complications represent an important adverse event of endoscopic procedures. We screened for respiratory complications after endoscopic procedures using a questionnaire and followed-up patients suggestive of respiratory infection. METHOD: In this prospective observational, multicenter study performed in Outpatient practices of gastroenterology we investigated 15,690 patients by questionnaires administered 24 hours after the endoscopic procedure. RESULTS: 832 of the 15,690 patients stated at least one respiratory symptom after the endoscopic procedure: 829 patients reported coughing (5.28%), 23 fever (0.15%) and 116 shortness of breath (SOB, 0.74%); 130 of the 832 patients showed at least two concomitant respiratory symptoms (107 coughing + SOB, 17 coughing + fever, 6 coughing + coexisting fever + SOB) and 126 patients were followed-up to assess their respiratory complaints. Twenty-nine patients (follow-up: 22.31%, whole sample: 0.18%) reported signs of clinically evident respiratory infection and 15 patients (follow-up: 11.54%; whole sample: 0.1%) received therefore antibiotic treatment. Coughing or vomiting during the endoscopic procedure resulted in a 156.12-fold increased risk of respiratory complications (95% CI: 67.44 - 361.40) and 520.87-fold increased risk of requiring antibiotic treatment (95% CI: 178.01 - 1524.05). All patients of the follow-up sample who coughed or vomited during endoscopy developed clinically evident signs of respiratory infection and required antibiotic treatment while this occurred in a significantly lower proportion of patients without these symptoms (17.1% and 5.1%, respectively). CONCLUSIONS: We demonstrated that respiratory complications following endoscopic sedation are of comparably high incidence and we identified major predictors of aspiration pneumonia which could influence future surveillance strategies after endoscopic procedures.