Genomic Characterization of Cholangiocarcinoma in Primary Sclerosing Cholangitis Reveals Therapeutic Opportunities.

BACKGROUND AND AIMS: Lifetime risk of biliary tract cancer (BTC) in primary sclerosing cholangitis (PSC) may exceed 20%, and BTC is currently the leading cause of death in patients with PSC. To open new avenues for management, we aimed to delineate clinically relevant genomic and pathological features of a large panel of PSC-associated BTC (PSC-BTC). APPROACH AND RESULTS: We analyzed formalin-fixed, paraffin-embedded tumor tissue from 186 patients with PSC-BTC from 11 centers in eight countries with all anatomical locations included. We performed tumor DNA sequencing at 42 clinically relevant genetic loci to detect mutations, translocations, and copy number variations, along with histomorphological and immunohistochemical characterization. Regardless of the anatomical localization, PSC-BTC exhibited a uniform molecular and histological characteristic similar to extrahepatic cholangiocarcinoma. We detected a high frequency of genomic alterations typical of extrahepatic cholangiocarcinoma, such as TP53 (35.5%), KRAS (28.0%), CDKN2A (14.5%), and SMAD4 (11.3%), as well as potentially druggable mutations (e.g., HER2/ERBB2). We found a high frequency of nontypical/nonductal histomorphological subtypes (55.2%) and of the usually rare BTC precursor lesion, intraductal papillary neoplasia (18.3%). CONCLUSIONS: Genomic alterations in PSC-BTC include a significant number of putative actionable therapeutic targets. Notably, PSC-BTC shows a distinct extrahepatic morpho-molecular phenotype, independent of the anatomical location of the tumor. These findings advance our understanding of PSC-associated cholangiocarcinogenesis and provide strong incentives for clinical trials to test genome-based personalized treatment strategies in PSC-BTC.

Epigenetic changes of the thioredoxin system in the tx-j mouse model and in patients with Wilson disease.

Wilson disease (WD) is caused by mutations in the copper transporter ATP7B, leading to copper accumulation in the liver and brain. Excess copper inhibits S-adenosyl-L-homocysteine hydrolase, leading to variable WD phenotypes from widespread alterations in DNA methylation and gene expression. Previously, we demonstrated that maternal choline supplementation in the Jackson toxic milk (tx-j) mouse model of WD corrected higher thioredoxin 1 (TNX1) transcript levels in fetal liver. Here, we investigated the effect of maternal choline supplementation on genome-wide DNA methylation patterns in tx-j fetal liver by whole-genome bisulfite sequencing (WGBS). Tx-j Atp7b genotype-dependent differences in DNA methylation were corrected by choline for genes including, but not exclusive to, oxidative stress pathways. To examine phenotypic effects of postnatal choline supplementation, tx-j mice were randomized to one of six treatment groups: with or without maternal and/or continued choline supplementation, and with or without copper chelation with penicillamine (PCA) treatment. Hepatic transcript levels of TXN1 and peroxiredoxin 1 (Prdx1) were significantly higher in mice receiving maternal and continued choline with or without PCA treatment compared to untreated mice. A WGBS comparison of human WD liver and tx-j mouse liver demonstrated a significant overlap of differentially methylated genes associated with ATP7B deficiency. Further, eight genes in the thioredoxin (TXN) pathway were differentially methylated in human WD liver samples. In summary, Atp7b deficiency and choline supplementation have a genome-wide impact, including on TXN system-related genes, in tx-j mice. These findings could explain the variability of WD phenotype and suggest new complementary treatment options for WD.

Pregnancy in Wilson's disease: Management and outcome.

Wilson's disease (WD) is a rare inherited disorder of copper metabolism causing toxic hepatic and neural copper accumulation. Clinical symptoms vary widely, from asymptomatic disease to acute liver failure or chronic liver disease with or without neuropsychiatric symptoms. Continuation of specific medical treatment for WD is recommended during pregnancy, but reports of pregnancy outcomes in WD patients are sparse. In a retrospective, multicenter study, 282 pregnancies in 136 WD patients were reviewed. Age at disease onset, age at conception, and WD-specific treatments were recorded. Maternal complications during pregnancy, rate of spontaneous abortions, and birth defects were analyzed with respect to medical treatment during pregnancy. Worsening of liver function tests was evident during 16 of 282 (6%) pregnancies and occurred in undiagnosed patients as well as in those under medical treatment. Liver test abnormalities resolved in all cases after delivery. Aggravation of neurological symptoms during pregnancy was rare (1%), but tended to persist after delivery. The overall spontaneous abortion rate in the study cohort was 73 of 282 (26%). Patients with an established diagnosis of WD receiving medical treatment experienced significantly fewer spontaneous abortions than patients with undiagnosed WD (odds ratio, 2.853 [95% confidence interval, 1.634-4.982]). Birth defects occurred in 7 of 209 (3%) live births. CONCLUSION: Pregnancy in WD patients on anticopper therapy is safe. The spontaneous abortion rate in treated patients was lower than that in therapy-naïve patients. Although the teratogenic potential of copper chelators is a concern, the rate of birth defects in our cohort was low. Treatment for WD should be maintained during pregnancy, and patients should be monitored closely for hepatic and neurological symptoms. (Hepatology 2018;67:1261-1269).

Sequencing of FIC1, BSEP and MDR3 in a large cohort of patients with cholestasis revealed a high number of different genetic variants.

BACKGROUND & AIMS: The bile salt export pump (BSEP, ABCB11), multidrug resistance protein 3 (MDR3, ABCB4) and the ATPase familial intrahepatic cholestasis 1 (FIC1, ATP8B1) mediate bile formation. This study aimed to determine the contribution of mutations and common variants in the FIC1, BSEP and MDR3 genes to cholestatic disorders of differing disease onset and severity. METHODS: Coding exons with flanking intron regions of ATP8B1, ABCB11, and ABCB4 were sequenced in cholestatic patients with assumed genetic cause. The effects of new variants were evaluated by bioinformatic tools and 3D protein modeling. RESULTS: In 427 patients with suspected inherited cholestasis, 149 patients carried at least one disease-causing mutation in FIC1, BSEP or MDR3, respectively. Overall, 154 different mutations were identified, of which 25 were novel. All 13 novel missense mutations were disease-causing according to bioinformatics analyses and homology modeling. Eighty-two percent of patients with at least one disease-causing mutation in either of the three genes were children. One or more common polymorphism(s) were found in FIC1 in 35.3%, BSEP in 64.3% and MDR3 in 72.6% of patients without disease-causing mutations in the respective gene. Minor allele frequencies of common polymorphisms in BSEP and MDR3 varied in our cohort compared to the general population, as described by gnomAD. However, differences in ethnic background may contribute to this effect. CONCLUSIONS: In a large cohort of patients, 154 different variants were detected in FIC1, BSEP, and MDR3, 25 of which were novel. In our cohort, frequencies for risk alleles of BSEP (p.V444A) and MDR3 (p.I237I) polymorphisms were significantly overrepresented in patients without disease-causing mutation in the respective gene, indicating that these common variants can contribute to a cholestatic phenotype. LAY SUMMARY: FIC1, BSEP, and MDR3 represent hepatobiliary transport proteins essential for bile formation. Genetic variants in these transporters underlie a broad spectrum of cholestatic liver diseases. To confirm a genetic contribution to the patients' phenotypes, gene sequencing of these three major cholestasis-related genes was performed in 427 patients and revealed 154 different variants of which 25 have not been previously reported in a database. In patients without a disease-causing mutation, common genetic variants were detected in a high number of cases, indicating that these common variants may contribute to cholestasis development.

Vitamin A deficiency in chronic cholestatic liver disease: Is vitamin A therapy beneficial?

Chronic cholestatic diseases are progressive diseases of the biliary tract that cause hepatic fibrosis and ultimately lead to liver failure. Liver transplantation is the sole curative option currently available, and because of high morbidity and mortality rates of these diseases, new therapeutic approaches are needed. Vitamin A is a nutrient essential for health as it regulates many processes, including epithelial growth and immunological processes. Vitamin A is primarily stored in hepatic stellate cells, and during liver injury, through an unknown mechanism, these cells lose vitamin A and convert into collagen-producing myofibroblasts, which contributes to hepatic fibrosis. Vitamin A deficiencies in chronic cholestatic diseases have been frequently reported, and therefore, retinoid metabolism has attracted a lot of attention. Retinoids have been shown to attenuate or even prevent hepatic fibrosis, and to regulate hepatic immunological response to cholestatic injury in different rodent models of chronic cholestasis. Recently, their potential as therapeutic drugs in primary sclerosing cholangitis patients was analyzed. The aim of this review is to summarize the existing knowledge and hypotheses about vitamin A role and the disease progression in cholestatic liver disease.

Comparative assessment of clinical rating scales in Wilson's disease.

BACKGROUND: Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism resulting in multifaceted neurological, hepatic, and psychiatric symptoms. The objective of the study was to comparatively assess two clinical rating scales for WD, the Unified Wilson's Disease Rating Scale (UWDRS) and the Global Assessment Scale for Wilson's disease (GAS for WD), and to test the feasibility of the patient reported part of the UWDRS neurological subscale (termed the "minimal UWDRS"). METHODS: In this prospective, monocentric, cross-sectional study, 65 patients (median age 35 [range: 15-62] years; 33 female, 32 male) with treated WD were scored according to the two rating scales. RESULTS: The UWDRS neurological subscore correlated with the GAS for WD Tier 2 score (r = 0.80; p < 0.001). Correlations of the UWDRS hepatic subscore and the GAS for WD Tier 1 score with both the Model for End Stage Liver Disease (MELD) score (r = 0.44/r = 0.28; p < 0.001/p = 0.027) and the Child-Pugh score (r = 0.32/r = 0.12; p = 0.015/p = 0.376) were weak. The "minimal UWDRS" score significantly correlated with the UWDRS total score (r = 0.86), the UWDRS neurological subscore (r = 0.89), and the GAS for WD Tier 2 score (r = 0.86). CONCLUSIONS: The UWDRS neurological and psychiatric subscales and the GAS for WD Tier 2 score are valuable tools for the clinical assessment of WD patients. The "minimal UWDRS" is a practical prescreening tool outside scientific trials.

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.

Location of a biliary leak after liver resection determines success of endoscopic treatment.

BACKGROUND: Bile leaks after hepatic resection are serious complications associated with substantial morbidity and mortality. The aim of this prospective observational study was to determine the therapeutic success of endoscopic treatment of biliary leakage after liver resection. PATIENTS AND METHODS: Grade B biliary leaks were considered for endoscopic treatment in patients after liver resection between 1/09 and 4/12. Endoscopic treatment (sphincterotomy only, plastic stent distal to leak or bridging) was defined as successful when the patient remained without symptoms after drain removal and without extravasation follow-up ERC 8 weeks later. RESULTS: Overall rate of biliary leak was 7.4 % (61/826). 35 patients with a grade B bile leak were considered for endoscopic treatment. 22 (63 %) had bile leaks that were peripherally located, and 13 (37 %) had bile leaks at central location. In 3 patients, sphincterotomy only was performed; in 19 patients, a stent distal to the leak and in 13 patients, a bridging stent was inserted. The overall success rate was 74 % (26/35 patients). Endoscopic treatment failed in 26 % (9/35), and mortality rate was 11 % (4/35). In all patients with leaks located at the right or left hepatic duct, treatment with the bridging stent was successful. CONCLUSION: Endoscopic therapy for biliary leakage after liver resection is safe and effective and should be considered as a first-line therapy in patients who are suitable for an interventional, non-surgical approach. Patients with a centrally located leak who are treated with a bridging stent are more likely to benefit from endoscopic intervention.

Biliary strictures and recurrence after liver transplantation for primary sclerosing cholangitis: A retrospective multicenter analysis.

Liver transplantation (LT) is the only definitive treatment for patients with end-stage liver disease due to primary sclerosing cholangitis (PSC), but a high rate of biliary strictures (BSs) and of recurrent primary sclerosing cholangitis (recPSC) has been reported. In this multicenter study, we analyzed a large patient cohort with a long follow-up in order to evaluate the incidence of BS and recPSC, to assess the impact on survival after LT, and to identify risk factors. We collected clinical, surgical, and laboratory data and records on inflammatory bowel disease (IBD), immunosuppression, recipient and graft outcome, and biliary complications (based on cholangiography and histology) of all patients who underwent LT for PSC in 10 German transplant centers between January 1990 and December 2006; 335 patients (68.4% men; mean age, 38.9 years; 73.5% with IBD) underwent transplantation 8.8 years after PSC diagnosis with follow-up for 98.8 months. The 1-, 5-, and 10-year recipient and graft survival was 90.7%, 84.8%, 79.4% and 79.1%, 69.0%, 62.4%, respectively. BS was diagnosed in 36.1% after a mean time of 3.9 years, and recPSC was diagnosed in 20.3% after 4.6 years. Both entities had a significant impact on longterm graft and recipient survival. Independent risk factors for BS were donor age, ulcerative colitis, chronic ductopenic rejection, bilirubin, and international normalized ratio (INR) at LT. Independent risk factors for recPSC were donor age, IBD, and INR at LT. These variables were able to categorize patients into risk groups for BS and recPSC. In conclusion, BS and recPSC affect longterm graft and patient survival after LT for PSC. Donor age, IBD, and INR at LT are independent risk factors for BS and recPSC and allow for risk estimation depending on the recipient-donor constellation.

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.

Hepatobiliary malignancies in Wilson disease.

BACKGROUNDS & AIMS: Reports of hepatobiliary malignancies in Wilson disease are sparse. The aim of this study was to evaluate hepatobiliary malignancies in Wilson disease patients concerning the clinical course of tumour disease and pathological analysis of tumour tissue. METHODS: Multicenter cohort study of patients with confirmed diagnosis of Wilson disease treated at the Second Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland, the university hospitals Heidelberg, Duesseldorf and Dresden, Germany, and the Department of Hepatology, University Leuven, Belgium. Occurrence, treatment and outcome of hepatobiliary tumours were analysed retrospectively. RESULTS: Of a total of 1186 patients, fourteen developed hepatobiliary malignancies. Eight were hepatocellular carcinomas (HCC) and six were intrahepatic cholangiocellular carcinomas (ICC). The prevalence of hepatobiliary malignancies in the cohort was 1.2% and the incidence was 0.28 per 1000 person years. Pathological analysis of tumour material showed no abnormal copper concentration. CONCLUSIONS: The rate of hepatobiliary malignancies in Wilson disease is very low, even in cirrhotic patients. As a result of the relevant number of ICC in addition to HCC histological analysis through surgical resection or biopsy should be mandatory when a suspect liver lesion is detected. The influence of copper depletion from Wilson disease-specific medical treatment on tumour activity remains to be elucidated.

Increased Prevalence of Subcutaneous Lipomas in Patients With Wilson Disease.

GOALS: To determine the prevalence and characteristics of lipomas in patients with Wilson disease. BACKGROUND: Wilson disease is an autosomal recessive disorder resulting in copper accumulation in the liver and the central nervous tissue. Subcutaneous lipomas were often noted by the authors during clinical examinations of patients with Wilson disease. This is the first study to analyze the prevalence and progression of lipoma development in patients with Wilson disease. STUDY: Eighty consecutive patients attending a tertiary care center were examined for the presence of subcutaneous lipomas. RESULTS: Subcutaneous lipomas could be detected during the examination of 21 (26%) of the 80 patients with Wilson disease. Multiple subcutaneous lipomas were present in 16 (76%) of the 21 affected patients. Lipomas were mainly found on the extremities and the trunk. Neither initial presentation nor decoppering treatment influenced the presence or course of lipomas in these patients. CONCLUSIONS: Subcutaneous lipoma formation is more common in patients with Wilson disease than in the general population. We suggest that the presence of lipomas contributes to the differential diagnosis of Wilson disease.

Genome-wide association analysis in primary sclerosing cholangitis and ulcerative colitis identifies risk loci at GPR35 and TCF4.

UNLABELLED: Approximately 60%-80% of patients with primary sclerosing cholangitis (PSC) have concurrent ulcerative colitis (UC). Previous genome-wide association studies (GWAS) in PSC have detected a number of susceptibility loci that also show associations in UC and other immune-mediated diseases. We aimed to systematically compare genetic associations in PSC with genotype data in UC patients with the aim of detecting new susceptibility loci for PSC. We performed combined analyses of GWAS for PSC and UC comprising 392 PSC cases, 987 UC cases, and 2,977 controls and followed up top association signals in an additional 1,012 PSC cases, 4,444 UC cases, and 11,659 controls. We discovered novel genome-wide significant associations with PSC at 2q37 [rs3749171 at G-protein-coupled receptor 35 (GPR35); P = 3.0 × 10(-9) in the overall study population, combined odds ratio [OR] and 95% confidence interval [CI] of 1.39 (1.24-1.55)] and at 18q21 [rs1452787 at transcription factor 4 (TCF4); P = 2.61 × 10(-8) , OR (95% CI) = 0.75 (0.68-0.83)]. In addition, several suggestive PSC associations were detected. The GPR35 rs3749171 is a missense single nucleotide polymorphism resulting in a shift from threonine to methionine. Structural modeling showed that rs3749171 is located in the third transmembrane helix of GPR35 and could possibly alter efficiency of signaling through the GPR35 receptor. CONCLUSION: By refining the analysis of a PSC GWAS by parallel assessments in a UC GWAS, we were able to detect two novel risk loci at genome-wide significance levels. GPR35 shows associations in both UC and PSC, whereas TCF4 represents a PSC risk locus not associated with UC. Both loci may represent previously unexplored aspects of PSC pathogenesis.

Safety analysis of endoscopist-directed propofol sedation: a prospective, national multicenter study of 24 441 patients in German outpatient practices.

BACKGROUND AND AIM: Since 2008, there exists a German S3-guideline allowing non-anesthesiological administration of propofol for gastrointestinal endoscopy. In this prospective, national, multicenter study, we evaluated the safety of endoscopist-administered propofol sedation (EDP) in German outpatient practices of Gastroenterology. METHODS: In this multicenter survey of 53 ambulatory practices of Gastroenterology, we prospectively evaluated 24 441 patients that had received EDP. We recorded adverse events during the endoscopic procedure and additionally retrieved questionnaires investigating subjective parameters 24 h after the endoscopic procedure. RESULTS: In 24 441 patients 13 793 colonoscopies, 6467 esophagogastroduodenoscopies, and 4181 double examinations were performed. In this study, 52.1% of the patients received propofol mono-sedation, and 47.9% received a combination of midazolam and propofol. Major adverse events occurred in four patients (0.016%) enrolled to this study (three mask ventilations and one laryngospasm). Minor adverse events were observed in 112 patients (0.46%) with hypoxemia being the most common minor event. All patients with adverse events recovered without persistent impairment. Minor adverse events occurred more frequently in patients sedated with propofol mono compared to propofol and midazolam (P < 0.0001) and correlated with increasing propofol dosages (P < 0.001; Pearson correlation coefficient r = 0.044). Twenty-four hours after the endoscopy, patients sedated with propofol plus midazolam stated a significantly reduced sensation of pain (P < 0.01) and improved symptoms of dizziness, nausea and vomiting (P < 0.001) compared to patients having received propofol mono-sedation. CONCLUSION: Four years after the implementation of a German S3-Guideline for endoscopic sedation, we demonstrated that EDP is a safe procedure.

Effect of delayed CNI-based immunosuppression with Advagraf® on liver function after MELD-based liver transplantation [IMUTECT].

BACKGROUND: MELD-based allocation for liver transplantation follows the "sickest-patient-first" strategy. The latter patients present with both, decreased immune competence and poor kidney function which is further impaired by immunosuppressants. METHODS/DESIGN: In this prospective observational study, 50 patients with de novo low-dose standard Advagraf®-based immunosuppression consisting of Advagraf®, Mycophenolat-mofetil and Corticosteroids after liver transplantation will be evaluated. Advagraf® trough levels of 7-10 µg/l will be reached at the end of the first postoperative week. Immunostatus, infectious complications, graft and kidney function are compared between patients with a pretransplant calculated MELD-score of ≤20 and >20. Each group comprises of 25 consecutive patients. Prior to liver transplantation and on the postoperative days 1, 3 and 7, the patients' graft function (LiMAx test) will be evaluated. On the postoperative days 3, 5 and 7 the patients' immune status will be evaluated by the measurement of their monocytic HLA-DR status.Infectious complications (CMV-reactivation, wound infection, urinary tract infection, and pneumonia), graft- and kidney function will be analysed on day 0, within the first week, and 1, 3, 6, 9 and 12 months after liver transplantation. DISCUSSION: This study was designed to assess the effect of a standard low-dose Calcineurin inhibitor-based immunosuppression regime with Advagraf® on the rate of infectious complications, graft and renal function after liver transplantation. TRIAL REGISTRATION: The trial is registered at "Clinical Trials" (http://www.clinicaltrials.gov), NCT01781195.

In-vitro renal epithelial cell infection reveals a viral kidney tropism as a potential mechanism for acute renal failure during Middle East Respiratory Syndrome (MERS) Coronavirus infection.

BACKGROUND: The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) causes symptoms similar to Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), yet involving an additional component of acute renal failure (ARF) according to several published case reports. Impairment of the kidney is not typically seen in Coronavirus infections. The role of kidney infection in MERS is not understood. FINDINGS: A systematic review of communicated and peer-reviewed case reports revealed differences in descriptions of kidney involvement in MERS versus SARS patients. In particular, ARF in MERS patients occurred considerably earlier after a median time to onset of 11 days (SD ±2,0 days) as opposed to 20 days for SARS, according to the literature. In-situ histological staining of the respective cellular receptors for MERS- and SARS-Coronavirus showed highly similar staining patterns with a focus of a receptor-specific signal in kidney epithelial cells. Comparative infection experiments with SARS- and MERS-CoV in primary human kidney cells versus primary human bronchial epithelial cells showed cytopathogenic infection only in kidney cells, and only if infected with MERS-CoV. Kidney epithelial cells produced almost 1000-fold more infectious MERS-CoV progeny than bronchial epithelial cells, while only a small difference was seen between cell types when infected with SARS-CoV. CONCLUSION: Epidemiological studies should analyze kidney impairment and its characteristics in MERS-CoV. Virus replication in the kidney with potential shedding in urine might constitute a way of transmission, and could explain untraceable transmission chains leading to new cases. Individual patients might benefit from early induction of renoprotective treatment.

Bacteriobilia and fungibilia are associated with outcome in patients with endoscopic treatment of biliary complications after liver transplantation.

BACKGROUND AND STUDY AIMS: To determine the importance of bacteriobilia and fungibilia in patients with endoscopic treatment of biliary complications after orthotopic liver transplantation (OLT). PATIENTS AND METHODS: In a prospective study at a tertiary center, 213 patients underwent 857 endoscopic retrograde cholangiographies (ERCs) after OLT. Findings at first ERC were: anastomotic stricture in 24.4%, nonanastomotic stricture in 18.3%, leakage in 11.3%, and gallstones in 4.7%. RESULTS: Bile samples from first ERC showed Gram-positive bacterial isolates in 102/180 (57%) and Gram-negative in 44/180 (24%). Main species were Enterococcus spp. (40%; 72/180) and Escherichia coli (10%; 18 /180). Enteric bacteria (present in 47%) and Candida spp. (present in 18%) were both associated with clinical signs of cholangitis, but not with laboratory signs of inflammation. Multiresistant strains (present in 12% of samples) showed no association with clinical or laboratory parameters. Detection of microbiological isolates was independent of endoscopic findings and treatment. In patients with successful endoscopic intervention, the actuarial survival free of retransplantation was significantly lower in those with detection of enteric bacteria, being 51.8 months (95% confidence interval [CI] 42.9-60.6) vs. 62.9 months (95% CI 59.1-66.7); P = 0.025). Fungibilia was associated with significantly lower actuarial retransplantation-free survival, independently of successful endoscopic treatment (mean 35.1 months [95% CI 23.5-46.7] vs. 53.1 months [(95% CI 48.0-58.2]; P = 0.019). CONCLUSIONS: Bacteriobilia and fungibilia can frequently be detected by routine microbiological sampling in patients after OLT. Regular bile sampling is recommended since the presence of difficult-to-treat multiresistant strains is unpredictable. Survival is affected by this altered biliary microbiological environment after OLT.

Non-IBD immunological diseases are a risk factor for reduced survival in PSC.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease. It is known to be associated with immunological diseases (IDs), such as inflammatory bowel disease (IBD) and autoimmune hepatitis (AIH). AIM: We evaluated the presence of IDs besides IBD and AIH in a cohort of PSC patients, and its association with clinical outcome. METHODS: This is a prospective cohort study of 195 PSC patients that were evaluated over the period 1987-2010 in our tertiary care centre. The presence of ID was determined using a retrospective chart review. IDs were subclassified into autoimmune disease (AID) and immune-mediated inflammatory disease (IMID), according to current guidelines. RESULTS: Twenty-seven of 195 (13.8%) PSC patients had at least one additional ID other than IBD (70%) or AIH (5%). The most frequent AIDs were autoimmune thyroiditis (2.6%) and diabetes mellitus type 1 (2.1%). The most frequent IMIDs were psoriasis (3.6%) and sarcoidosis (2.1%). After more than 20 years of follow-up, concomitant IDs represent an independent risk factor for reduced transplantation-free survival in patients with PSC (mean: 8.9 years vs. 16.3 years, P = 0.012). Further subgroup analysis revealed a significantly reduced survival especially in patients with concomitant IMID (P = 0.017). CONCLUSION: Patients with concomitant IDs, especially IMID, are a clinically important subgroup of PSC patients. This significant phenotype warrants further genetic and immunological studies.

Indications for intestinal transplantation: recognizing the scope and limits of total parenteral nutrition.

Total parenteral nutrition (TPN) is currently the treatment of choice for patients with intestinal failure. Intestinal failure in adults is mostly due to short bowel syndrome, which is most often caused by ischemia and Crohn's disease. However, TPN fails in a substantial number of cases. For patients with TPN failure, intestinal transplantation (ITx) may be offered as a treatment. TPN failure is considered to be present either if nutrition itself is not possible or if complications of TPN occur. These complications can, for example, originate from recurrent line infections or thrombosis. As TPN is usually a lifelong therapy and is associated with substantial impairment of the quality of life, the tolerance of each patient to this procedure is another important consideration in the decision making about whether to perform transplantation. The survival rates of intestinal transplant recipients have now reached the same level as that of recipients of other solid organ transplants. A five-yr survival of up to 80% has been reported in specialized centers, whereas registry data show rates of <80%. Although in about one-third of patients, isolated ITx is sufficient, patients with concurrent liver disease (mostly due to TPN) benefit from combined intestinal and liver transplantation. In some cases, multivisceral transplantation is necessary. Here, we review the current indications for ITx with a special focus on TPN.

Modified body mass index and time interval between diagnosis and operation affect survival after liver transplantation for hereditary amyloidosis: a single-center analysis.

INTRODUCTION: Familial amyloid polyneuropathy (FAP) is the most common subtype of hereditary amyloidosis. The amyloid protein transthyretin deposits as rigid amyloid fibers in the extracellular matrix of various tissues including peripheral nerves, heart, and gastrointestinal tract. As the mutated amyloid protein is mainly produced in the liver, one form of treatment to halt the progression of disease is liver transplantation (LT). This study was performed to identify risk factors for decreased overall survival. METHODS: Clinical data of 21 transplant patients who underwent LT for FAP between 1996 and 2011 were analyzed retrospectively. RESULTS: The majority of patients had cardiac symptoms (76%), gastrointestinal symptoms (71%), or peripheral polyneuropathy (71%). A conventional operating technique was performed on 11 patients using end-to-end caval anastomoses, while the modified piggyback technique by Belghiti was performed on 10 patients. Overall survival analysis revealed a one-yr survival rate of 74.3% and three- and five-yr survival rates of 60.0% and 52.5%, respectively. Pre-operative modified body mass index (mBMI) <700 kg g/L m² and time interval between diagnosis and operation before LT resulted in significantly lower overall survival (p = 0.0137; p = 0.033). CONCLUSION: The pre-operative nutritional status and time interval between diagnosis and operation before LT influence overall survival after LT for hereditary amyloidosis.