Search

Primary sclerosing cholangitis is associated with an increased risk of biliary tract cancer. Carbohydrate antigen 19-9 (CA19-9) can be used to screen for these malignancies.To perform a longitudinal analysis of CA19-9 in patients with primary sclerosing cholangitis.We conducted a retrospective analysis of CA19-9 values in patients who had primary sclerosing cholangitis, with and without biliary malignancy. We calculated the index of individuality and reference change value in patients who were cancer-free. Long-term analysis of CA19-9 in cancer-free patients was performed and we assessed the change of CA19-9 prior to diagnosis of cancer.We obtained 1818 CA19-9 values from 247 patients, including 32 with malignancy. Median CA19-9 in cancer-free individuals was 15.6 U/mL. The index of individuality was 0.37 and the reference change value was 46.23%. In cancer-free patients, no significant change in CA19-9 was observed at 1, 2, 5, 7, 10, 15, and 20 years after initial diagnosis of primary sclerosing cholangitis. In patients with biliary tract cancer, CA19-9 was higher at 3 months prior to diagnosis (P 0.05) than at 6 months before diagnosis and was also higher than at 3 months prior to last follow-up in cancer-free patients (P 0.05). In 92.9% of patients with biliary cancer, we found an increase in CA19-9 of46.23% in the year prior to cancer diagnosis.CA19-9 in patients with primary sclerosing cholangitis is highly individual, and the reference change value should be preferred to reference intervals. In this study, CA19-9 remained stable in patients who were cancer-free but increased early in those who developed biliary tract cancer. Regular CA19-9 measurement might improve early detection of these malignancies.

Background and aims Carriage of rs738409:G in patatin-like phospholipase domain containing 3 (PNPLA3) is associated with an increased risk for developing alcohol-related cirrhosis and hepatocellular carcinoma (HCC). Recently, rs72613567:TA in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) was shown to be associated with a reduced risk for developing alcohol-related liver disease and to attenuate the risk associated with carriage of PNPLA3 rs738409:G. This study explores the risk associations between these two genetic variants and the development of alcohol-related cirrhosis and HCC. Approach and results Variants in HSD17B13 and PNPLA3 were genotyped in 6,171 participants, including 1,031 with alcohol-related cirrhosis and HCC, 1,653 with alcohol-related cirrhosis without HCC, 2,588 alcohol misusers with no liver disease, and 899 healthy controls. Genetic associations with the risks for developing alcohol-related cirrhosis and HCC were determined using logistic regression analysis. Carriage of HSD17B13 rs72613567:TA was associated with a lower risk for developing both cirrhosis (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.72-0.88; P = 8.13 × 10-6 ) and HCC (OR, 0.77; 95% CI, 0.68-0.89; P = 2.27 × 10-4 ), whereas carriage of PNPLA3 rs738409:G was associated with an increased risk for developing cirrhosis (OR, 1.70; 95% CI, 1.54-1.88; P = 1.52 × 10-26 ) and HCC (OR, 1.77; 95% CI, 1.58-1.98; P = 2.31 × 10-23 ). These associations remained significant after adjusting for age, sex, body mass index, type 2 diabetes, and country. Carriage of HSD17B13 rs72613567:TA attenuated the risk for developing cirrhosis associated with PNPLA3 rs738409:G in both men and women, but the protective effect against the subsequent development of HCC was only observed in men (ORallelic , 0.75; 95% CI, 0.64-0.87; P = 1.72 × 10-4 ). Conclusions Carriage of variants in PNPLA3 and HSD17B13 differentially affect the risk for developing advanced alcohol-related liver disease. A genotypic/phenotypic risk score might facilitate earlier diagnosis of HCC in this population.

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.

Summary Background Transjugular intrahepatic portosystemic shunt (TIPSS) cause haemodynamic changes in patients with cirrhosis, yet little is known about long-term cardiopulmonary outcomes. Aim To evaluated 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.

Primary sclerosing cholangitis (PSC) patients are at increased risk of biliary tract cancer, and carcinoembryonic antigen (CEA) serum levels might be used for screening.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.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.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.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.

Urinary copper excretion rates and non-caeruloplasmin associated copper concentrations are increased in patients with Wilson disease. However, there is little literature describing the monitoring of these parameters over the long term. This is a monocentric retrospective study including data collected between 2003 and 2015 from 321 patients with Wilson disease by chart review. The patients were under therapy with D-penicillamine, trientine, or zinc. 24-h urinary copper excretion rates, non-caeruloplasmin associated copper, and total serum copper concentrations were determined at the start of therapy, as well as 6, 12, 18, 24, 36, and ≥ 60 months after the start of therapy. For patients taking chelating agents, all parameters were measured while under continued therapy, as well as after a 48-h dose interruption. A mathematical formula to predict 24-h urinary copper excretion rates under different therapies was established. In all treatment groups, urinary copper excretion rates decreased over time, but the inter-individual variation of the results was high. Non-caeruloplasmin associated copper concentrations tended to decline over time, but with a higher variation of results than that observed for urinary copper excretion rates. Due to their variability, urinary copper excretion rates and serum copper concentrations are less than ideal parameters by which to monitor the benefit of a copper-reducing therapy. Urinary copper excretion rates seem to be more suitable than non-caeruloplasmin associated copper concentrations for this purpose.

SummaryBackground 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

Background and Aims The rs738409 variant (I148M) of the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene is associated with several liver malfunctions. Its impact on end-stage liver disease has not been addressed yet. Methods The I148M polymorphism was genotyped in a well-characterized cohort of 421 Caucasian patients and retrospectively analyzed from the time of enrollment at Eurotransplant. Results The G allele of the I148M variant was significantly overrepresented in patients with alcoholic liver disease (ALD, P

Wilson's disease is an autosomal recessively inherited copper overload disorder that leads to hepatic and/or neurologic symptoms. More than a century after the first description of Wilson's disease, the available medical treatment options have not been standardized. The efficacy of the commonly used drugs is satisfactory for hepatic disease, but disappointing in the neurologic patients, including the risk of neurologic deterioration after the initiation of chelation therapy. An approach to overcome this problem is the careful and systematic assessment of biochemical response patterns and the quantitative monitoring of symptoms using validated rating scales. Standardized dosage strategies that address changes in copper pools might improve adherence and reduce side effects. Such an approach may reduce long-term morbidity. In this paper, we discuss considerations for an effective medical treatment and requirements for future studies in Wilson's disease.

Summary 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

Background Wilson disease (WD) is an autosomal recessive copper storage disease resulting in hepatic and neurologic dysfunction. Liver transplantation is an effective treatment for fulminant cases for patients with chronic liver disease. Reports on the outcome of neuropsychiatric symptoms after orthotopic liver transplantation (OLT) are limited. Aim To assess the course of neuropsychiatric and hepatic symptoms after liver transplantation for Wilson disease Methods Nineteen patients with Wilson disease received liver transplantation and were followed prospectively from 2005 to 2010 for the development of hepatic, neurological and psychiatric symptoms. Results Eight patients (all female) were transplanted for acute liver failure and eleven patients for chronic liver failure. Patient survival rates one and five yr after transplantation were 78% and 65%, respectively. Of the surviving patients, hepatic symptom scores improved in all patients and neurological symptom scores improved in all but one patient after OLT compared to the time of initial diagnosis and compared to pre-OLT status. Psychiatric symptoms showed moderate improvements. Conclusion Survival after OLT for Wilson disease with end-stage liver disease is excellent. Overall, neuropsychiatric symptoms improved after transplantation, substantiating arguments for widening of the indication for liver transplantation in symptomatic neurologic Wilson disease patients with stable liver function.

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

Wilson disease (WD) is an autosomal-recessive copper overload disorder caused by mutations in the copper-transporting adenosine triphosphatase (ATPase) ATP7B. It presents with a highly variable clinical phenotype ranging from asymptomatic to fulminant hepatic failure or progressive neurological involvement. No clear genotype-phenotype correlation has been established. Thus, variants in modifier genes could have an impact on WD manifestation and severity. Recently, the antiapoptotic protein baculoviral IAP repeat-containing protein 4 BIRC4/XIAP has been suggested as a regulator of copper-induced cell death. With the aim of investigating a putative role of BIRC4/XIAP as modifier gene in individuals with copper overload, we analyzed a WD patient cohort (n = 98) for sequence variants at the BIRC4/XIAP locus. When compared with clinical data, the previously described coding single nucleotide polymorphisms (SNPs) at the BRIC4/XIAP locus (rs28382721, rs28382722, rs28382723, rs5956583, rs28382740, rs12838858, rs28382741) did not correlate with age of onset or clinical presentation in our collective. However, three previously unreported variants in the BIRC4/XIAP gene were identified (c.1-26 T > G; c.1408A > T; p.T470S; c.1019A > G; p.N340S). The two patients with variants leading to amino acid exchanges in the BIRC4/XIAP protein showed a remarkably early disease onset at the age of 5 years. Furthermore, one of these patients was only heterozygous for disease-causing mutations in the ATP7B gene. In summary, these data emphasize the need to further elucidate a role of BIRC4/XIAP variants as putative pathogenetic factors in copper overload disorders.

Im ersten Teil dieser Arbeit [1] wurde uber Messungen an einem laminaren Stickstoff-Plasmastrahl berichtet, die zur Bestimmung von Temperatur, Stromungsgeschwindigkeit sowie Warmestromdichte als Funktion des Ortes im Strahl fuhrten. Der zweite Teil befast sich mit der theoretischen Behandlung des Warme-uberganges durch erzwungene Konvektion auf eine umstromte Kugel. Es kann gezeigt werden, das die von Sibulkin [4] angegebene Formel bis zu etwa 4000°K sehr gut mit den Messungen in Einklang steht. Die von Fay [5] unter Berucksichtigung der Dissoziation abgeleitete Formel kann erst ab 5000°K verwendet werden.