Effect of scheduled endoscopic dilatation of dominant strictures on outcome in patients with primary sclerosing cholangitis.

OBJECTIVE: Scheduled endoscopic dilatation of dominant strictures (DS) in primary sclerosing cholangitis (PSC) might improve outcome relative to endoscopic treatment on demand, but evidence is limited. Since randomisation is difficult in clinical practice, we present a large retrospective study comparing scheduled versus on-demand endoscopic retrograde cholangiopancreatography (ERCP) based on patient preferences. DESIGN: Between 1987 and 2017, all new patients with PSC had been offered scheduled ERCP with dilatation of a DS if diagnosed; the latter was repeated at defined intervals until morphological resolution, independent of clinical symptoms (treatment group). Patients who refused participation were clinically evaluated annually and received endoscopic treatment only on demand (control group). The primary clinical endpoint was transplantation-free survival. Secondary outcomes were overall survival, bacterial cholangitis episodes, hepatic decompensation of liver cirrhosis and endoscopy-related adverse events. RESULTS: The final study included 286 patients, 133 (46.5%) receiving scheduled ERCP and 153 (53.5%) receiving on-demand ERCP. After a mean follow-up of 9.9 years, the rate of transplantation-free survival was higher in patients receiving scheduled ERCP (51% vs 29.3%; p<0.001), as was transplantation-free survival time (median: 17.9 vs 15.2 years; log-rank: p=0.008). However, the benefit of scheduled ERCP was significant only in patients with the initial (17.1%) or later (45.5%) diagnosis of a DS (17.8 vs 11.1 years; log-rank: p<0.001). IBD (p=0.03), DS (p=0.006), higher Mayo Risk Score (p=0.02) and non-adherence to scheduled endoscopy (p=0.005) were independently associated with transplantation-free survival. CONCLUSION: In our large retrospective study, regular ERCP with endoscopic balloon dilatation significantly benefits patients with PSC with DS, diagnosed both at initial presentation and during surveillance, even if asymptomatic. Further studies have to find out how to best identify stricture patients non-invasively.

Evaluation of Biliary Calprotectin as a Biomarker in Primary Sclerosing Cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the bile ducts with limited therapeutic options except liver transplantation. Reliable biomarkers to predict the disease course are unavailable, and currently employed disease activity scores such as the Mayo risk score (MRS) have limitations. The present study aims to evaluate biliary calprotectin as a marker of disease activity and prognosis in PSC.This is a monocentric retrospective observational study. Calprotectin concentrations were measured by an enzyme-linked immunosorbent assay in bile samples collected by endoscopic retrograde cholangiography from 106 PSC patients and 20 controls. Biliary calprotectin concentrations were compared between the 2 groups. In PSC patients, results were evaluated with regard to the presence of dominant bile duct stenoses, bile microbiology, MRS, survival free of liver transplantation, and necessity for bile duct interventions in the further disease course.Median (interquartile ranges) biliary calprotectin concentrations were higher in PSC patients than in controls (3646 ng/mL, 249-9748 vs 116 ng/mL, 104-655; P < 0.001). In the PSC cohort, higher biliary calprotectin concentrations were associated with the presence of microbes in bile (P = 0.02), the occurrence of dominant bile duct stenosis at any time in the disease course (P = 0.005), and the necessity for future bile duct interventions (P = 0.02). Patients with biliary calprotectin concentrations above a cut-off of 11,610 ng/mL displayed significantly shorter transplantation-free survival than those with biliary calprotectin concentrations ≤11,610 ng/mL (P < 0.001). Univariate Cox regression analysis revealed high biliary calprotectin concentration (>11,610 ng/mL) as a risk factor of shorter transplantation-free survival of PSC patients (P < 0.001) beside high plasma alkaline phosphatase (ALP) concentration (>142.5 U/L) (P = 0.006), high MRS (≥2) (P < 0.001), and nonsterility of bile (P = 0.03). Multivariate analysis identified only MRS (P = 0.002) and ALP concentration (P = 0.04) as independent risk factors.Our data strongly suggest that biliary calprotectin may be a valuable additional marker for disease activity and a predictor of outcome in PSC, so that further studies for evaluation of calprotectin in this disease are warranted.

Kinetics of primary bile acids in patients after proctocolectomy and ileal pouch-anal anastomosis.

BACKGROUND: The high incidence of cholesterol gallstones in patients after proctocolectomy with ileal pouch-anal anastomosis (IPAA) may be due to an increased loss of bile acids. We aimed to evaluate the kinetics of the primary bile acids cholic acid (CA) and chenodeoxycholic acid (CDCA) in these patients. METHODS: Pool sizes, synthesis rates, and fractional turnover rates of CA and CDCA were determined by combined capillary gas chromatography/isotope ratio mass spectrometry in serum samples after administration of [¹³C]CA and [¹³C]CDCA in 6 patients and 9 healthy volunteers. RESULTS: In patients with IPAA, pool sizes of CA and CDCA were 11.5 (8.2-23.8) and 12.1 (6.7-20.1) µmol/kg, respectively, and were significantly lower than in healthy controls [36.0 (24-47) and 29.0 (21-42) µmol/kg, respectively; p < 0.05, each]. Fractional turnover rates of CA [1.19 (1.06-1.82) vs. 0.31 (0.13-0.54) per day] and CDCA [1.01 (0.50-1.63) vs. 0.23 (0.09-0.36) per day] were increased fourfold in patients with IPAA (p < 0.05, each). Synthesis rates of CDCA [10.2 (5.2-32.9) vs. 6.6 (2.7-10.5) µmol/kg per day, p = 0.05] and CA [15.1 (9.3-39.4) vs. 11.5 (3.1-20.5) µmol/kg per day, n.s.] tended to be higher in patients with IPAA than in controls. CONCLUSION: The reduced pool size of primary bile acids may contribute to the high incidence of cholesterol gallstones in patients after proctocolectomy and IPAA.

Biliary phosphatidylcholine and lysophosphatidylcholine profiles in sclerosing cholangitis.

AIM: To analyze phospholipid profiles in intrahepatic bile from patients with primary sclerosing cholangitis (PSC) and secondary sclerosing cholangitis (SSC). METHODS: Intrahepatic bile specimens collected via endoscopic retrograde cholangiography from 41 patients were analyzed. Fourteen of these patients were diagnosed with PSC, 10 with SSC, 11 with choledocholithiasis or no identifiable biliary disease, and 6 with cholangiocellular carcinoma (CCC). Bile acid, cholesterol, protein, and bilirubin contents as well as pancreas lipase activity in bile were determined by biochemical methods. Phosphatidylcholine (PC) and lysophosphatidylcholine (LPC) species were quantified using nano-electrospray ionization tandem mass spectrometry. RESULTS: Bile from all the examined patient groups showed a remarkably similar PC and LPC species composition, with only minor statistical differences. Total biliary PC concentrations were highest in controls (8030 ± 1843 µmol/L) and lowest in patients with CCC (1969 ± 981 µmol/L) (P = 0.005, controls vs SSC and CCC, respectively, P < 0.05). LPC contents in bile were overall low (4.2% ± 1.8%). Biliary LPC/PC ratios and ratios of biliary PC to bilirubin, PC to cholesterol, PC to protein, and PC to bile acids showed no intergroup differences. CONCLUSION: PC and LPC profiles being similar in patients with or without sclerosing cholangitis, these phospholipids are likely not of major pathogenetic importance in this disease group.

A frequent PNPLA3 variant is a sex specific disease modifier in PSC patients with bile duct stenosis.

BACKGROUND AIMS: Primary sclerosing cholangitis predominantly affects males and is an important indication for liver transplantation. The rs738409 variant (I148M) of the PNPLA3 gene is associated with alcoholic and non-alcoholic liver disease and we evaluated its impact on the disease course of PSC. METHODS: The I148M polymorphism was genotyped in 121 German PSC patients of a long-term prospective cohort and 347 Norwegian PSC patients. RESULTS: In the prospective German cohort, actuarial survival free of liver transplantation was significantly reduced for I148M carriers (p = 0.011) compared to wildtype patients. This effect was restricted to patients with severe disease, as defined by development of dominant stenosis (DS) requiring endoscopic intervention. DS patients showed markedly decreased survival (p = 0.004) when carrying the I148M variant (I148M: mean 13.8 years; 95% confidence interval: 11.6-16.0 vs. wildtype: mean 18.6 years; 95% confidence interval: 16.3-20.9) while there was no impact on survival in patients without a DS (p = 0.87). In line with previous observations of sex specific effects of the I148M polymorphism, the effect on survival was further restricted to male patients (mean survival 11.9 years; 95% confidence interval: 10.0-14.0 in I148M carriers vs. 18.8 years; 95% confidence interval: 16.2-21.5 in wildtype; p<0.001) while female patients were unaffected by the polymorphism (p = 0.65). These sex specific findings were validated in the Norwegian cohort (p = 0.013). CONCLUSIONS: In male PSC patients with severe disease with bile duct stenosis requiring intervention, the common I148M variant of the PNPLA3 gene is a risk factor for reduced survival.

Oblique bile duct predisposes to the recurrence of bile duct stones.

BACKGROUND AND STUDY AIMS: Bile stones represent a highly prevalent condition and abnormalities of the biliary tree predispose to stone recurrence due to development of biliary stasis. In our study, we assessed the importance of an altered bile duct course for stone formation. PATIENTS AND METHODS: 1,307 patients with choledocholithiasis in the absence of any associated hepatobiliary disease who underwent endoscopic retrograde cholangiopancreatography (ERCP) between 2002 and 2009 were analysed. The angle enclosed between the horizontal portion of the common bile duct (CBD) and the horizontal plane was measured (angle α). Oblique common bile duct (OCBD) was defined as a CBD with angle α < 45°. RESULTS: 103 patients (7.9%) were found to harbour OCBD and these were compared to 104 randomly selected control subjects. Compared to controls, OCBD patients were (i) significantly older (72 ± 13 vs. 67 ± 13, p<0.00001); (ii) more frequently underwent a cholecystectomy (p = 0.02) and biliary surgery (p = 0.003) prior to the diagnosis and (iii) more often developed chronic pancreatitis (p = 0.04) as well as biliary fistulae (p = 0.03). Prior to and after ERCP, OCBD subjects displayed significantly elevated cholestatic parameters and angle α negatively correlated with common bile duct diameter (r = -0.29, p = 0.003). OCBD subjects more often required multiple back-to-back ERCP sessions to remove bile stones (p = 0.005) as well as more ERCPs later on due to recurrent stone formation (p<0.05). CONCLUSION: OCBD defines a novel variant of the biliary tree, which is associated with chronic cholestasis, hampers an efficient stone removal and predisposes to recurrence of bile duct stones.

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.

Hepcidin is an antibacterial, stress-inducible peptide of the biliary system.

BACKGROUND/AIMS: Hepcidin (gene name HAMP), an IL-6-inducible acute phase peptide with antimicrobial properties, is the key negative regulator of iron metabolism. Liver is the primary source of HAMP synthesis, but it is also produced by other tissues such as kidney or heart and is found in body fluids such as urine or cerebrospinal fluid. While the role of hepcidin in biliary system is unknown, a recent study demonstrated that conditional gp130-knockout mice display diminished hepcidin levels and increased rate of biliary infections. METHODS: Expression and localization of HAMP in biliary system was analyzed by real time RT-PCR, in-situ hybridization, immunostaining and -blotting, while prohepcidin levels in human bile were determined by ELISA. RESULTS: Hepcidin was detected in mouse/human gallbladder and bile duct epithelia. Biliary HAMP is stress-inducible, in that it is increased in biliary cell lines upon IL-6 stimulation and in gallbladder mucosa of patients with acute cholecystitis. Hepcidin is also present in the bile and elevated prohepcidin levels were observed in bile of primary sclerosing cholangitis (PSC) patients with concurrent bacterial cholangitis compared to PSC subjects without bacterial infection (median values 22.3 vs. 8.9; p = 0.03). In PSC-cholangitis subjects, bile prohepcidin levels positively correlated with C-reactive protein and bilirubin levels (r = 0.48 and r = 0.71, respectively). In vitro, hepcidin enhanced the antimicrobial capacity of human bile (p<0.05). CONCLUSION: Hepcidin is a stress-inducible peptide of the biliary epithelia and a potential marker of biliary stress. In the bile, hepcidin may serve local functions such as protection from bacterial infections.

A novel method of forceps biopsy improves the diagnosis of proximal biliary malignancies.

BACKGROUND AND AIMS: Tissue specimen collection represents a cornerstone in diagnosis of proximal biliary tract malignancies offering great specificity, but only limited sensitivity. To improve the tumor detection rate, we developed a new method of forceps biopsy and compared it prospectively with endoscopic transpapillary brush cytology. PATIENTS AND METHODS: 43 patients with proximal biliary stenoses, which were suspect for malignancy, undergoing endoscopic retrograde cholangiography were prospectively recruited and subjected to both biopsy [using a double-balloon enteroscopy (DBE) forceps under a guidance of a pusher and guiding catheter with guidewire] and transpapillary brush cytology. The cytological/histological findings were compared with the final clinical diagnosis. RESULTS: 35 out of 43 patients had a malignant disease (33 cholangiocarcinomas, 1 hepatocellular carcinoma, 1 gallbladder carcinoma). The sensitivity of cytology and biopsy in these patients was 49 and 69%, respectively. The method with DBE forceps allowed a pinpoint biopsy of the biliary stenoses. Both methods had 100% specificity, and, when combined, 80% of malignant processes were detected. All patients with non-malignant conditions were correctly assigned by both methods. No clinically relevant complications were observed. CONCLUSIONS: The combination of forceps biopsy and transpapillary brush cytology is safe and offers superior detection rates compared to both methods alone, and therefore represents a promising approach in evaluation of proximal biliary tract processes.

Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci.

Primary sclerosing cholangitis (PSC) is a chronic bile duct disease affecting 2.4-7.5% of individuals with inflammatory bowel disease. We performed a genome-wide association analysis of 2,466,182 SNPs in 715 individuals with PSC and 2,962 controls, followed by replication in 1,025 PSC cases and 2,174 controls. We detected non-HLA associations at rs3197999 in MST1 and rs6720394 near BCL2L11 (combined P = 1.1 × 10⁻¹6 and P = 4.1 × 10⁻8, respectively).

Mutational characterization of the bile acid receptor TGR5 in primary sclerosing cholangitis.

BACKGROUND: TGR5, the G protein-coupled bile acid receptor 1 (GPBAR1), has been linked to inflammatory pathways as well as bile homeostasis, and could therefore be involved in primary sclerosing cholangitis (PSC) a chronic inflammatory bile duct disease. We aimed to extensively investigate TGR5 sequence variation in PSC, as well as functionally characterize detected variants. METHODOLOGY/PRINCIPAL FINDINGS: Complete resequencing of TGR5 was performed in 267 PSC patients and 274 healthy controls. Six nonsynonymous mutations were identified in addition to 16 other novel single-nucleotide polymorphisms. To investigate the impact from the nonsynonymous variants on TGR5, we created a receptor model, and introduced mutated TGR5 constructs into human epithelial cell lines. By using confocal microscopy, flow cytometry and a cAMP-sensitive luciferase assay, five of the nonsynonymous mutations (W83R, V178M, A217P, S272G and Q296X) were found to reduce or abolish TGR5 function. Fine-mapping of the previously reported PSC and UC associated locus at chromosome 2q35 in large patient panels revealed an overall association between the TGR5 single-nucleotide polymorphism rs11554825 and PSC (odds ratio = 1.14, 95% confidence interval: 1.03-1.26, p = 0.010) and UC (odds ratio = 1.19, 95% confidence interval 1.11-1.27, p = 8.5 x 10(-7)), but strong linkage disequilibrium precluded demarcation of TGR5 from neighboring genes. CONCLUSIONS/SIGNIFICANCE: Resequencing of TGR5 along with functional investigations of novel variants provided unique insight into an important candidate gene for several inflammatory and metabolic conditions. While significant TGR5 associations were detected in both UC and PSC, further studies are needed to conclusively define the role of TGR5 variation in these diseases.

Endoscopic retrograde cholangiopancreatography in diagnosis and treatment of primary sclerosing cholangitis.

Primary sclerosing cholangitis is characterized by progressive fibrosing obliteration of the biliary tract. In some cases the disease is restricted to the small bile ducts, but most patients develop fibrotic stenoses of the larger bile ducts. Despite advances in magnetic resonance cholangiography, in unclear cases endoscopic retrograde cholangiography is necessary to make the correct diagnosis. In patients with total or subtotal strictures of the large bile ducts, these so-called dominant stenoses may be treated by endoscopic balloon dilatation and/or stent placement, though in the large majority of cases a stent placement is not necessary. Several studies showed an improvement of biochemical parameters after endoscopic treatment, and actuarial survival in these patients was improved compared with predicted survival. Endoscopic retrograde cholangiography allows tissue sampling, brush cytology, and bile analysis for early detection of cholangiocarcinoma, a major complication of primary sclerosing cholangitis. Despite successful endoscopic opening of bile duct stenoses, patients often progress to liver failure, leading to liver transplantation as the treatment of choice.

In PSC with dominant bile duct stenosis, IBD is associated with an increase of carcinomas and reduced survival.

BACKGROUND & AIMS: In patients with primary sclerosing cholangitis (PSC) treated with ursodeoxycholic acid (UDCA), dominant stenoses are associated with reduced survival free of liver transplantation and the role of inflammatory bowel disease (IBD) in such patients is unclear. In the present study the influence of IBD on the outcome in patients with and without dominant stenosis has been evaluated. METHODS: In a prospective study, 171 patients were followed for up to 20 years. All patients were treated with ursodeoxycholic acid; patients with dominant stenosis in addition were treated endoscopically. RESULTS: A total of 97 out of 171 patients had or developed dominant bile duct stenoses and 96 out of 97 were treated endoscopically. In patients with dominant stenosis without IBD, no carcinoma was found whereas all six bile duct and two gallbladder carcinomas and 6/7 colo-rectal carcinomas were found in patients with dominant stenosis with IBD (p=0.012). In patients without dominant stenosis but with IBD, 1 out of 7 had colo-rectal carcinoma. In patients with dominant stenosis without IBD (n=30), actuarial survival free of liver transplantation at 18 years was 77.8% and in those with dominant stenosis and inflammatory bowel disease (n=67) it was 23.0% (p=0.045). In PSC patients without dominant stenosis and without IBD (n=21), actuarial survival free of liver transplantation at 18 years was 68.2% and in those with inflammatory bowel disease (n=53) it was 78.4% (n.s.). CONCLUSIONS: In patients without dominant stenosis, IBD had no effect on the incidence of carcinomas and survival. Only patients with dominant stenosis with additional IBD had an increased carcinoma rate. This may contribute to the reduced survival free of liver transplantation in such patients.

Endoscopic dilation of dominant stenoses in primary sclerosing cholangitis: outcome after long-term treatment.

BACKGROUND: Primary sclerosing cholangitis is characterized by progressive fibrotic inflammation and obliteration of intra- and/or extrahepatic bile ducts. Total or subtotal stenoses of major bile ducts are associated with reduced survival. OBJECTIVE: To evaluate the outcome after long-term endoscopic treatment. DESIGN: Prospective, single-center study. SETTING: Tertiary care academic medical center. PATIENTS: A total of 171 patients treated with ursodeoxycholic acid were followed for as long as 20 years. At entry, 20 patients had dominant stenoses, and during a median follow-up period of 7.1 years, dominant stenosis developed in another 77. INTERVENTIONS: Ninety-six patients with dominant stenoses were treated by repeated balloon dilation; 5 patients with complete obstruction with bacterial cholangitis were stented. MAIN OUTCOME MEASUREMENTS: Survival free of liver transplantation, number of procedures, complications. RESULTS: In total, 500 balloon dilations were performed and 5 stents were placed. Complications were pancreatitis (2.2%), bacterial cholangitis (1.4%), and bile duct perforation (0.2%); there were no deaths. Repeated endoscopic interventions allowed the preservation of a functioning common bile duct and of at least 1 hepatic duct up to 2 cm above the bifurcation in all patients. Progression of intrahepatic bile duct and liver disease led to the need for liver transplantation in 22 of 96 patients. Five years after the first dilation of a dominant stenosis, the survival free of liver transplantation rate was 81%, and after 10 years, it was 52%. LIMITATIONS: Single-center study, no control group, primary end-stage liver disease excluded. CONCLUSION: Repeated endoscopic balloon dilations of dominant stenoses allow the preservation of a functioning common bile duct for many years.

Genome-wide association analysis in primary sclerosing cholangitis.

BACKGROUND & AIMS: We aimed to characterize the genetic susceptibility to primary sclerosing cholangitis (PSC) by means of a genome-wide association analysis of single nucleotide polymorphism (SNP) markers. METHODS: A total of 443,816 SNPs on the Affymetrix SNP Array 5.0 (Affymetrix, Santa Clara, CA) were genotyped in 285 Norwegian PSC patients and 298 healthy controls. Associations detected in this discovery panel were re-examined in independent case-control panels from Scandinavia (137 PSC cases and 368 controls), Belgium/The Netherlands (229 PSC cases and 735 controls), and Germany (400 cases and 1832 controls). RESULTS: The strongest associations were detected near HLA-B at chromosome 6p21 (rs3099844: odds ratio [OR], 4.8; 95% confidence interval [CI], 3.6-6.5; P = 2.6 x 10(-26); and rs2844559: OR, 4.7; 95% CI, 3.5-6.4; P = 4.2 x 10(-26) in the discovery panel). Outside the HLA complex, rs9524260 at chromosome 13q31 showed significant associations in 3 of 4 study panels. Lentiviral silencing of glypican 6, encoded at this locus, led to the up-regulation of proinflammatory markers in a cholangiocyte cell line. Of 15 established ulcerative colitis susceptibility loci, significant replication was obtained at chromosomes 2q35 and 3p21 (rs12612347: OR, 1.26; 95% CI, 1.06-1.50; and rs3197999: OR, 1.22; 95% CI, 1.02-1.47, respectively), with circumstantial evidence supporting the G-protein-coupled bile acid receptor 1 and macrophage-stimulating 1, respectively, as the likely disease genes. CONCLUSIONS: Strong HLA associations and a subset of genes involved in bile homeostasis and other inflammatory conditions constitute key components of the genetic architecture of PSC.

Influence of dominant bile duct stenoses and biliary infections on outcome in primary sclerosing cholangitis.

BACKGROUND/AIMS: In primary sclerosing cholangitis (PSC) dominant stenoses are frequently associated with bacterial, and in part, also fungal infections of the bile ducts. In the present study, the influence of dominant stenoses and of biliary infections on the long-term outcome was studied. METHODS: In a prospective study, 171 patients were followed up for 20 years. All patients were treated with ursodeoxycholic acid. Dominant stenoses were treated endoscopically and during endoscopic procedures, bile was obtained for microbiologic analysis. RESULTS: Of the 171 patients, 97 had or developed major bile duct stenoses and 96/97 were treated endoscopically. In the 55/97 patients with dominant stenosis, bile samples were obtained and of these, 41/55 had bacteria, five had also Candida and 2/55 had only Candida in their bile. Survival free of liver transplantation in patients without dominant stenosis at 18 years was 73.1% and of patients with dominant stenosis was 25.0% (p=0.011). Bacteria in bile had no effect on survival whereas Candida in bile was associated with reduced survival (p=0.025). CONCLUSIONS: In patients with dominant stenosis, survival free of liver transplantation is reduced. Bacteria in bile do not worsen the outcome if dominant stenoses are opened endoscopically and infection is adequately treated with antibiotics. Candida in bile is associated with a poor prognosis and these patients need liver transplantation relatively soon.

A mutation in the canalicular phospholipid transporter gene, ABCB4, is associated with cholestasis, ductopenia, and cirrhosis in adults.

UNLABELLED: Cholestatic liver disease (CLD) is a major cause of progressive liver damage and liver failure. Several forms of biliary cirrhosis are caused by mutations in specific genes. We sought to identify a genetic defect in a family with CLD impossible to assign to a distinct pathogenic entity. Clinical and histopathological characterization of the family members, microarray-based single-nucleotide polymorphism genotyping, and analysis of candidate genes were performed. Among six of 11 siblings severely affected by idiopathic CLD in a family from a population isolate in Transylvania, three died of cirrhosis (aged 5, 7, and 43 years) and three had adult-onset disease with small duct cholangiopathy, including ductopenia. Others were mildly affected and experienced intrahepatic cholestasis of pregnancy, miscarriages, or stillbirth. Pedigree studies revealed distant parental consanguinity. Genome-wide linkage analysis and autozygosity mapping yielded a single maximal lod-score of 3.88 on chromosome 7q21.1-7q22, excluding other genomic loci. Sequencing of ABCB4 at this locus revealed a novel missense mutation c.2362C>T (p.Arg788Trp) which cosegregated with severity of disease. Bile from a mutation homozygote showed a reduced phosphatidylcholine/bile acid ratio, consistent with reduced ABCB4 phosphatidylcholine transport activity. CONCLUSION: We show that a missense mutation in ABCB4 is a cause for ductopenic CLD in adulthood. Allelic status correlated with severity of liver disease ranging from intrahepatic cholestasis of pregnancy through fibrosis to cirrhosis and death in childhood and adulthood. Mutational analysis of ABCB4 should be generally considered in all patients with cholestatic liver disease of unknown etiology regardless of age and onset of disease.

Secondary sclerosing cholangitis after intensive care unit treatment: clues to the histopathological differential diagnosis.

Secondary sclerosing cholangitis (SSC) is a chronic cholestatic disorder caused by mechanical, infectious, toxic, or ischemic factors. A new variant of SSC occurring after long-term treatment in intensive care units (ICU) has been recently described and characterized from the clinical point of view. The aim of this study was the histomorphological characterization of ICU-treatment-related SSC (ICU-SSC) and the definition of histological changes occurring over time based on the morphological findings. Liver biopsies of ten patients affected by ICU-SSC obtained at different time points (1.5 to 57 months) after the initial injury were analyzed. The main morphological alterations included degenerative changes of portal bile ducts, portal edema, inflammation, and fibrosis as well as biliary interface activity and bilirubinostasis. Perivenular necroses and bile infarcts were found in eight and six patients, respectively. Bile duct loss was not observed. No correlation between morphological features of biopsies and liver chemistry tests or outcome could be established. Based on the morphological observation, a possible disease-progression model starting with an initial damage of portal bile ducts (primary insult) with associated portal/periportal changes (inflammation, ductular reaction) and resulting in secondary parenchymal changes is proposed.

The incidence of cholangiocarcinoma in primary sclerosing cholangitis after long-time treatment with ursodeoxycholic acid.

BACKGROUND/AIMS: Cholangiocarcinoma represents a serious complication of primary sclerosing cholangitis. Ursodeoxycholic acid may possibly influence the incidence of cholangiocarcinoma in man. The aim of this study was to evaluate the incidence rate of cholangiocarcinoma in a large group of primary sclerosing cholangitis patients after long-time treatment with ursodeoxycholic acid. PATIENTS AND METHODS: From May 1987 up to May 2005 a total of 150 patients with primary sclerosing cholangitis but without evidence of cholangiocarcinoma at entry were included in the study. All patients were treated with ursodeoxycholic acid and controls were performed in at least yearly intervals. RESULTS: The median treatment time of the 150 patients was 6.4 years. Altogether five patients developed a cholangiocarcinoma during treatment yielding a rate of 3.3%. The patients developed 0.58 cholangiocarcinoma per 100 patient-years in years 0-2.5, 0.59 cholangiocarcinoma in years 2.5-8.5, and no cholangiocarcinoma thereafter up to 18 years after entry into the study. The Kaplan-Meier estimate of cholangiocarcinoma incidence during ursodeoxycholic acid treatment reached a plateau after 8.3 years. SUMMARY AND CONCLUSION: The annual incidence rate of cholangiocarcinoma in primary sclerosing cholangitis treated with ursodeoxycholic acid is lower than expected and decreases with time of treatment.

Treatment of primary sclerosing cholangitis.

Aims of treatment for primary sclerosing cholangitis are as follows: prevention of progression of hepatobiliary disease, reduction of symptoms and consequences of cholestasis (pruritus, osteoporosis), and prevention of complications (colorectal cancer, hepatobiliary cancer). Ursodeoxycholic acid (UDCA) improves biliary secretion and laboratory parameters of cholestasis, but its effects on liver histology and survival are not clear. It reduces the incidence of dysplasias and carcinomas of the colon in patients with colitis and possibly has a beneficial effect on the incidence of bile duct carcinomas. At present, UDCA represents the most promising therapeutic option. Immunosuppressive treatment has not been proven to be effective; it appears to be indicated in the overlap syndrome with autoimmune hepatitis but may be harmful in bacterial cholangitis. Bacterial cholangitis is common in patients with dominant stenoses and requires antibiotic treatment. Endoscopic treatment of dominant stenoses improves cholestasis and prolongs survival in comparison to predicted survival. Pruritus represents a problem in some patients, and cholestyramine represents the first-line treatment. If ineffective, opioid antagonists, rifampin, or ondansetron may be tried. For treatment of osteoporosis and osteopenia, calcium and vitamin D supplementation are recommended, and in selected cases, bisphosphonates may be indicated. In patients with severe cholestasis and coagulation defects, parenteral supplementation of vitamin K may be indicated. During treatment, all patients should be regularly screened for colonic and bile duct carcinomas. Patients with cirrhosis of the liver and its complications are treated accordingly, and in end-stage disease, liver transplantation is indicated.