Course Of Primary Sclerosing Cholangitis Research Articles

Role of PAR1 -506 deletion/insertion polymorphism in primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease characterized by inflammation of the intra- and extrahepatic bile ducts. Pathogenesis of PSC is still enigmatic but is likely to be multifactorial. Recently, we identified an interleukin-6 (IL-6)-dependent signal transducer and activator of transcription 3 (STAT3) activation in CD4+ TH1 and TH17 cells in PSC. The IL-6/STAT3 pathway was shown to be regulated by protease-activated receptor 1 (PAR1) contributing to inflammation. The role of the PAR1 -506 deletion/insertion (Del/Ins) polymorphism in PSC has not yet been investigated. Two hundred eighty four PSC patients (200 patients with inflammatory bowel diseases [IBD] and 84 without IBD) and 309 healthy controls were genotyped for PAR1 rs11267092 (-506 Del/Ins -13bp). Results were correlated with clinical characteristics and transplant-free survival. The frequency of PAR1 -506 Ins allele carriers (Del/Ins and Ins/Ins) was significantly higher in PSC patients (57.0%) compared to healthy controls (39.8%). Furthermore, carriers of PAR1 -506 Ins allele were more likely to have PSC than noncarriers (odds ratio 2.01; 95% confidence interval, 1.45-2.79). Patients with PSC carrying the PAR1 -506 Ins allele showed significantly higher alanine aminotransferase serum levels (p=0.0357) and a trend toward shorter transplant-free survival time compared to noncarriers (8.9±6.6years vs. 10.5±7.1years; p=0.076). Our study shows that PAR1 -506 Ins is significantly more frequent in people with PSC. As PAR1 -506 Ins allele carriers tended to have a shorter transplant-free survival, PAR1 might play a role in the development and course of PSC.

DOP14 Proctocolectomy is associated with improved transplant-free survival in patients with primary sclerosing cholangitis: results from a pooled collaborative international study

Abstract Background It is hypothesized that the gut-liver axis plays a pivotal role in the aetiology of primary sclerosing cholangitis (PSC). Colectomy before liver transplantation is associated with decreased rates of recurrent PSC.1 We previously observed that proctocolectomy with permanent ileostomy is associated with better transplant-free survival in a population-based Dutch cohort.2 The aim of the present study is to confirm the effect of colectomy on PSC disease course in an international context. Methods We conducted a retrospective analysis on the International PSC Registry (IPSCR), comprising patients from Finland, Norway, Sweden, and the Netherlands. Endpoints were defined as liver transplantation (LT) and PSC-related death (excluding colorectal carcinoma) and were censored in the first year after colectomy to allow for a delayed protective effect. Cox proportional hazards regression was performed, with correction for the following known risk factors; sex, age at diagnosis, large or small duct PSC, features of auto-immune hepatitis, and inflammatory bowel disease (IBD) status (i.e. ulcerative colitis, Crohn’s disease or IBD unspecified). IBD status and colectomy status were included as time-dependent exposure variables, the latter stratified for extent and indication for colectomy. Results A total of 2595 patients were included, of which 1341 from the Netherlands, 560 from Finland, 528 from Norway, and 166 from Sweden. Of all patients 1900(73%) were diagnosed with IBD and 346(15%) had undergone a colectomy; 34(9%) hemi-, 91(26%) subtotal, and 172(50%) proctocolectomy with pouch and 65(19%) with ileostomy. During a total follow-up of 28,282 patient years, 848(33%) patients reached the endpoint LT or PSC-related death. Hazard ratio (HR) of reaching LT or PSC-related death was significantly decreased in patients with proctocolectomy (0.70(0.52-0.93)) compared to patients without colectomy with variation per country (Netherlands 0.82(0.56-1.19), Finland 0.52(0.24-1.13), Norway 0.59(0.31-1.03), Sweden 0.28(0.06-1.24)). This effect was less pronounced in case of a hemi- or subtotal colectomy (HR 0.84(059-1.20)). The effect was most pronounced in the proctocolectomy with permanent ileostomy group (HR 0.55(0.30-0.99)). Of the known risk factors only a concurrent IBD diagnosis had no significant effect on transplant-free survival. Conclusion Our extended data confirm that colectomy is associated with a decreased risk of liver transplantation and PSC-related death. An incremental effect was seen with the extent of the colectomy, with the most pronounced effect in the proctocolectomy group with permanent ileostomy. Our data support the putative role of the gut-liver axis in the disease course of PSC.

Elevated Liver Fibrosis Progression in Isolated PSC Patients and Increased Malignancy Risk in a PSC-IBD Cohort: A Retrospective Study.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease often associated with inflammatory bowel disease (IBD), particularly ulcerative colitis (CU), and rarely with Crohn's disease (CD). Various long-term analyses show different rates of cancer and the need for orthotopic liver transplantation (OLT) in patients with isolated PSC and with concomitant IBD, respectively. However, data on the detailed course of PSC with or without IBD are limited. We aimed to analyze the clinical disease course of PSC patients without IBD compared to PSC patients with UC and CD, respectively. A retrospective data analysis of patients with isolated PSC (n = 41) and of patients with concomitant IBD (n = 115) was performed. In detail, PSC disease characteristics including occurrence of dominant stenoses, liver cirrhosis, OLT and malignancy, as well as the temporal course of PSC activity and disease progression, were analyzed. A multivariable Cox regression model and a Fine-Gray competing risk model were further used for the independent risk factor analysis of cirrhosis development and OLT. Patients with isolated PSC were significantly older at first diagnosis than patients with PSC-IBD (39 vs. 28 years, p = 0.02). A detailed analysis of the course of PSC revealed a faster PSC progression after initial diagnosis in isolated PSC patients compared to PSC-IBD including significantly earlier diagnosis of dominant stenoses (29 vs. 74 months, p = 0.021) and faster progression to liver cirrhosis (38 vs. 103 months, p = 0.027). Patients with isolated PSC have a higher risk of developing cirrhosis than patients with PSC-IBD (Gray's test p = 0.03). OLT was more frequently performed in male patients with isolated PSC compared to males with coincident IBD (48% (n = 13) vs. 33% (n = 25), p = 0.003). Colorectal carcinoma was significantly more often diagnosed in patients with PSC-IBD than in isolated PSC (8.7% vs. 0%, p = 0.042). Patients with isolated PSC seem to have a different clinical course of disease than PSC patients with concomitant IBD characterized by a more pro-fibrotic disease course with earlier onset of liver cirrhosis and dominant stenosis but with less malignancy. These data may be interpreted as either a more progressive disease course of isolated PSC or a later diagnosis of the disease at an advanced disease stage. The different clinical courses of PSC and the underlying mechanisms of the gut-liver axis need further attention.

OP10 Proctocolectomy with permanent ileostomy is associated with better transplant-free survival in patients with primary sclerosing cholangitis: a retrospective cohort study

Abstract Background Inflammatory bowel disease (IBD) is the strongest known risk factor for primary sclerosing cholangitis (PSC) and seems associated with a worse prognosis. After liver transplantation, colectomy is associated with decreased rates of recurrent PSC and better graft survival.1 At the same time, the effect of colectomy on the disease course of PSC remains unclear.2 Available evidence depends either on small patient numbers, may be confounded by unobserved risk factors or colectomy was not considered as time-depending covariate. The aim of our study is to estimate the effect of colectomy on the disease course of PSC by taking time dependency and known risk factors into account. Methods We conducted a retrospective cohort study between January 1st 2008 and December 31st 2021 based on the Dutch population-based EpiPSC2 cohort. Transplant-free survival was defined as liver transplantation or PSC-related death (excluding colorectal carcinoma). The effect of colectomy was determined as time depending variable via Cox proportional hazards regression and was corrected for the following known risk factors; sex, age at diagnosis, large or small duct PSC, features of auto-immune hepatitis, time depending IBD status (i.e. no IBD, ulcerative colitis (UC), Crohn’s disease (CD) or IBD Unspecified (IBD-U)), and tertiary centre inclusion. Effect of colectomy was stratified for extent (i.e. hemi-, subtotal, or proctocolectomy with pouch or ileostomy). Indication of colectomy (i.e. active disease, dysplasia and colorectal carcinoma or other) was also considered as predictor variable. Events in the first year after colectomy were censored due to a presumed delayed effect of colectomy on disease course. Results Of the 1341 patients included, 912(68%) were diagnosed with IBD and 187(14%) had undergone a colectomy. During a total follow-up of 14,393 patient years, 370(28%) patients underwent liver transplantation and 318(24%) patients died due to a PSC-related cause. Median transplant-free survival time was 20 years. Hazard ratio (HR) was significantly decreased in patients who had undergone proctocolectomy with ileostomy (HR 0.47(0.24-0.93)) compared to patients without colectomy. This effect was absent in the group with any other type of colectomy (HR 0.90(0.67-1.19)). Indication of colectomy had no apparent effect. Presence of UC, CD or IBD-U was not associated with a worse prognosis compared to absence of IBD (HR 0.99(0.81-1.21), HR 0.85(0.64-1.13), HR 0.75(0.43-1.29)). Conclusion Our data suggest that proctocolectomy with ileostomy confers protection for liver transplantation and PSC-related death. This points towards the putative pathophysiologic role of the colonic microbiota in PSC and may open avenues to a better understanding of the aetiology of PSC.

Bile Duct Colonization With Enterococcus sp. Associates With Disease Progression in Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC) is characterized by chronic inflammation of the biliary mucosa. Bile ducts in PSC are often colonized with bacteria. Although accumulating evidence demonstrates the importance of microbiota for mucosal immunity, little is known about the impact of bile duct colonization with bacteria on the clinical course of PSC. Bile samples were sent to culture during endoscopic retrograde cholangio-pancreatography before the administration of peri-interventional antibiotics. Procedures during overt bacterial cholangitis or with prior antibiotic treatment were excluded. The primary endpoint was defined as a composite clinical endpoint of decompensated cirrhosis and/or liver transplantation or death. A cohort of 189 patients with 591 bile fluid cultures was included. In multivariable Cox regression analysis, the presence of Enterococci (present in 28% of the patients), but not of other bacterial species, conferred risk of disease progression with a hazard ratio of 3.61 (95% confidence interval, 1.6-8.11; P= .002) to reach the composite clinical endpoint. Fungobilia, present in 19.6% of patients, was confirmed to associate with disease progression with a hazard ratio of 3.25 (95% confidence interval, 1.87-5.66; P < .001) to reach the composite clinical endpoint. The novel association of biliary colonization by Enterococci with disease progression underlines the importance of microbiota-mucosal interplay for the pathogenesis of PSC. These results should stimulate further mechanistic studies on the role of microbiota in PSC and highlight potential new therapeutic targets for a disease without effective treatment options.

Primary sclerosing cholangitis - an insidious enemy of the liver - case report

Background and introduction&#x0D; Primary sclerosing cholangitis (PSC) is a chronic liver disease with features of cholestasis as a result of inflammation and damage to the bile ducts, which can eventually lead to liver fibrosis and parenchymal failure at an advanced stage.&#x0D; Case Report&#x0D; A 22-year-old man was admitted urgently to the Department of Gastroenterology for complaints of abdominal pain, weakness and tarry stools. A panel of detailed examinations was performed to establish the diagnosis. An abdominal ultrasound scan showed significant enlargement of the liver and spleen. Gastroscopy revealed variceal columns of II degree in the lower esophagus, which were cauterized. Laboratory tests confirmed anemia, reduced platelet and white blood cell counts, increased activity of ALT, ASP, GTP, ALP and slight elevation of total bilirubin in the blood. Based on the clinical disease manifestation and the results of diagnostic tests, cirrhosis of unknown origin was suspected. Subsequent magnetic resonance cholangiopancreatography (MRCP) revealed the presence of multiple strictures in the intra- and extrahepatic bile ducts and gave rise to the diagnosis of PSC. Pharmacological treatment was administered. Currently, the patient remains under the close care of the Transplant Clinic, where he undergoes regular checks of liver function, and endoscopic variceal ligation (EVL) as required.&#x0D; Discussion with conclusions&#x0D; The case presented here shows that the course of PSC can be insidious and asymptomatic. Despite the absence of clinical symptoms, the disease can lead to the development of advanced cirrhosis even in patients of young age and be diagnosed as late as at the decompensated stage, when the only treatment option remains organ transplantation.

Association of autoimmune hepatobiliary pathology with inflammatory bowel diseases in children

Introduction. Hepatobiliary pathology (HBP) occurs in approximately 30% of patients with inflammatory bowel disease (IBD). However, the features of its course in the pediatric cohort of patients remain insufficiently studied. Purpose: to study the features of the course of autoimmune forms of HBD in children with IBD. Materials and methods. A comprehensive clinical, laboratory and instrumental examination was carried out in 84 children with autoimmune forms of HBP in combination with IBD (HBP+IBD), which made up the main group, and 79 patients with isolated forms of IBD included in the comparison group. Results. The prevalence of autoimmune HBP in IBD children was 10.2%. Primary sclerosing cholangitis (PSC) was diagnosed in 64.3% of cases, which was mainly associated with ulcerative colitis. The incidence of autoimmune hepatitis (AIH) was 8.3%. In the structure of the overlap syndrome, the most frequent combination was AIH+PSC (15.5%). The debut of the disease was manifested by diarrhea, abdominal pain syndrome, cytolysis and cholestasis syndromes, haemicolitis. With HBP+IBD, there was an increase in serum concentrations of alanine (ALT) and aspartate aminotransferases (AST), total protein, γ-glutamyl transferase (GGT), alkaline phosphatase, direct bilirubin and IgG. Approximately with the same frequency in PSC, antibodies to saccharomycetes (ASCA) - 80% and antibodies to the cytoplasm of neutrophils (ANCA) - 75% were detected. In AIH, antinuclear antibodies (ANA) and antibodies to liver and kidney microsomes (anti-LKM1) were detected in 100%. HBP-IBD equally (28.6%) revealed moderate fibrosis and cirrhosis, no fibrosis in 20.6%, moderate fibrosis in 15.9% of cases, mild fibrosis in 6,3%. Cirrhosis of the liver in 55.6% of cases was the outcome of the course of PSC, in 16.7% - AIH, in 27.8% was associated with the course of the overlap syndrome. Conclusion. Various forms of autoimmune HBP occur in 10.2% of cases, are more often associated with UC, are represented by PSC and AIH, occur in males, at the onset signs are clinically presented by diarrhea, abdominal pain syndrome, cytolysis and cholestasis syndromes, and haemicolitis.

P258 Impact of inflammatory bowel diseases on the phenotype and severity of primary sclerosing cholangitis - a systematic review with meta-analysis

Abstract Background Data regarding the impact of co-occurring inflammatory bowel diseases (IBD) on the phenotype and severity of primary sclerosing cholangitis (PSC) are emerging. The purpose of our study was to characterize the phenotype and disease course of PSC in relation to co-occurring IBD. Methods The purpose of our study was to characterize the phenotype and disease course of PSC in relation to co-occurring IBD. The systematic review and meta-analysis were conducted according to Cochrane’s recommendations. PubMed and EMBASE were searched from database inception till January 2020 for studies reporting disease phenotype and severity of PSC in association with co-occurrence of IBD. Meta-analyses were performed using a random-effects model. The quality of the studies was assessed by the Newcastle-Ottawa Scale (NOS). Results The electronic search yielded 12,220 studies which were narrowed down to 132 after screening based on study titles and abstracts. Of these, a full-text review identified 42 eligible studies, including a total of 8,081 and 5,728 patients with PSC and with or without co-occurring IBD, respectively (Figure 1). The mean NOS score was 6.4 ad included 23 (54.8%) and 18 (42.9%) studies of moderate and high methodological quality, respectively. The meta-analysis demonstrated that co-occurrence of IBD was associated with significantly less frequent involvement of the extra-hepatic ducts (risk ratio (RR)=0.50 (95% CI 0.33–0.75), p&amp;lt;0.01, I2=0%) as compared with patients without co-occurring IBD. However, IBD-PSC and PSC without IBD had similar rate of small-duct PSC, histologic stages of PSC, risk of developing cirrhosis, and features of decompensation. Furthermore, in comparison to patients with isolated PSC, co-occurring IBD was associated with an increased overall risk of malignancies (RR=1.53 (95% CI 1.01–2.32), p=0.04, I2=46%), which was ascribed to colorectal cancers (RR=4.77 (95% CI 2.50–9.09), p&amp;lt;0.01, I2=0%) and not cholangiocarcinomas (RR=0.88 (95% CI 0.59–1.31), p=0.54, I2=31%), gallbladder cancers (RR=2.28 (95% CI 0.39–13.21), p=0.36, I2=0%), or hepatocellular carcinomas (RR=4.49 (95% CI 0.57–35.46), p=0.15, I2=0%). Regarding long-term PSC outcomes, having IBD was not associated with the need of liver transplantation (RR=0.84 (95% CI 0.50–1.41), p=0.52, I2=60%) or mortality (RR=0.74 (95% CI 0.37–1.50), p=0.40, I2=37%), but was associated with a longer liver transplantation-free survival (hazard ratio = 0.70 (95% CI 0.60–0.82), p&amp;lt;0.01, I2=5%). Conclusion This systematic review with meta-analysis suggests that IBD is associated with a distinct phenotype and course of PSC, thus emphasizing the importance of a multidisciplinary approach to patients with co-occurring PSC and IBD.

Defining Primary Sclerosing Cholangitis: Results From an International Primary Sclerosing Cholangitis Study Group Consensus Process

Defining Primary Sclerosing Cholangitis: Results From an International Primary Sclerosing Cholangitis Study Group Consensus Process

Dehydroepiandrosterone sulfate indicates decreased sulfation capacity and impaired quality of life in patients with primary sclerosing cholangitis.

Impaired elimination of toxic compounds via inadequate sulfation may contribute to the pathogenesis of primary sclerosing cholangitis (PSC). Dehydroepiandrosterone (DHEA), which is metabolized into its sulfated form (DHEA-S) in the liver, has been linked with health-related quality of life (HRQoL) in various conditions. We aimed to assess the sulfation capacity of the liver in PSC using DHEA-S as a surrogate marker. We assessed serum levels of DHEA-S in 233 patients with PSC and in 201 patients with other liver conditions serving as controls. We also evaluated the effect of low levels of DHEA-S on the course of PSC and HRQoL assessed using the 36-Item Short Form Health Survey (SF-36) and the PBC-40. The proportion of patients with low DHEA-S in the PSC group was 7-fold higher than in the control group (21% vs 3%; P <⁠0.001). Patients with decreased levels of DHEA-S were younger at the time of PSC diagnosis (median age, 23 vs 29 years; P = 0.007) and presented with lower HRQoL scores, particularly regarding the physical domains of the SF-36. Patients with low DHEA-S also complained of more severe fatigue (31 vs 23; P = 0.006) assessed with the PBC-40. Our findings support the role of impaired liver sulfation capacity in the development of PSC. Low levels of DHEA-S are associated with increased fatigue, a devastating symptom significantly affecting HRQoL. Thus, the effects of DHEA administration on chronic fatigue and other measures of HRQoL in patients with PSC warrant further attention.

Curative intent resections for cholangiocarcinoma in primary sclerosing cholangitis (PSC) patients: the Mayo Clinic experience

Presenter: Ron Pery MD | Mayo Clinic, Rochester Background: Primary Sclerosing Cholangitis (PSC) is a chronic cholestatic liver disease of unknown origin. Although the course of PSC is variable, it is frequently progressive and can lead to life threatening complications such as Cholangiocarcinoma which is usually unresectable upon diagnosis and is often the cause of death in PSC patients. Although liver transplantation may offer the ideal treatment in selected non metastatic cases, that option is limited due to organ shortage and may be limited due to tumor type and/or presentation. Traditionally resection has been avoided due to concerns about progressive liver failure postoperatively. the short and long-term outcomes of PSC patients undergoing oncologic resections of the liver or pancreas are not well defined. Herein we describe our experience with 21 cases of PSC patients who underwent curative intent resection surgery for Cholangiocarcinoma. Methods: The Mayo Clinic clinical record was used to identify PSC patients who underwent curative intent resection of the liver or pancreas for Cholangiocarcinoma between 01/2010-12/2020. Clinicopathological characteristics, operative details and outcomes of patients were collected and retrospectively analyzed with specific emphasis on post-operative complications, recurrence and survival patterns. Results: Twenty-one patients with PSC underwent curative intent resection for Cholangiocarcinoma at Mayo clinic between 01/2010 and 12/2020. The mean age of patients was 58±16.7 and none of them had any clinical or biochemical evidence of cirrhosis or portal hypertension. Three patients underwent whipple operation, seven patients had major hepatectomy with bile duct resection and hepaticojejunostomy, six patients had major hepatectomy and five patients had minor hepatectomy defined as 3 segments or fewer. Five patients had major vascular involvement. Seven (29%) patients had severe post-operative complications (Clavien Dindo score ≥3) with no 90-day mortality. On pathology, 13 (62%) patients had nodal positive disease and 7 (33%) patients had positive resection margins. 13 (62%) patients had adjuvant chemotherapy. The cohort’s median overall survival (OS) was 17.2±2.4 months and the median disease-free survival (DFS) was 13.7±0.6 months. Node positive disease was associated with much worse median OS and DFS (14.2±3.3 versus 59.3±39.4 and 7.9±1.2 versus 17.5 months, respectively). Positive resection margins were associated with worse median OS and DFS (11.0±2.5 versus 31.6±10.0 and 6.7 versus 17.5±6.2 months, respectively). Major vascular involvement was associated with worse median OS and DFS (10.3±1.2 versus 17.7±8.0 and 4.1±1.0 versus 17.5±8.4 months, respectively). Conclusion: With the given limitations of a naturally small cohort, PSC patients tend to present with Cholangiocarcinoma at earlier age and are more likely to have nodal diseases at presentation when compared to sporadic historical controls. Nodal disease, positive resection margins and major vascular involvement are related to worse prognosis. The OS and DFS are comparable to sporadic historic controls and PSC patients who had node negative disease had exceptionally high median overall survival. Therefore, when other treatment options such as transplant are not possible, resection can be considered with acceptable risk and complication profiles.

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

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. We determined serum miR-122 levels in a long-term, prospective cohort of 114 PSC patients and a second validation cohort. 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). 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. .

Search for Genetic Modifiers of PSC: Time to Increase the Number of Needles in the Haystack

Primary sclerosing cholangitis (PSC) belongs to the most obscure liver diseases. Patients with progressive PSC require liver transplantation as only therapeutic option. Previously several HLA- and non-HLA-associated PSC risk variants have been discovered, however their involvement in the development of PSC seems to be minor in comparison to environmental determinants. Lately, variant rs853974 at the RSPO3 gene locus has been shown to modulate the course of PSC. Here we briefly discuss the phenotypes related to this polymorphism and propose alternative directions of research that might help to identify new genetic modifiers of PSC progression.

P410 Vedolizumab is safe and effective for IBD, but has no effect on liver biochemistry in patients with concurrent PSC

Background: Blocking of lymphocyte trafficking is a potential mechanism to alter the disease course of primary sclerosing cholangitis (PSC). We studied the effect of the selective α4β7 integrin antibody, vedolizumab, on liver biochemistry and inflammatory bowel disease (IBD) activity in patients with IBD and PSC (IBD-PSC). Methods: We reviewed electronic medical records of adult patients who had an established diagnosis of IBD-PSC from five tertiary centers. We assessed baseline patient and disease characteristics and treatment exposures. The primary outcome was change in serum alkaline phosphatase at weeks 14 and 30. Secondary outcomes included changes in other liver biochemistries, the Mayo Risk Score for PSC and IBD clinical and endoscopic remission. We also performed a safety analysis for the development of adverse events including liver-related complications. Results: We identified 34 patients with IBD-PSC. Nine (26%) had a history of orthotopic liver transplant, 7 were on stable doses of ursodeoxycholic acid (UDCA) and 2 patients commenced UDCA during the study period. Median follow-up was 9 (IQR: 7–16) months; 28 (92%) had at least 6 months of clinical follow-up. Serum alkaline phosphatase activities did not significantly decrease with vedolizumab therapy (median 268 (IQR: 105–551) IU/L at baseline versus 249 (IQR: 183–634) IU/L, p=0.9899 at week 30). Of the 18 patients with an abnormal alkaline phosphatase at baseline (>120IU/L), 11 (61%) had improvement with treatment. In these patients, alkaline phosphatase trended down from 475 IU/L (IQR: 241–757) at baseline to 283 IU/L (IQR: 207–658), p=0.267 at week 30 but none of these normalized (Figure 1). Median alkaline phosphatase changes remained similar when patients exposed to UDCA were excluded. Of the 8 patients (31%) with normal alkaline phosphatase at baseline, 4 (50%) had a subsequent increase to abnormal levels by week 30, from a baseline median of 98 IU/L (IQR: 77–102) to 146 IU/L (IQR: 90–203), p=0.036 at week 30 (Figure 2). No significant changes in other liver biochemistries or the Mayo PSC Risk Score were demonstrated at week 30. 55% of Crohn's disease and 21% of ulcerative colitis patients achieved clinical remission at week 30. Seven patients (21%) ceased vedolizumab therapy; one for a deterioration in liver biochemistry thought to be a drug reaction and six for IBD primary non-response. Two patients developed ascending cholangitis but continued vedolizumab. Conclusions: Vedolizumab therapy in patients with IBD-PSC has little overall effect on liver biochemistry, but is safe and does improve IBD clinical activity. Treatment earlier in the disease course of PSC and assessment of longer-term exposure of lymphocyte trafficking blockade in IBD-PSC remains of interest.

Criteria Used in Clinical Practice to Guide Immunosuppressive Treatment in Patients with Primary Sclerosing Cholangitis.

Background & AimsCurrent guidelines recommend immunosuppressive treatment (IT) in patients with primary sclerosing cholangitis (PSC) and elevated aminotransferase levels more than five times the upper limit of normal and elevated serum IgG-levels above twice the upper limit of normal. Since there is no evidence to support this recommendation, we aimed to assess the criteria that guided clinicians in clinical practice to initiate IT in patients with previously diagnosed PSC.MethodsThis is a retrospective analysis of 196 PSC patients from seven German hepatology centers, of whom 36 patients had received IT solely for their liver disease during the course of PSC. Analyses were carried out using methods for competing risks.ResultsA simplified autoimmune hepatitis (AIH) score >5 (HR of 36, p<0.0001) and a modified histological activity index (mHAI) greater than 3/18 points (HR 3.6, p = 0.0274) were associated with the initiation of IT during the course of PSC. Of note, PSC patients who subsequently received IT differed already at the time of PSC diagnosis from those patients, who did not receive IT during follow-up: they presented with increased levels of IgG (p = 0.004) and more frequently had clinical signs of cirrhosis (p = 0.0002).ConclusionsThis is the first study which investigates the parameters associated with IT in patients with PSC in clinical practice. A simplified AIH score >5 and a mHAI score >3, suggesting concomitant features of AIH, influenced the decision to introduce IT during the course of PSC. In German clinical practice, the cutoffs used to guide IT may be lower than recommended by current guidelines.

Normalization of Serum Alkaline Phosphatase in Primary Sclerosing Cholangitis Associated with Ulcerative Colitis

Primary sclerosing cholangitis (PSC) is commonly associated with ulcerative colitis (UC). PSC progresses independently of UC ultimately resulting in liver failure. There is no established medical treatment to improve the natural course of PSC. Normalization of serum alkaline phosphatase (ALP) in early stage might delay the progress of PSC. A 20-year-old female, had a sudden attack of right hypochondralgia with high fever and abnormal liver function tests without elevation of bilirubin: ALP 478 IU/L, aspartate aminotransferase 360 IU/L, alanine aminotransferase 174 IU/L. Abnormal liver function tests returned to normal after the attacks. Morphological examinations initially indicated then confirmed a diagnosis of PSC. One month after displaying PSC symptoms administration of ursodeoxycholic acid was initiated. Similar attacks of cholangitis were repeated several times over the following two years. Even in the absence of these attacks, she always suffered postprandial hypochondralgia. There was no acute cholangitis in the year prior to the last hospitalization due to abdominal pain and bloody diarrhea. Findings were consistent with UC in the form of entire colitis. Sulfasalazine, metronidazole and semi-vegetarian diet (SVD) were initiated. Metronidazole is routinely used in inflammatory bowel disease (IBD) in our practice with the expectation of elimination of any potentially pathogenic bacteria. SVD was designed for IBD hoping to increase beneficial bacteria. A remission of UC was ascertained during hospitalization. Elevated ALP, in the absence of clinical cholangitis, was decreased to normal after the therapy for UC.

Radiologic course of primary sclerosing cholangitis: Assessment by three-dimensional magnetic resonance cholangiography and predictive features of progression

Magnetic resonance imaging (MRI) with magnetic resonance cholangiography (MRC) has become the radiologic standard of reference for diagnosis of primary sclerosing cholangitis (PSC). However, natural history of radiologic features of PSC is poorly known. In the current study, we aimed at analyzing the course of PSC using three-dimensional (3D) MRC and liver MRI to find predictive radiologic features of progression. PSC patients, followed up in our center, with at least two 3D MRCs performed in at least a 1-year interval, were retrospectively reviewed. We built an interpretation standard model to score precisely bile ducts and liver parenchyma features. The primary endpoint was overall radiologic course, including worsening, improvement, or stabilization. Radiologic features were analyzed by logistic regression. We reviewed 289 MRIs from 64 patients upon a mean radiologic follow-up of 4 years (range, 1-9). Radiologic features worsened in 37 patients (58%) and stabilized in 27 (42%); no patient showed improvement. Multivariate analysis resulted in two MRI progression risk scores, based on the combination of predictive radiologic features (score without gadolinium administration = 1 × dilatation of intrahepatic bile ducts + 2 × dysmorphy + 1 × portal hypertension; score with gadolinium administration = 1 × dysmorphy + 1 × parenchymal enhancement heterogeneity). These scores were associated with radiologic progression, with an area under the curve of 80 and 83% ± 4%. A majority of PSC patients develop radiologic aggravation upon MRI over 4 years. Two simple scores can predict radiologic progression.

A frequent PNPLA3 variant predicts disease course in PSC patients with dominant bile duct strictures

Background and aims: Primary sclerosing cholangitis (PSC) is caused by chronic inflammation of the bile ducts and can progress to end-stage liver disease. 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.

Hepatopancreatobiliary manifestations and complications associated with inflammatory bowel disease

Diseases involving the hepatopancreatobiliary (HPB) system are frequently encountered in patients with inflammatory bowel disease (IBD). Hepatobiliary manifestations constitute some of the most common extraintestinal manifestations of IBD. They appear to occur with similar frequency in patients with Crohn's disease or ulcerative colitis. HPB manifestations may occur in following settings: 1) disease possibly associated with a shared pathogenetic mechanism with IBD including primary sclerosing cholangitis (PSC), small-duct PSC/pericholangitis and PSC/autoimmune hepatitis overlap, acute and chronic pancreatitis related to IBD; 2) diseases which parallel structural and physiological changes seen with IBD, including cholelithiasis, portal vein thrombosis, and hepatic abscess; and 3) diseases related to adverse effects associated with treatment of IBD, including drug-induced hepatitis, pancreatitis (purine-based agents), or liver cirrhosis (methotrexate), and reactivation of hepatitis B, and biologic agent-associated hepatosplenic lymphoma. Less common HPB manifestations that have been described in association with IBD include autoimmune pancreatitis (AIP), IgG4-associated cholangitis (IAC), primary biliary cirrhosis (PBC), fatty liver, granulomatous hepatitis, and amyloidosis. PSC is the most significant hepatobiliary manifestation associated with IBD and poses substantial challenges in management requiring a multidisciplinary approach. The natural disease course of PSC may progress to cirrhosis and ultimately require liver transplantation in spite of total proctocolectomy with ileal-pouch anal anastomosis. The association between AIP, IAC, and elevated serum IgG4 in patients with PSC is intriguing. The recently reported association between IAC and IBD may open the door to investigate these complex disorders. Further studies are warranted to help understand the pathogenesis of HPB manifestations associated with IBD, which would help clinicians better manage these patients. An interdisciplinary approach, involving gastroenterologists, hepatologists, and, in advanced cases, general, colorectal, and transplant surgeons is advocated.

The urgent need for evaluating recurrent primary sclerosing cholangitis in living donor liver transplantation

In an earlier issue this year, Alabraba and colleagues1 evaluated the risk factors for recurring primary sclerosing cholangitis (PSC); we read with great interest their article entitled “A Re-Evaluation of the Risk Factors for the Recurrence of Primary Sclerosing Cholangitis in Liver Allografts.” Analyzing prospectively collected data for 230 consecutive deceased donor liver transplantation (DDLT) procedures for PSC over a 20-year period with an 83-month follow-up, the authors reported that 54 (24%) of the DDLT recipients presented with recurrent PSC at a median of 4.6 years after transplantation. An analysis of the risk factors indicated that colectomy offered a protective effect against PSC recurrence, whereas the use of grafts recovered under extended donor criteria (EDC) was associated with a higher rate of recurrence. Indeed, although liver transplantation has become an accepted treatment for PSC with liver failure with excellent overall survival, recurrent disease continues to be a threat with a higher rate of retransplantation.2 Identification of the factors affecting recurrence is therefore important. In this context, we were disappointed that some of the recently reported disturbing aspects of living donor liver transplantation (LDLT) are not discussed in the article.1 In contrast to Western countries, liver transplantation from a living donor remains the most realistic option in the Far East. Following the successful results with DDLT reported from the West, LDLT has been applied for PSC with liver failure in Japan. One concern in applying LDLT for PSC has been the unknown effect of a shared genetic disposition in a blood-related recipient and donor pair, which may affect the recurrence of PSC and hence graft survival over the long term. Until recently, however, only sporadic case reports have been published with short follow-up periods, and little information on this aspect has been available. To fill the void, we conducted a retrospective study on the clinical course of PSC after LDLT at our institution. The results of our analysis indicated that PSC not only recurred as in the DDLT series but also recurred at a much higher rate.3 When the analysis was restricted to cases with biologically related live donors, recurrent PSC occurred in 50% of the recipients with a mean time to diagnosis from LDLT of 3.3 years. An observation supporting this finding was reported by another high-volume center.4 Among the 22 patients who survived for more than a year in the series, 13 (59%) presented with PSC recurrence with a mean follow-up period of 2.6 years, 5 of whom died or required retransplantation for graft failure. These preliminary reports have raised considerable concerns, and currently, a nationwide survey, supported by the Ministry of Health, Labor, and Welfare, is ongoing in Japan. The first study by the authors analyzing the risk factors for recurrent PSC in the allograft was published in 2002,5 and since then, LDLT has evolved and spread worldwide, becoming a realistic option in the West and in the East because of the universal organ shortage. Findings regarding the mid-term to long-term outcomes of LDLT for PSC from European or North American series, however, have not been reported despite the rapid accumulation of adult-to-adult LDLT cases. In their analysis, Alabraba and colleagues1 reported that the use of EDC grafts resulted in a 5-fold increase of recurrent PSC, with a 5-year recurrence-free survival of 71% versus 91% for non-EDC grafts. Preliminary studies in LDLT, however, have suggested a further significant impact when a graft donated by a blood-related living donor is used for PSC. In this era of severe graft shortage, the interpretation of these outcomes requires caution, but the implications are nonetheless alarming. Further validation is urgently needed. Currently, however, PSC accounts for less than 3% of all LDLT procedures performed in Japan because of its rarity in comparison with the higher prevalence in Nordic countries and the United States. Studies focusing on the outcomes of LDLT for PSC in a Western series are greatly anticipated. Sumihito Tamura*, Yasuhiko Sugawara*, Noriyo Yamashiki*, Junichi Kaneko*, Norihiro Kokudo*, * Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo Tokyo, Japan.