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Abstract

Management of primary or secondary sclerosing cholangitis is challenging. These Clinical Practice Guidelines have been developed to provide practical guidance on debated topics including diagnostic methods, prognostic assessment, early detection of complications, optimal care pathways and therapeutic (pharmacological, endoscopic or surgical) options both in adults and children.

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... Several practice guidelines have been published on the management of adult PSC, [6][7][8] but currently, there is no standardized guidance for the management of patients with childhood-onset IBD and PSC. To address this, the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) governing board commissioned a core group of experts from the Hepatology Committee and the Paediatric IBD Porto group to provide a position article. ...
... In adults, it is recommended to evaluate a diagnosis of PSC when serum markers of cholestasis, including alkaline phosphatase, GGT and/or bilirubin, are elevated. 8 Due to its variation with age because of increased bone turnover and growth, alkaline phosphatase is not a reliable marker of biliary injury in children, hence should not be included in diagnostic testing. 12 T A B L E 1 GRADE certainty ratings. ...
... 21 Antinuclear cytoplasmatic antibody (ANCA) positivity is common in colonic IBD and therefore not useful when screening for AIH. 8 Remission of AIH is considered complete when transaminases and IgG levels are normal, and when autoantibodies are negative or low-titer (i.e., <1:20 for ANA and SMA and <1:10 for anti-LKM1 and anti-LC1). 22 ...
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Objective We aimed to provide an evidence‐supported approach to diagnose, monitor, and treat children with inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC). Methods The core group formulated seven PICO‐structured clinical questions. A systematic literature search from inception to December 2022 was conducted by a medical librarian using MEDLINE and EMBASE. Core messages from the literature were phrased as position statements and then circulated to a sounding board composed of international experts in pediatric gastroenterology and hepatology, histopathology, adult gastroenterology and hepatology, radiology, and surgery. Statements reaching at least 80% agreement were considered as final. The other statements were refined and then subjected to a second online vote or rejection. Results Regular screening for gamma‐glutamyltransferase (GGT) is essential for detecting possible biliary disease in children with IBD. MR cholangiopancreatography is the radiological modality of choice for establishing the diagnosis of PSC. Liver biopsy is relevant in the evaluation of small duct PSC or autoimmune hepatitis. Children who do not have known IBD at the time of PSC diagnosis should undergo initial screening with fecal calprotectin for asymptomatic colitis, and then at least once yearly thereafter. Children with a cholestatic liver enzyme profile can be considered for treatment with ursodeoxycholic acid and can continue if there is a meaningful reduction or normalization in GGT. Oral vancomycin may have a beneficial effect on GGT and intestinal inflammation, but judicious use is recommended due to the lack of long‐term studies. Children with PSC–IBD combined with convincing features of autoimmune hepatitis may benefit from corticosteroids and antimetabolites. Conclusions We present state‐of‐the‐art guidance on the diagnostic criteria, follow‐up strategies, and therapeutic strategies and point out research gaps in children and adolescents with PSC–IBD.
... In the following section, we will discuss the drugs suggested by the different guidelines based on their pharmacological category. Figure 3 shows all treatments proposed by EASL and AASLD for cholestatic pruritus [3,6,8,9]. The first step generally involves the use of bile acid sequestrants, followed by the use of rifampicin, opioid antagonists, and serotonin reuptake inhibitors up to the removal of catabolites through the use of physical approaches and liver transplantation. ...
... Following the EASL 2017 guidelines, the second-line treatment is rifampicin [3]. Rifampicin is also recommended during the third trimester in women with ICP, as it has been proven to be effective and safe, and in general, it is safe throughout pregnancy [6,67]. A multicenter, randomized, open-label, controlled study is currently ongoing to evaluate whether rifampicin is superior to UDCA in reducing pruritus in ICP [68]. ...
... A multicenter, randomized, open-label, controlled study is currently ongoing to evaluate whether rifampicin is superior to UDCA in reducing pruritus in ICP [68]. The EASL and AASLD guidelines for sclerosing cholangitis strongly recommend the use of rifampicin in cases of moderate or severe pruritus [6,8]. The exact mechanism by which rifampicin reduces pruritus is not yet fully understood, but it has been suspected that the activation of PXR may induce a reduction in ATX transcription [46]. ...
Article
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Cholestasis is a clinical and laboratory syndrome indicating impaired bile production or excretion. One of the hallmark symptoms of cholestasis is pruritus. Itch can be severe and debilitating for patients, impacting their quality of life similarly to pain, and, in some cases, it can be refractory. Current therapies like anion exchange resins and rifampicin, offer partial relief but with side effects. Effective, well-tolerated treatments are urgently needed. This literature review examines existing options (bile acid sequestrants, antihistamines, opioid antagonists, sertraline, and rifampicin) and explores novel therapies (monoclonal antibodies, PPAR agonists, and bile-acid-based therapies). We analyze mechanisms, limitations, and adverse effects to aid clinicians and researchers. Novel approaches include monoclonal antibodies to inhibit bile recirculation and PPAR agonists targeting pruritus signaling. Despite the limited current options, ongoing research promises better treatments for cholestatic pruritus, addressing its distressing impact. In summary, cholestasis-associated pruritus poses a significant challenge with limited treatments. Advancements in understanding its pathophysiology offer hope for more effective therapies in the future.
... PSC is a condition characterized by the inflammation and fibrosis of the bile ducts that could culminate in end-stage liver disease [45]. The pooled prevalence in IBD is 5.01%, and it is more frequently associated with UC, 2.47%, than CD, 0.96% (OR 1.69, 95% CI 1.24-2.29) ...
... Although PSC could be suspected based on elevated cholestatic liver enzymes, magnetic resonance cholangiopancreatography (MRCP) is the method of choice for the diagnosis [48]. Liver biopsy should be reserved for cases in which AIH overlap or small ducts PSC (negative MRCP) are suspected [45]. Importantly, patients with PSC and IBD should undergo yearly colonoscopy due to the 7-fold increased risk of developing colorectal cancer associated with PSC [49]. ...
... Ursodeoxycholic acid at the dose of 15-20 mg/kg/day can improve liver biochemistry, but it does not improve symptoms, the risk of cholangiocarcinoma, or mortality [116]. Liver transplantation should be considered for patients with advanced cirrhosis, recurrent cholangitis (when the palliative treatment of bile duct stenosis with endoscopic retrograde cholangiopancreatography has failed), and suspected early-stage biliary neoplasia [45]. Almost 50% of patients with PSC will require a liver transplant 15-20 years after diagnosis [117], and the overall survival rate after liver transplantation is excellent, with a 91% survival rate at 1-5 years post-transplant [118]. ...
Article
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The inflammatory bowel diseases (IBDs) are systemic conditions that affect not only the gastrointestinal tract but also other parts of the body. The presence of extraintestinal manifestations can significantly impact the quality of life in IBD patients. Peripheral arthritis, episcleritis, and erythema nodosum are frequently associated with active intestinal inflammation and often improve with standard treatment targeting intestinal inflammation. In contrast, anterior uveitis, ankylosing spondylitis, and primary sclerosing cholangitis typically occur independently of disease flares. The incidence of these conditions in individuals with IBD can reach up to 50% of patients over the course of their lifetime. In addition, some advanced therapies utilized for the treatment of IBD potentially result in side effects that may resemble extraintestinal manifestations. This review provides a thorough analysis of the pathophysiology and treatment of extraintestinal manifestations associated with Crohn’s disease and ulcerative colitis.
... Primary sclerosing cholangitis (PSC) is a chronic inflammatory cholangiopathy defined by irreversible damage to the intra and extrahepatic biliary tree and often associated with inflammatory bowel disease (IBD) [1]. The disease evolves with fibrosis of the bile ducts, leading to cholestasis, bile duct strictures, and hepatic fibrosis with progress towards cirrhosis, increased risk of cholangiocarcinoma, and colorectal cancer [2][3][4][5]. The evolution of the disease is characterized by an essential variability with an overall survival without liver transplant ranging from 13-22 years [5,6]. ...
... Another aspect that can influence long-term evolution is the association with other autoimmune diseases, such as autoimmune hepatitis or inflammatory bowel diseases, which must be clarified when a PSC diagnosis is established [4]. ...
... Patients diagnosed with primary sclerosing cholangitis (PSC), as determined through magnetic resonance imaging (MRI) assessments, with or without histopathological confirmation via liver biopsy, and corroborated by clinical and paraclinical evaluations, were recruited for this study. The diagnosis was established on typical findings on high-quality MRCP images or liver biopsy after excluding the causes of secondary sclerosing cholangitis and other causes of chronic cholestasis, including Primary Biliary Cholangitis (PBC), based on available guidelines [3,4]. IgG4 status was evaluated only in patients with clinical suspicion of IgG4-related disease. ...
Article
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Background: Primary sclerosing cholangitis (PSC) is an immune-mediated disease that has an unfavorable prognosis and needs a liver transplant (LT). The aim of this paper was to show the usefulness of the Majoie classification on magnetic resonance cholangiopancreatography (MRCP) images in assessing the prognosis in adult patients with PSC. Methods: Our work presents a retrospective monocentric study performed on 64 adult patients with PSC of the large bile ducts. Two radiologists evaluated the MRCP of diagnosis and calculated MRCP scores using the Majoie classification. Liver-related outcome (LT or liver-related death) was marked as a primary endpoint. Results: Univariate analysis showed that patients with more severe lesions (sum score of intrahepatic and extrahepatic ducts > 3) had a lower age at diagnosis, of 37.2 years, complicated with liver cirrhosis (53.1% of patients) and recurrent cholangitis (28.1%) p < 0.05, without significant differences in mortality, association with IBD or LT. Concordance analysis between MRCP prognostic scores and progression to a PSC-related event showed a moderate relationship (c-statistic 0.662), and a good AUROC was observed for the UKPSC score (0.893) and the MRS (0.936). Conclusions: In the study, we observed a good correlation between the imaging scores based on the Majoie classification and the evolution of the patients. These scores were outperformed by the UKPSC, MRS, and PREsTo clinical models. Their utility was best in predicting recurrent cholangitis.
... 3,4 PBC and PSC are autoimmune liver diseases affecting bile ducts, leading to cholestasis and ongoing liver damage. 5,6 Common symptoms include fatigue, pruritus, and abdominal pain. [7][8][9] While both conditions can lead to inflammation, fibrosis, and cirrhosis, PBC involves progressive destruction of the small intrahepatic bile ducts, 2,10,11 whereas PSC can also affect the larger extrahepatic bile duct. ...
... 8 Liver transplantation becomes necessary when conventional pharmacological treatments are unable to adequately maintain liver function in both PBC and PSC. 6,24 While transplantation offers long-term survival, acquiring a suitable donor organ can be challenging. Moreover, the potential for disease recurrence posttransplantation, especially in patients with primary sclerosing cholangitis (PSC) and concurrent inflammatory bowel disease, remains a concern. ...
Article
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Cholestatic liver diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), lead to inflammation and severe hepatic damage with limited therapeutic options. This study assessed the efficacy of the inverse RORγt agonist, GSK805, both in vitro using the hepatic stellate cell‐line LX‐2 and in vivo using male bile duct‐ligated BALB/c mice. In vitro, 0.3 μM GSK805 reduced alpha‐smooth muscle actin expression in LX‐2 cells. In vivo, GSK805 significantly decreased IL‐23R, TNF‐α, and IFN‐γ expression in cholestatic liver. Despite high concentrations of GSK805 in the liver, no significant reduction in fibrosis was noticed. GSK805 significantly increased aspartate aminotransferase and alanine aminotransferase activity in the blood, while levels of glutamate dehydrogenase, alkaline phosphatase, and bilirubin were not substantially increased. Importantly, GSK805 did neither increase an animal distress score nor substantially reduce body weight, burrowing activity, or nesting behavior. These results suggest that a high liver concentration of GSK805 is achieved by daily oral administration and that this drug modulates inflammation in cholestatic mice without impairing animal well‐being.
... Consensus guidelines recommend using multiple surrogate biomarkers-circulating, imaging, and histologicfor prognostic purposes in both clinical care and trial development. [7,8] In pediatric PSC, normalization of GGT levels over the first year of diagnosis was shown to be associated with less adverse liver-related outcomes. [9] However, similarly to ALP in adult PSC, it is possible that GGT fluctuates over the course of the disease. ...
Article
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Background Children with autoimmune liver disease (AILD) may develop fibrosis-related complications necessitating a liver transplant. We hypothesize that tissue-based analysis of liver fibrosis by second harmonic generation (SHG) microscopy with artificial intelligence analysis can yield prognostic biomarkers in AILD. Methods Patients from single-center studies with unstained slides from clinically obtained liver biopsies at AILD diagnosis were identified. Baseline demographics and liver biochemistries at diagnosis and 1 year were collected. Clinical endpoints studied included the presence of varices, variceal bleeding, ascites, HE, and liver transplant. In collaboration with HistoIndex, unstained slides underwent SHG/artificial intelligence analysis to map fibrosis according to 10 quantitative fibrosis parameters based on tissue location, including total, periportal, perisinusoidal, and pericentral area and length of strings. Results Sixty-three patients with AIH (51%), primary sclerosing cholangitis (30%), or autoimmune sclerosing cholangitis (19%) at a median of 14 years old (range: 3–24) were included. An unsupervised analysis of quantitative fibrosis parameters representing total and portal fibrosis identified a patient cluster with more primary sclerosing cholangitis/autoimmune sclerosing cholangitis. This group had more fibrosis at diagnosis by METAVIR classification of histopathological review of biopsies (2.5 vs. 2; p = 0.006). This quantitative fibrosis pattern also predicted abnormal 12-month ALT with an OR of 3.6 (1.3–10, p = 0.014), liver complications with an HR of 3.2 (1.3–7.9, p = 0.01), and liver transplantation with an HR of 20.1 (3–135.7, p = 0.002). Conclusions The application of SHG/artificial intelligence algorithms in pediatric-onset AILD provides improved insight into liver histopathology through fibrosis mapping. SHG allows objective identification of patients with biliary tract involvement, which may be associated with a higher risk for refractory disease.
... The incidence in children can reach 18%, with a 5-year survival rate of only 25% (4, 5). LCH-associated SC, like other primary and secondary forms of SC, is characterized by the elevation of cholestasis-associated liver enzymes, and the appearance on MRCP of multifocal stenosis and dilation of the intrahepatic and extrahepatic biliary tree (6). A definitive diagnosis requires positive immunohistochemical staining for CD1a, CD207, and S100. ...
Article
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Background Langerhans cell histiocytosis (LCH) is a systemic neoplasia with diverse clinical manifestations, predominantly affecting bone and skin. However, in children, LCH presenting primarily with cholestasis is rare. Case summary We present the case of a 22-month-old boy who was admitted to our hospital with a history of intermittent fever and abdominal distension for over 2 months, and jaundice for over 1 month. Prior to admission, the child had been managed with anti-infective and anti-inflammatory drugs and supportive care at multiple hospitals without significant improvement. He was then referred to our facility for further treatment. Upon admission, a series of laboratory tests, imaging studies, and pathological examinations were conducted, revealing the presence of diabetes insipidus, sclerosing cholangitis (SC), and liver cirrhosis. These findings led to a clinical diagnosis of LCH. Given the absence of definitive pathological evidence, his progression to decompensated liver cirrhosis and his pronounced growth retardation, the child was deemed a candidate for living donor liver transplantation. Following the liver transplant, pathological examination of the explanted liver tissue confirmed the clinical diagnosis of LCH. The child received postoperative chemotherapy, which resolved his systemic symptoms and normalized liver function. There was no evidence of LCH recurrence. The symptoms of diabetes insipidus were controlled with desmopressin acetate, however, the existing destructive lesions in the pituitary gland persisted. Conclusion Sclerosing cholangitis is a late and severe form of liver involvement in LCH that may be accompanied by lesions in other tissues or organs. Along with pathological evidence, a diagnosis should be made based on characteristic rashes, osteolytic lesions, and thickening of the pituitary stalk. In children with LCH complicated by SC for whom pathological diagnostic evidence cannot be obtained, liver transplantation may be considered once signs of decompensated liver cirrhosis appear, followed by systemic chemotherapy to control active disease. This strategy represents a therapeutic approach with the potential to achieve a better prognosis in children with LCH.
... Our study was aimed to analyze how qualitative (morphologic and functional) and quantitative (ADC and RE) 3 T MRI evaluations correlate with the biomarkers of disease activity and fibrosis used by the hepatologists for clinical characterization of PSC patients [38]. ...
Article
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Purpose To analyze the role of qualitative and quantitative 3 T MR imaging assessment as a non-invasive method for the evaluation of disease severity in patients with primary sclerosing cholangitis (PSC). Methods A series of 26 patients, with histological diagnosis of PSC undergoing 3 T MRI and hepatological evaluation, was retrospectively enrolled. All MR examinations included diffusion-weighted imaging (DWI), T2-weighted (T2w) and T1-weighted (T1w) sequences, before and after administration of Gd-EOB-DTPA with the acquisition of both dynamic and hepato-biliary phase (HBP). Qualitative analysis was performed by assessment of liver parenchyma and biliary tract changes, also including biliary excretion of gadoxetic acid on HBP. Quantitative evaluation was conducted on liver parenchyma by measurement of apparent diffusion coefficient (ADC) and relative enhancement (RE) on 3-minute delayed phase and on HBP. Results of blood tests (ALT, ALP, GGT, total and direct bilirubin, albumin, and platelets) and transient elastography-derived liver stiffness measurements (TE-LSM) were collected and correlated with qualitative and quantitative MRI findings. Results Among qualitative and quantitative findings, fibrosis visual assessment and RE had the best performance in estimating disease severity, showing a statistically significant correlation with both biomarkers of cholestasis and TE-LSM. Statistical analysis also revealed a significant correlation of gadoxetic acid biliary excretion with ALT and direct bilirubin, as well as of ADC with total bilirubin. Conclusion Qualitative and quantitative 3 T MR evaluation is a promising non-invasive method for the assessment of disease severity in patients with PSC.
... Diagnosis of PSC is established by the typical morphology of the biliary tree in cholangiography, laboratory parameters of cholestasis, compatible histological findings, and the absence of secondary causes. 3,19 The etiopathogenesis of PSC remains elusive. Autoantibodies are typically used in the definition of immune-mediated liver diseases, 20 but autoantibodies that discriminate PSC from other chronic liver diseases are currently lacking in clinical practice. ...
Article
Background Recently, autoantibodies directed against the epithelial adhesion protein integrin αVβ6 have been identified that are strongly associated with ulcerative colitis (UC). We aimed to elucidate whether anti-integrin αVβ6 (anti-αVβ6) is present in primary sclerosing cholangitis (PSC), its associated inflammatory bowel disease, or other cholestatic liver diseases and their persistence after proctocolectomy. Methods We detected anti-αVβ6 by an enzyme-linked immunosorbent assay in sera collected at 2 German tertiary centers, including healthy controls (N = 62), UC (N = 36), Crohn’s disease (CD, N = 65), PSC-inflammatory bowel diseases (IBD) (78 samples from N = 41 patients), PSC without IBD (PSC, 41 samples from N = 18 patients), primary biliary cholangitis (PBC, N = 24), autoimmune hepatitis (AIH, N = 32), secondary sclerosing cholangitis (SSC, N = 12), and metabolic dysfunction-associated steatotic liver disease (MASLD, N = 24). In addition, sera after proctocolectomy were studied (44 samples/N = 10 patients). Immunofluorescent analyses were performed in tissue samples from liver, large bile duct from surgical resections, and colon of PSC patients. Results Anti-αVβ6 occurred in 91% of UC, 17% of CD, 73% of PSC-IBD, 39% of PSC, 4% of PBC, 14% of AIH, and 0% of healthy controls, SSC, or MASLD. Integrin αVβ6 is selectively expressed in disease-associated epithelia of both bile duct and colon. Anti-αVβ6 levels correlate moderately with intestinal disease activity in PSC-IBD, but only weakly with biliary disease. Conclusions Anti-αVβ6 frequently occurs in patients suffering from PSC, especially in PSC-IBD. Anti-αVβ6 levels positively correlate to IBD activity in PSC-IBD, but may also occur in the absence of clinically manifest IBD in PSC.
... The development of CRC is contingent upon two principal events occurring in sequence: firstly, a driver event, which involves the accumulation of genetic or epigenetic mutations that result in replicative and survival advantages. Secondly, tumor promotion must occur, which entails the clonal expansion of altered cells leading to the formation of a frank tumor [19]. ...
Article
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Simple Summary Hereditary colorectal cancer syndromes (HCCS) and inflammatory bowel disease (IBD) carry a high risk of developing colorectal cancer (CRC). The co-occurrence of IBD and HCCS is extremely rare. Individuals with HCCS and IBD are prone to developing CRC at a younger age compared to those without IBD, with patients who have ulcerative colitis at such an especially high risk. The interplay between chronic inflammation and genetic predispositions remains poorly understood. Abstract Background and aims: Hereditary colorectal cancer syndromes (HCCS), including familial adenomatous polyposis (FAP) and Lynch syndrome (LS), are the two most important high-risk conditions for colorectal cancer (CRC). Inflammatory bowel disease (IBD) increases the risk by two to six times compared with that in the general population. The intersection of these two conditions has rarely been documented in literature. We aimed to summarize the prevalence, pathogenesis, and current evidence-based management of IBD and HCCS and the underlying molecular mechanisms of accelerated carcinogenesis due to combined inflammation and genetic predisposition. Methods: PubMed and Scopus were searched until June 2024 to identify relevant studies investigating the epidemiology, pathogenesis, and management of IBD and coexisting hereditary CRC syndromes. Results: Co-occurrence of IBD and hereditary CRC syndromes is exceptionally uncommon. Individuals with LS and IBD tend to develop CRC at a younger age than those without IBD, with patients with ulcerative colitis facing particularly elevated risks. The interaction between mismatch deficiency and chronic inflammation requires further investigation.
... An exception to this has been described in only one conference abstract, but in which the patients had preexisting liver diseases [23]. To diagnose SSC-CIP, it is essential to ensure that the patient has no history of biliary liver disease and that there is no known pathological process or injury responsible for blocking the bile duct [24]. The hepatocytes get blood from hepatic arteries and portal vein, while branches of gastroduodenal and hepatic arteries vascularize the common bile duct. ...
Article
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Cholangiopathy has been described in survivors of severe COVID-19, presenting significant clinical parallels to the pre-pandemic condition of secondary sclerosing cholangitis in critically ill patients (SSC-CIP). We aimed to examine the liver histopathology of individuals with persistent cholestasis after severe COVID-19. Methods: We subjected post-COVID-19 cholestasis liver samples to routine staining techniques and cytokeratin 7 immunostaining and semi-quantitatively analyzed the portal and parenchymal changes. Results: All ten patients, five men, had a median age of 56, an interquartile range (IQR) of 51–60, and required intensive care unit and mechanical ventilation. The median and IQR liver enzyme concentrations proximal to biopsy were in IU/L: ALP 645 (390–1256); GGT 925 (664–2169); ALT 100 (86–113); AST 87 (68–106); and bilirubin 4 (1–9) mg/dL. Imaging revealed intrahepatic bile duct anomalies and biliary casts. We performed biopsies at a median of 203 (150–249) days after molecular confirmation of infection. We found portal and periportal fibrosis, moderate-to-severe ductular proliferation, and bile duct dystrophy in all patients, while we observed hepatocyte biliary metaplasia in all tested cases. We observed mild-to-severe parenchymal cholestasis and bile plugs in nine and six cases. We also observed mild swelling of the arteriolar endothelial cells in five patients. We observed a thrombus in a small portal vein branch and mild periductal fibrosis in one case each. One patient developed multiple small biliary infarctions. We did not observe ductopenia in any patient. Conclusions: The alterations were like those observed in SSC-CIP; however, pronounced swelling of endothelial cells, necrosis of the vessel walls, and thrombosis in small vessels were notable.
... patients required biliary interventions. All our patients had symptomatic disease, which contrasts with the western data, which report only 15% to 21% to be symptomatic at presentation [4]. This might be related to the fact that we included patients who were admitted to our hospital with cholestatic jaundice. ...
Article
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Primary sclerosing cholangitis in India is extremely rare. We aimed to explore the frequency of PSC among patients with cholestatic jaundice.
Article
Primary sclerosing cholangitis (PSC) is associated with a high risk of hepatobiliary malignancy, especially cholangiocarcinoma (CCA). There are no good tumor markers to screen for CCA, and current recommendations for PSC monitoring are mainly based on expert opinions. The optimal strategy to assess disease progression and screen for CCA – the main cause of death of PSC patients – remains unclear. We aimed to compare three different surveillance strategies and their effect on patient outcomes. Data from three distinct PSC cohorts with different surveillance strategies – scheduled endoscopic retrograde cholangiopancreatography (ERCP), annual magnetic resonance imaging/cholangiopancreatography (MRI/MRCP) surveillance, and on-demand ERCP according to ESGE/EASL guidelines – was collected. Patients with PSC diagnosed in 1990 or later were included and the last day of follow-up was 31 December 2023. The composite end point consisted of hepatobiliary malignancy, liver transplantation, or liver-related death. 1629 PSC patients were included, with a median follow-up of 8–11 years. The cumulative incidence of the composite end point was lowest in the group undergoing scheduled ERCP (14.1%, 95%CI 12.0%–16.4%) and highest in the on-demand ERCP cohort (35.0%, 95%CI 28.4%–42.0%). Although the cumulative incidence of CCA was lower in the scheduled ERCP group than in the other groups, it did not differ statistically significantly from the MRI/MRCP surveillance group. No differences were seen in liver-related deaths between the surveillance strategies. In this study comparing scheduled ERCP, annual MRI/MRCP surveillance, and on-demand ERCP, the strategy based on scheduled ERCP using individual risk stratification is associated with better overall prognosis and outcome.
Article
Background/Aims Epidemiological data on mortality in autoimmune liver diseases (AILDs) are scarce. We examined all‐cause and cancer‐related mortality in individuals with AILD from Sweden. Methods We identified 9654 individuals with AILD (3342 with autoimmune hepatitis (AIH), 3751 with primary biliary cholangitis (PBC), and 2561 with primary sclerosing cholangitis (PSC)) using national Swedish registries between 2001 and 2020. These were matched with 80 685 comparators from the general population at a ratio of 1:10 on age, sex, year of diagnosis and municipality. Rates of outcomes were estimated using Cox regression models, adjusted for matching factors and cardiovascular disease, diabetes, inflammatory bowel disease, chronic obstructive pulmonary disease, and education. Results Individuals with AILD had higher mortality than comparators (adjusted hazard ratio (aHR) = 2.3, 95% CI = 2.2–2.4) and higher rates of cancer‐related death (aHR = 2.1, 95% CI = 1.9–2.3). The presence of liver cirrhosis in AILD was related to even higher mortality, with aHR 5.8 (95% CI = 5.1–6.6). Both males and females with AILD had increased mortality (males aHR = 2.6, 95% CI = 2.4–3.0, and females aHR = 2.2, 95% CI = 2.1–2.3). The mortality was higher in individuals aged 18–50 years (aHR = 4.6, 95% CI = 3.6–5.8), than in individuals above 50 years (aHR = 2.2, 95% CI = 2.1–2.3). Overall mortality rates and cancer‐related death were particularly high in individuals with PSC compared to their matched comparators, with aHR = 4.1 (95% CI = 3.2–5.2) and aHR = 6.4 (95% CI = 4.0–10.3), respectively. Conclusions Patients with AILDs have increased rates of overall and cancer‐related mortality compared to matched comparators, and relative risks are highest in cirrhosis, younger age and PSC.
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Chronic hepatobiliary damage progressively leads to fibrosis, which may evolve into cirrhosis and/or hepatocellular carcinoma. The fight against the increasing incidence of liver-related morbidity and mortality is challenged by a lack of clinically validated early-stage biomarkers and the limited availability of effective anti-fibrotic therapies. Current research is focused on uncovering the pathogenetic mechanisms that drive liver fibrosis. Drugs targeting molecular pathways involved in chronic hepatobiliary diseases, such as inflammation, hepatic stellate cell activation and proliferation, and extracellular matrix production, are being developed. Etiology-specific treatments, such as those for hepatitis B and C viruses, are already in clinical use, and efforts to develop new, targeted therapies for other chronic hepatobiliary diseases are ongoing. In this review, we highlight the major molecular changes occurring in patients affected by metabolic dysfunction-associated steatotic liver disease, viral hepatitis (Delta virus), and autoimmune chronic liver diseases (autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis). Further, we describe how this knowledge is linked to current molecular therapies as well as ongoing preclinical and clinical research on novel targeting strategies, including nucleic acid-, mesenchymal stromal/stem cell-, and extracellular vesicle-based options. Much clinical development is obviously still missing, but the plethora of promising potential treatment strategies in chronic hepatobiliary diseases holds promise for a future reversal of the current increase in morbidity and mortality in this group of patients.
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Objective Secondary sclerosing cholangitis (SSC) represents a disease with a poor prognosis increasingly diagnosed in clinical settings. Notably, SSC in critically ill patients (SSC-CIP) is the most frequent cause. Variables associated with worse prognosis remain unclear. The primary aim of this study was to identify factors associated with transplant-free survival in SSC-CIP patients using readily available data. Methods A cohort of 47 patients diagnosed with SSC-CIP was retrospectively analysed for clinical, biochemical and endoscopic variables. Kaplan-Meier survival curves, log-rank tests and univariate Cox proportional hazards models were used to assess associations with transplant-free survival. A multivariable Cox regression model was constructed using Lasso regularisation and validated with Bootstrap resampling. Model performance was assessed using the C-statistic for discrimination. Results Kaplan-Meier analysis identified bile duct obstruction requiring stent placement, and cholangitis episodes, as significant prognostic factors. In univariable analysis, age over 47 years (HR 2.61 (95% CI 1.02, 7.06), p=0.04), at least one cholangitis episode (HR 2.46 (95% CI 1.005, 6.06), p=0.04), stent placement (HR 2.89 (95% CI 1.13, 7.38), p=0.03), lower albumin levels (HR 0.52 (95% CI 0.28, 0.97), p=0.04) and higher international normalised ratio (INR) (HR 3.22 (95% CI 1.09, 9.53), p=0.03) were significant. Multivariable analysis showed that age at diagnosis, albumin and INR were significant independent predictors. The C-index was 0.78 (95% CI 0.65, 0.91), surpassing the model of end-stage liver disease score’s prognostic accuracy (Concordance Index at 3 years: 66.2% vs 74.9%). Conclusion These findings provide valuable insights for establishing standard exception criteria for this rare liver disease, which could lead to improved organ allocation. Further prospective multicentre studies are necessary to validate our findings.
Article
Incidence of hepatobiliary malignancies in primary sclerosing cholangitis: systematic review and meta-analysis Background and Aims Primary sclerosing cholangitis (PSC) is a known risk factor for hepatobiliary malignancies. We conducted a systematic review and meta-analysis of published studies to determine the incidence and risk factors for hepatobiliary malignancies in people with PSC. Methods Pubmed and Embase databases were searched from inception to April 10, 2024 for cohort studies reporting data on the incidence of cholangiocarcinoma (CCA), hepatocellular carcinoma (HCC), or gallbladder cancer (GBC) in PSC. Pooled incidence rates with 95% confidence intervals (CIs) were estimated using a random effects model. Results We identified 51 eligible studies involving 26482 patients. The total follow-up was 221258.1 person-years (PYs). The pooled incidence rates for overall PSC were 9.31 (95%CI, 6.84; 12.67, I2=74%), 1.73 (95%CI, 1.20; 2.51, I2=55%), and 1.06 (95%CI, 0.85; 1.31, I2=0%) per 1000 PYs for CCA, HCC, and GBC, respectively. In PSC patients with inflammatory bowel disease (IBD), rates were 7.16 (95%CI, 4.48; 11.44, I2=96%), 2.19 (95%CI, 1.48; 3.25, I2=58%), and 1.52 (95%CI, 1.21; 1.90, I2=0%) per 1000 PYs, respectively. Subgroup analysis showed that the incidence of CCA was higher in smaller studies (<200 patients), and the incidence of HCC varied significantly by region (p=0.03), with Oceania having the highest incidence and Europe having the lowest. Meta-regression determined that PSC-IBD was associated with HCC incidence. Conclusion The incidence of CCA in PSC is substantial, whereas HCC and GBC are rare. PSC-IBD patients may be at higher risk for HCC. These data should be validated in large, prospective studies, and may guide the development of evidence-based surveillance strategies for hepatobiliary malignancies in PSC.
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Background: Immune-mediated liver and biliary conditions, such as IgG4-related pancreatobiliary disease (IgG4-PB) and a subset of primary sclerosing cholangitis (PSC- high(h)IgG4), exhibit increased IgG4 levels in the blood. The relative expression of IgG4+ and IgG1+ B cells in the blood and the expression of complement and Fc receptors on these IgG1+ and IgG4+ B cells in IgG4-PB and PSC have not been previously described. We hypothesised that the patterns of expression of these cells and their receptors would differ, are relevant to disease pathogenesis and may represent therapeutic targets. Methods: CD19+ B cells were sorted from blood collected from patients with IgG4-PB, PSC-high(h)IgG4 and healthy volunteers. Cells were stained with fluorescent labelled antibodies specific to IgG1, IgG4, complement receptors (CR1 and CR2), Fc receptors (FcεRII and FcγRIIb) and chemokine receptors (CXCR3, CXCR4, CXCR5) and were analysed by flow cytometry. Findings: IgG4-PB, compared to healthy volunteers, showed decreased CR2 expression on IgG1+ B cells (MFI 416 (275–552) vs. 865 (515–3631), p = 0.04) and IgG4+ B cells (MFI 337 (231–353) vs. 571 (398–2521), p = 0.03). IgG4-PB, compared to healthy volunteers, showed increased FcεRII expression on IgG4+ B cells (MFI 296 (225–617) vs. 100 (92–138), p = 0.0145) and decreased FcγRIIb expression on IgG1+ B cells (134 (72–161) vs. 234 (175–291), p = 0.0262). FcγRIIb expression was also decreased in IgG1+ B cells in patients with PSC-hIgG4 compared to healthy volunteers. Conclusions: This exploratory study indicates that in IgG4-PB, B cells have decreased CR2 and FcγRIIb expression and increased FcεRII expression, suggesting altered sensitivity to complement, IgG-mediated inhibition and sensitisation by IgE, which may promote the relative expansion of IgG4+ B cells in this disease.
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Immunotherapy has changed the treatment landscape for patients with cancer in the past decade. Immune checkpoint inhibitor (ICI)-based therapies have proven effective in a range of malignancies, including liver and gastrointestinal cancers, but they can cause diverse off-target organ toxicities. With the increasingly wider application of these drugs, immune-mediated liver injury from ICIs has become a commonly encountered challenge in clinical hepatology and gastroenterology. In this Review, we discuss the evidence from human and animal studies on the immunological mechanisms of immune-mediated liver injury from ICIs and summarize its clinical features and practical considerations for its management.
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Aim: to highlight the challenges of diagnosing and treating a patient with severe intrahepatic cholangiolithiasis. Key points . Primary sclerosing cholangitis is a chronic progressive liver disease characterized by destructive inflammation and fibrosis in the bile ducts, leading to biliary strictures, secondary biliary cirrhosis, portal hypertension and liver failure. Cholangiolithiasis occurs in more than half of cases of primary sclerosing cholangitis and can be both a complication and a cause of secondary sclerosing cholangitis, maintaining inflammation in the ducts and facilitating stone formation. Genetic mutations are known to contribute to the development of gallstones in young patients, including low phospholipid-associated cholelithiasis. Despite the wide range of modern methods of radiological and endoscopic diagnostics, there are still difficulties in differential diagnostics of bile duct diseases. This article presents a clinical case of a 39-year-old male patient with primary sclerosing cholangitis, dyslipidemia and multiple cholangioliths in the gallbladder, intraand extrahepatic bile ducts. Conclusion . The presented clinical case demonstrates the difficulties in assessing pathogenesis, choosing diagnostic and therapeutic approaches in patients with severe intrahepatic lithiasis that may mimic hepatic neoplasm. Combination of non-invasive and endoscopic methods, such as magnetic resonance imaging, magnetic resonance cholangiopancreatography, endoscopic retrograde cholangiopancreatography, and cholangioscopy, appears to be the most effective both diagnostically and therapeutically.
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Background & Aims: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease often associated with underlying inflammatory bowel disease (IBD). We aimed to study how the phenotype in PSC patients compares to IBD alone and its association with altered inflammatory immune responses. Methods A case-control study was conducted involving a cohort of 75 patients, including 16 with PSC (14 with concomitant IBD), 39 with IBD alone, and 20 control individuals. Fecal gut microbiota, colonic tissue proteomics and immune-related gene expression, serum proteomics and targeted metabolomics were analyzed. Results Intestinibacter taxa were increased in patients with PSC. Proinflammatory mRNA markers TWIST1 , COX2 , IL-8 , and CCL2 , and pro-oncogenic markers LGR5 and SNAIL were upregulated in colonic tissue from PSC patients. Additionally, a unique proinflammatory proteomic signature, elevated glycochenodeoxycholic acid (GCDCA), and increased miR-21 were identified in serum from PSC patients. Co-incubation of human-derived monocytes with miR-21 and GCDCA reproduced the inflammatory profile observed in PSC patients. Conclusions These findings suggest an interplay between gut microbiota dysbiosis and the proinflammatory peripheral immune response contributing to the unique PSC phenotype
Article
Background Secondary sclerosing cholangitis (SSC), is one of the phenotypes of DILI first described in the 1980s. Check point inhibitors (CPIs) are currently the most frequent cause of SCC. Aims: To describe the epidemiology, clinical and biochemical features at presentation, differential diagnoses, pathophysiology, imaging, histological characteristics and management associated with SSC. Materials and Methods A language and date‐unrestricted Medline literature search was conducted to identify case reports and clinical series on SSC with special emphasis on CPIs (2007‐2023). Results We identified 19 different drugs that have been shown to induce SSC. A total of 64 cases with SSC due to CPIs are presented. This was mostly seen in patients treated with anti‐Programmed cell death (PD)‐1/PD‐L1 inhibitors. The most frequent presenting signs and symptoms were abdominal pain and jaundice. Large‐duct cholangitis induced by CPIs is a very rare condition while small‐duct cholangitis is more common. Nivolumab and pembrolizumab were the most commonly implicated agents. Biopsies have revealed predominant CD8+ T cell infiltration in biliary strictures. Corticosteroids is linked to a low frequency of success and is the only agent recommended to begin the treatment. Conclusions CPIs‐induced SSC seems to affect the entire biliary system. Clinicians should consider and suspect SSC when a probable CPIs‐induced hepatitis does not respond to corticosteroids. Additionally, further randomized, controlled trials should prospectively investigate alternative therapies for treatment.
Article
Background and Aims Individuals with primary sclerosing cholangitis (PSC) have expressed a need for more dietary information. The aim of this study was to evaluate the dietary intake of individuals with PSC and compare it with Nordic nutrition recommendations 2023 (NNR2023). Methods A cross‐sectional assessment of dietary intake was performed using a food‐frequency questionnaire among 120 individuals with PSC from five regions across Sweden. Macro‐ and micronutrient intake was compared to NNR2023. Dietary quality was evaluated using an index developed by the National Food Agency in Sweden. Results The median age was 47 years (IQR 18), and median body mass index (BMI) was 25.2 kg/m ² (IQR 5.9). Eight percent had a BMI < 20, and 13% had a BMI > 30. The average fibre intake was 18 g (IQR 18). Median energy distribution included 36% from fat (15% saturated, 4.6% polyunsaturated), 17% from protein and 43% from carbohydrates, highlighting an imbalanced diet with low carbohydrate, fibre and polyunsaturated fat intake and high saturated fat consumption. More than half reported suboptimal intake of zinc, selenium and vitamins C, D and K and > 30% suboptimal intake of vitamins A, B6, E, niacin, folate, potassium, magnesium and iron. Forty percent had poor dietary quality. Longer PSC duration and previous colectomy were associated with a lower dietary quality. Conclusions Many individuals with PSC do not reach the recommended levels of various micronutrients, especially fat‐soluble vitamins and report a poor dietary quality. The results highlight the need for a comprehensive approach to nutritional management in this population. Trial Registration ClinicalTrials.gov identifier: NCT04133792
Article
It has proven difficult to establish robust evidence for significant clinical benefits of medical treatment in primary sclerosing cholangitis (PSC). For ursodeoxycholic acid, clinical practice guidelines only offer vague recommendations, leading to a situation of variable prescription rates depending on local reimbursement policies and physician preference. The difficulty in drug development in PSC is partly related to poor understanding of critical disease processes with failure to identify relevant mechanisms of action of putative drugs. The variable disease course, both intra-individually and between individuals, and lack of robust definitions of what success looks like for clinical trials in PSC have also contributed to the negative outcomes of trials performed. In this review article we will discuss these uncertainties and challenges, building on key previous and ongoing clinical trials. Despite the lack of consensus for an ideal phase II and phase III study design, several trials for diverse compounds are currently ongoing, indicating a shift from therapeutic nihilism towards hope for people with PSC. While waiting for robust efficacy data for drugs currently being tested, the current lack of effective interventions should not motivate prescription of compounds to people with PSC based on low-quality evidence.
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Autoimmune hepatitis (AIH) is a rare liver disease, of unknown origin, characterized by considerable heterogeneity. AIH can affect both sexes, of all ages, ethnicities and races. The revised Clinical Practice Guidelines (CPGs) of the Hellenic Association for the Study of the Liver aim to provide updated guidance to clinicians. The diagnosis of AIH is based on clinicopathological characteristics, such as elevation of immunoglobulin G (IgG) levels, detection of autoantibodies, portal or lobular hepatitis at the histological level, absence of viral hepatitis markers, and a favorable response to immunosuppressive treatment. Clinical manifestations at onset vary, from no symptoms to the fulminant form of the disease. Aminotransferases and bilirubin levels also vary, while liver biopsy is a prerequisite to establish a firm diagnosis. Investigation for detection of autoantibodies is the cornerstone for diagnosis, if it is performed according to the CPGs. Treatment of AIH should aim towards the achievement of complete biochemical response (CBR; normalization of aminotransferases and IgG) no later than 6-12 months after treatment initiation, and also histological remission of the disease. All patients with active disease, irrespective of the presence of cirrhosis, should receive personalized and response-guided first-line induction treatment with predniso(lo)ne combined with mycophenolate mofetil or azathioprine. Treatment should be given for at least 3-5 years, and for at least 2 years after the achievement of CBR, while liver biopsy should be considered before treatment cessation. The updated CPGs also provide guidance for the management of difficult-to-treat patients, including those with variants and specific forms of AIH.
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Hintergrund und Zielsetzung Erhöhte Leberwerte (ELW) sind in Deutschland häufig. Ärzten der Primärversorgung kommt eine besondere Rolle in der Früherkennung von Lebererkrankungen zu. Ziel dieses Artikels ist es, eine Übersicht für Ärzte im primärärztlichen Sektor über autoimmune Lebererkrankungen zu schaffen, mit dem Fokus auf die Labordiagnostik. Methode Als Referenz dienen die nationalen und internationalen Leitlinien und Übersichtsartikel, ergänzt durch die aktuellen Prävalenzdaten des Zentralinstituts kassenärztliche Vereinigung (ZI). Ergebnisse Im Jahr 2022 erhielten von den rund 59 Millionen primärärztlichen Patienten ab dem 20. Lebensjahr ca. 50–60/100 000 eine gesicherte Diagnose einer Autoimmun-Hepatitis oder primär biliären Cholangitis (nach ICD-10-GM-Diagnose). Die Diagnosen wurden bei Frauen 2- bis 6-mal häufiger gestellt als bei Männern. Die primär sklerosierende Cholangitis kam bei rund 10/100 000 primärärztlichen behandelten Personen vor; Frauen waren bis zu 2-mal häufiger betroffen, insbesondere ab einem Lebensalter von 60 Jahren. Daten zu Ätiologie, Klinik, labordiagnostischen Parametern, Therapiemöglichkeiten und Prognosedaten zu den 3 Krankheitsentitäten werden in diesem Artikel in Kürze dargestellt. Schlussfolgerung Die Labordiagnostik ist für die Diagnose autoimmuner Lebererkrankungen der zentrale Schritt. Ein generelles Laborwerte-Screening bei ELW ist jedoch nicht ratsam. Vielmehr muss bedacht werden, dass für diese Marker in der primärärztlichen Versorgung bislang keine validierten Kennzahlen vorliegen. Die Interpretation dieser Laborwerte ist also komplex. Es ist deshalb ratsam, unter Berücksichtigung der häufigen (und weniger häufigen) Ursachen, die zu ELW führen können, eine Bestimmung dieser speziellen Laborparameter in Betracht zu ziehen.
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Data on cholestasis and biliary injury in patients with COVID-19 are scarce. The primary aim of this study was to evaluate the prevalence of cholestasis and factors associated with its development and outcome in critically ill patients with COVID-19 associated acute respiratory distress syndrome (ARDS). In this retrospective exploratory study, COVID-19 patients with ARDS admitted to an intensive care unit (ICU) at the Medical University of Vienna were evaluated for the development of cholestasis defined as an alkaline phosphatase level of 1.67x upper limit of normal for at least three consecutive days. Simple and multiple logistic regression analysis was used to evaluate parameters associated with development of cholestasis and survival. Of 225 included patients 119 (53%) developed cholestasis during ICU stay. Patients with cholestasis had higher peak levels of alkaline phosphatase, gamma-glutamyl transferase, bilirubin and inflammation parameters. Factors independently associated with cholestasis were extracorporeal membrane oxygenation support, ketamine use, high levels of inflammation parameters and disease severity. Presence of cholestasis and peak ALP levels were independently associated with worse ICU and 6-month survival. Development of cholestasis is a common complication in critically ill COVID-19 patients and represents a negative prognostic marker for survival. It is associated with disease severity and specific treatment modalities of intensive care.
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Introduction: Primary sclerosing cholangitis (PSC) is the most specific hepatobiliary extraintestinal manifestation in inflammatory bowel disease (IBD). PSC ultimately has a poor prognosis, with disease progression resulting in liver cirrhosis and subsequent liver failure. While there is current data for the medical management of IBD, the optimal approach for concurrent PSC-IBD is unclear. Areas covered: This review focuses on the current literature of pharmacotherapy in the PSC-IBD population including anti-tumor necrosis factor agents, vedolizumab, JAK inhibitors, IL-12/23 inhibitors, and thiopurines. Regarding PSC-IBD, it focuses on effectiveness of IBD therapies on liver biochemistry and IBD activity as well as the advent of clinically relevant liver outcomes and safety. The authors also address the need for further advances in research. Expert opinion: The longer-term data for pharmacological management for IBD is well established. In the concomitant PSC-IBD population there is no drug to date that has effectively reduced disease related morbidity and mortality outcomes. There are limitations in the current, mostly retrospective data on IBD drugs in PSC-IBD with respect to samples sizes, heterogenous outcomes, and lack of a high-quality surrogate endpoint in PSC. However, current data for adalimumab offers encouraging results which require further exploration with larger prospective studies.
Article
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease marked by inflammation, fibrosis, and narrowing of the bile ducts, leading to cholestasis. Magnetic resonance cholangiopancrea-tography (MRCP) is the gold standard for the diagnosis of PSC allowing insight into biliary duct changes. The typical presentation of PSC includes multifocal anular and short-segmental strictures alternating with normal or slightly dilatated biliary ducts. Besides cholangio-graphic findings, magnetic resonance (MR) allows the assessment of liver parenchymal changes which might indicate the severity of the disease. The scoring systems based on MR findings, such as the ANA-LI score, and new computer-based software analysis termed MRCP+, provide a prediction of the course of disease and identify high-risk patients. Thus, Mr with MRCP is a promising diagnostic tool for the integrative evaluation of PSC patients allowing not only initial diagnosis and detection of complications but also has prognostic significance.
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Considerable progress has been made to explain the aetiology of intrahepatic cholestasis of pregnancy (ICP) and of the adverse pregnancy outcomes associated with high maternal total serum bile acids (TSBAs). The reported thresholds for non-fasting TSBA associated with the risk of stillbirth and spontaneous preterm birth can be used to identify pregnancies at risk of these adverse outcomes to decide on appropriate interventions and to give reassurance to women with lower concentrations of TSBA. Data also support the use of ursodeoxycholic acid to protect against the risk of spontaneous preterm birth. A previous history of ICP may be associated with higher rates of subsequent hepatobiliary disease: if there is a suspicion of underlying susceptibility, clinicians caring for women with ICP should screen for associated disorders or for genetic susceptibility and, where appropriate, refer for ongoing hepatology review.
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Background Primary sclerosing cholangitis (PSC) is associated with biliary obstructions that can require endoscopic retrograde cholangiopancreatography (ERCP). While the beneficial effects of ERCP are well documented, follow-up interventional strategies are less defined, and their long-term impact is debated. Methods We evaluated the outcome of a scheduled program of ERCP-guided interventions that have been developed and implemented at our tertiary liver center for more than 20 years. Within our center, follow-up ERCPs were performed at regular intervals to treat previously detected morphological stenosis independent of clinical symptoms. We calculated the transplant-free survival (TFS) of patients who were enrolled in the scheduled ERCP program and compared it to patients who received follow-up ERCPs only on clinical demand. Moreover, we documented the occurrence of hepatic decompensation, recurrent cholangitis episodes, hepatobiliary malignancies, and endoscopy-related adverse events. Results In our retrospective study, we included 201 patients with PSC who all received an ERCP. In all, 133 patients received scheduled follow-up ERCPs and 68 received follow-up ERCPs only on demand. The rates of TFS since initial diagnosis (median TFS: 17 vs. 27 y; P = 0.020) and initial presentation (median TFS: 16 vs. 11 y; P = 0.002) were higher in patients receiving scheduled versus on-demand ERCP. Subgroup analysis revealed that progression in cholangiographic findings between the first and second ERCP was associated with a poorer outcome compared to patients without progression (17 y vs. undefined; P = 0.021). Conclusion In conclusion, we report the outcome data of a scheduled follow-up ERCP program for patients with PSC in an experienced high-volume endoscopy center. Our data suggest the initiation of multicenter randomized controlled prospective trials to explore the full potential of regular endoscopic follow-up treatment as a strategy to prevent disease progression in patients with PSC.
Article
Primary sclerosing cholangitis (PSC) is a chronic inflammatory progressive cholestatic liver disease. Genetic risk factors, presence of autoantibodies, the strong clinical link with inflammatory bowel disease (IBD), and associations with other autoimmune disorders all suggest a pivotal role for the immune system in PSC pathogenesis. In this review, we provide a comprehensive overview of recent immunobiology insights in PSC. A particular emphasis is given to immunological concepts such as tissue-residency and knowledge gained from novel technologies including single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST). This review of the immunobiological landscape of PSC covers major immune cell types known to be enriched in PSC-diseased livers as well as recently described cell types whose biliary localization and contribution to PSC immunopathogenesis remain incompletely described. Finally, we emphasize the importance of time and space in relation to PSC heterogeneity as a key consideration for future studies interrogating the role of the immune system in PSC.
Article
Liver blood test (LBT) abnormalities are common in people with inflammatory bowel disease (IBD). The majority are self-limiting, with only 5% having clinically significant liver disease. Liver conditions most frequently associated with IBD include primary sclerosing cholangitis, metabolic dysfunction-associated steatotic liver disease and drug-induced liver injury (DILI). A combination of clinical assessment, blood tests and imaging can be used to help establish the causality and severity of abnormal LBTs in people with IBD. The use of immunomodulatory therapies for IBD has increased the incidence of abnormal LBTs. Most cases are self-limiting and clinically significant injury is rare, particularly with the newer therapeutic agents. Azathioprine and antitumour necrosis factor-α therapies have the greatest risk of liver injury. A clear timeline of drug initiation or dose escalation is essential when interpreting abnormal LBTs to identify DILI. Signs of serious liver dysfunction should prompt immediate cessation of the drug. Otherwise, a patient-centred approach is required when deciding on drug alteration, including the assessment of therapeutic efficacy and the availability of alternative treatment options.
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Background & Aims Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease with a strong association with inflammatory bowel disease and variable disease progression. We aimed to gain insights into the role of fecal bile acids (BA) on disease progression by determining the relationships between fecal BA, diet, and gut microbes, with markers of disease progression, BA synthesis, and farnesoid X receptor (FXR) activity. Methods BA levels in serum and stool, dietary intake, and markers of BA synthesis, and FXR activity were measured in 26 patients with early stage, large duct PSC. Fecal microbiota were quantified by 16S rRNA gene sequencing. Results Compared with controls, fecal unconjugated deoxycholic acid (DCA) levels were lower in patients with PSC (padj = 0.04). Alcohol intake and the abundance of Blautia and Lachnoclostridium were associated with greater fecal DCA levels in patients with PSC after adjusting for inflammatory bowel disease and treatment with ursodeoxycholic acid. Fecal DCA levels were negatively associated with total bilirubin levels in patients with PSC (p = 0.006) suggesting a protective role. However, fecal DCA was associated with greater serum levels of 7α-hydroxy-4-cholesten-3-one, a marker of BA synthesis, and was not associated with fibroblast growth factor 19, a marker of intestinal FXR activity. Conclusions Alcohol intake, Blautia and Lachnoclostridium abundance was associated with increased fecal DCA levels, which in turn seemed to have had a protective effect in patients with early-stage PSC. However, this effect was not mediated by BA synthesis or FXR activation. Impact and implications Primary sclerosing cholangitis (PSC) is a cholestatic liver disease with a direct interaction between the gut and the liver. In this study of patients with early-stage PSC, levels of fecal deoxycholic acid correlated with serum total bilirubin, a marker of clinical outcomes. In addition, Blautia and Lachnoclostridium were associated with fecal deoxycholic acid suggesting an interaction between these gut bacteria, fecal bile acids, and disease progression. Future research to determine the underlying mechanisms of these associations may lead to novel targets to prevent PSC disease progression.
Article
Background: Serum liver tests (serum tests) and histological assessment for T-cell mediated (TcM) rejection are essential for post-liver transplant monitoring. Liver biopsy carries risk of complications which are preferably avoided in low-risk patients. Multiparametric MRI (mpMRI) is a reliable non-invasive diagnostic method which quantifies liver disease activity and has prognostic utility. Our aim was to determine whether using mpMRI in combination with serum tests could noninvasively identify low-risk post-liver transplant patients who are eligible to avoid invasive liver biopsies. Methods: In a multicentre prospective study (RADIcAL2), including 131 adult and paediatric (children and adolescent) patients with previous liver transplant from the Netherlands, Portugal, and UK, concomitant mpMRI and liver biopsies were performed. Biopsies were centrally read by two expert pathologists. TcM rejection was assessed using BANFF global assessment (BANFF-GA). Diagnostic accuracy to discriminate no rejection vs. indeterminate or TcM liver transplant rejection was performed using area under the receiver operating characteristic curve (AUC). Results: In this study, 52% of patients received a routine (protocol) biopsy whilst 48% had a biopsy for suspicion of pathology. 38% of patients had no rejection, while 62% had either indeterminate (21%) or TcM rejection (41%). However, there was a high inter-observer variability (0<Cohen’s Kappa<0.85) across all histology scores. The combined score of mpMRI and serum tests had AUC 0.7 (NPV: 0.8) to identify those without either indeterminate or TcM rejection. Conclusion: Combining both imaging and serum biomarkers into a composite biomarker (imaging and serum biomarkers) has potential in monitoring the liver graft to effectively risk stratify patients and identify those most likely to benefit from a non-invasive diagnostic approach, reducing the need for liver biopsy.
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Background/aims: The assessment of liver fibrosis is crucial for managing autoimmune liver diseases such as primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), and primary sclerosing cholangitis (PSC). However, data on the efficacy of noninvasive tests (NITs) for these diseases are limited. This meta-analysis evaluated the diagnostic accuracy of vibration-controlled transient elastography (VCTE) for staging fibrosis in patients with autoimmune liver disease. Methods: Searches were conducted in PubMed, Embase, CINAHL, Web of Science, and Cochrane Library databases to assess the diagnostic accuracy of VCTE against histology as the reference standard in adult patients with autoimmune liver disease. The summary area under the curve (sAUC) and diagnostic odds ratio were calculated for significant fibrosis (SF), advanced fibrosis (AF), and cirrhosis, defined as METAVIR stages F≥2, F≥3, and F=4, respectively, according to liver biopsy. Results: Fourteen articles were included, comprising 559 PBC patients from six studies, 388 AIH patients from five studies, and 151 PSC patients from three studies. VCTE demonstrated good performance for fibrosis staging in PBC, AIH, and PSC. In PBC, sAUCs of VCTE were 0.87 (95% confidence interval, 0.80-0.94), 0.89 (0.85-0.94), and 0.99 (0.96-1.00) for staging SF, AF, and cirrhosis, respectively. In AIH, the sAUCs were 0.88 (0.84-0.92), 0.88 (0.83-0.93), and 0.92 (0.88-0.96), respectively, while in PSC, they were 0.88 (0.82-0.95), 0.95 (0.90-1.00), and 0.92 (0.84-0.99), respectively. The cutoff values for AF were 7.5-17.9 kPa in PBC, 8.18-12.1 kPa in AIH, and 9.6 kPa in PSC. Conclusions: VCTE shows high diagnostic accuracy for staging liver fibrosis in patients with autoimmune liver diseases such as PBC, AIH, and PSC. This non-invasive and reliable method serves as a valuable tool for the evaluation and monitoring of fibrosis in these lifelong diseases.
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Benign biliary strictures (BBS) ensue from inflammatory conditions (e.g., chronic pancreatitis) or post surgery (e.g., cholecystectomy and liver transplant). High-quality cross-sectional imaging studies such as computed tomography or magnetic resonance cholangiopancre atography are essential in the diagnosis and planning of therapeutic interventions and in ruling out malignancy. Endoscopic retrograde cholangiopancreatography with dilation and stenting is the mainstay treatment for BBS, while surgery is reserved for failed endoscopy or refractory cases.
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The National Osteoporosis Guideline Group (NOGG) has revised the UK guideline for the assessment and management of osteoporosis and the prevention of fragility fractures in postmenopausal women, and men age 50 years and older. Accredited by NICE, this guideline is relevant for all healthcare professionals involved in osteoporosis management. Introduction The UK National Osteoporosis Guideline Group (NOGG) first produced a guideline on the prevention and treatment of osteoporosis in 2008, with updates in 2013 and 2017. This paper presents a major update of the guideline, the scope of which is to review the assessment and management of osteoporosis and the prevention of fragility fractures in postmenopausal women, and men age 50 years and older. Methods Where available, systematic reviews, meta-analyses and randomised controlled trials were used to provide the evidence base. Conclusions and recommendations were systematically graded according to the strength of the available evidence. Results Review of the evidence and recommendations are provided for the diagnosis of osteoporosis, fracture-risk assessment and intervention thresholds, management of vertebral fractures, non-pharmacological and pharmacological treatments, including duration and monitoring of anti-resorptive therapy, glucocorticoid-induced osteoporosis, and models of care for fracture prevention. Recommendations are made for training; service leads and commissioners of healthcare; and for review criteria for audit and quality improvement. Conclusion The guideline, which has received accreditation from the National Institute of Health and Care Excellence (NICE), provides a comprehensive overview of the assessment and management of osteoporosis for all healthcare professionals involved in its management. This position paper has been endorsed by the International Osteoporosis Foundation and by the European Society for the Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases.
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Background & aims: Immunoglobulin G4-related disease (IgG4-RD) of the biliary tract and pancreas is a fibroinflammatory disease of unknown origin with striking male predominance. We aimed to investigate whether blue-collar work and occupational contaminant exposure are risk factors for IgG4-RD of the biliary tract and pancreas. Method: We performed an age-/sex-matched case-control study in the largest academic medical centers of the Netherlands. Occupational history was surveyed by questionnaires. The International Standard Classification of Occupations (ISCO88) was used to classify jobs. Job exposure matrices ALOHA and DOM were utilized to assess the years individuals were exposed to compounds. The disease control cohort consisted of patients from 6 equally sized groups. Conditional logistic regression was used to assess effects of blue-collar work and exposure to occupational contaminants on developing IgG4-RD of the biliary tract and pancreas. Results: Overall, 101 patients with IgG4-RD of the biliary tract and pancreas were matched 1:3 to 303 controls. Patients with IgG4-RD had a lower level of education (p = 0.001). Individuals who at least once performed blue-collar work (>1 year), had higher odds of developing IgG4-RD than individuals that only performed white-collar work (odds ratio [OR] 3.66; CI 2.18-6.13; p <0.0001). Being ever exposed (>1 year) to industrial ALOHA (e.g. mineral dust; vapors-dust-gases-fumes) and DOM compounds (e.g. asbestos) resulted in higher odds of IgG4-RD (OR 2.14; 95% CI 1.26-3.16; p <0.001 and OR 2.95; 95% CI 1.78-4.90; p <0.001, respectively). Conclusion: Blue-collar work is a risk factor for developing IgG4-RD of the biliary tract and pancreas putatively driven by exposure to selected industrial compounds; this may explain the striking male predominance among patients. Lay summary: Immunoglobulin G4-related disease (IgG4-RD) causes tumor-like lesions and typically affects middle-aged to elderly men. The background and cause of this disease remain relatively unknown. In this study, we identified blue-collar work as a risk factor for developing IgG4-RD of the biliary tract and pancreas, which may explain the striking male predominance among patients. Furthermore, these results suggest that toxic exposure to occupational contaminants may drive autoimmunity in IgG4-RD of the biliary tract and pancreas.
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Cholestatic and non-alcoholic fatty liver disease (NAFLD) share several key pathophysiological mechanisms which can be targeted by novel therapeutic concepts that are currently developed for both areas. Nuclear receptors (NRs) are ligand-activated transcriptional regulators of key metabolic processes including hepatic lipid and glucose metabolism, energy expenditure and bile acid (BA) homoeostasis, as well as inflammation, fibrosis and cellular proliferation. Dysregulation of these processes contributes to the pathogenesis and progression of cholestatic as well as fatty liver disease, placing NRs at the forefront of novel therapeutic approaches. This includes BA and fatty acid activated NRs such as farnesoid-X receptor (FXR) and peroxisome proliferator-activated receptors, respectively, for which high affinity therapeutic ligands targeting specific or multiple isoforms have been developed. Moreover, novel liver-specific ligands for thyroid hormone receptor beta 1 complete the spectrum of currently available NR-targeted drugs. Apart from FXR ligands, BA signalling can be targeted by mimetics of FXR-activated fibroblast growth factor 19, modulation of their enterohepatic circulation through uptake inhibitors in hepatocytes and enterocytes, as well as novel BA derivatives undergoing cholehepatic shunting (instead of enterohepatic circulation). Other therapeutic approaches more directly target inflammation and/or fibrosis as critical events of disease progression. Combination strategies synergistically targeting metabolic disturbances, inflammation and fibrosis may be ultimately necessary for successful treatment of these complex and multifactorial disorders.
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Purpose ANALI-scores are two prognostic magnetic resonance imaging (MRI)-based scores developed for patients with primary sclerosing cholangitis (PSC). Our study aims to assess the interreader agreement between expert radiologists of the two ANALI-scores and of the radiological parameters they utilize, and to test the prognostic performance of the scores in our population. Method Three radiologists evaluated MRIs of 98 PSC-patients from a prospectively collected cohort with median follow-up of 6.7 years. Each parameter of ANALI-scores was assessed, and the scores were calculated. Interreader agreement was assessed with intraclass correlation coefficient (ICC). After consensus reading was reached, the prognostic value of ANALI-scores was assessed with Cox regression, and outcome-free survival rates were evaluated with Kaplan-Meier estimates. Results The ANALI-score without gadolinium had poor to moderate (ICC=0.56, 95%CI: 0.42–0.68) and with gadolinium poor (ICC=0.30, 95%CI: 0.16–0.44) agreement. Liver deformity (ICC=0.28, 95%CI: 0.13–0.44) and parenchymal enhancement heterogeneity (ICC=0.24, 95%CI: 0.12–0.38) had poor agreement. Portal hypertension had poor to moderate (ICC=0.48, 95%CI: 0.36–0.59) and dilatation of the intrahepatic ducts had moderate (ICC=0.64, 95%CI: 0.54–0.73) agreement. Hazard ratios for liver-related death, transplantation or cirrhosis decompensation of the ANALI-scores with and without gadolinium were 3.53 (95%CI: 1.40–8.93) and 2.25 (95%CI: 1.56–3.24), respectively. Outcome-free survival was better for patients with low ANALI-scores. Conclusions The ANALI-scores show poor to moderate agreement, which challenges their usefulness in clinical practice. They are associated with clinical outcomes, confirming the value of imaging in prognosis of PSC, but need further multicenter evaluation.
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Non-invasive tests are increasingly being used to improve the diagnosis and prognostication of chronic liver diseases across aetiologies. Herein, we provide the latest update to the EASL Clinical Practice Guidelines on the use of non-invasive tests for the evaluation of liver disease severity and prognosis, focusing on the topics for which relevant evidence has been published in the last 5 years.
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Background Liver transplantation for primary sclerosing cholangitis (PSC) can be complicated by recurrence of PSC (rPSC). This may compromise graft survival but the effect on patient survival is less clear. We investigated the effect of post-transplant rPSC on graft and patient survival in a large European cohort. Methods Registry data from the European Liver Transplant Registry regarding all first transplants for PSC between 1980 and 2015 were supplemented with detailed data on rPSC from 48 out of 138 contributing transplant centres, involving 1,549 patients. Bayesian proportional hazards models were used to investigate the impact of rPSC and other covariates on patient and graft survival. Results Recurrence of PSC was diagnosed in 259 patients (16.7%) after a median follow-up of 5.0 years (quantile 2.5%-97.5%: 0.4–18.5), with a significant negative impact on both graft (HR 6.7; 95% CI 4.9–9.1) and patient survival (HR 2.3; 95% CI 1.5–3.3). Patients with rPSC underwent significantly more re-transplants than those without rPSC (OR 3.6, 95% CI 2.7–4.8). Conclusions PSC recurrence has a negative impact on both graft and patient survival, independent of transplant-related covariates. Recurrence of PSC leads to higher number of re-transplantations and a 33% decrease in 10-year graft survival.
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A diagnosis of primary sclerosing cholangitis (PSC) has been associated with increased risk of hepatobiliary cancers, colorectal cancer and all-cause mortality in several studies, while associations with cardiovascular disease have been inconsistent. We conducted a systematic review and meta-analysis of published cohort studies on the topic to summarize these associations. PubMed and Embase databases were searched up to January 13th, 2020. Cohort studies on PSC and risk of cancer, cardiovascular disease, or mortality were included. Summary relative risks (RRs) and 95% confidence intervals (95% CIs) were estimated using random effects models. The summary RR (95% CI) comparing persons with PSC to persons without PSC was 584.37 (269.42–1267.51, I2 = 89%, n = 4) for cholangiocarcinoma (CCA), 155.54 (125.34–193.02, I2 = 0%, n = 3) for hepatobiliary cancer, 30.22 (11.99–76.17, I2 = 0%, n = 2) for liver cancer, 16.92 (8.73–32.78, I2 = 88%, n = 4) for gastrointestinal cancer, 7.56 (2.42–23.62, I2 = 0%, n = 3) for pancreatic cancer, 6.10 (4.19–8.87, I2 = 14%, n = 7) for colorectal cancer (CRC), 4.13 (2.99–5.71, I2 = 80%, n = 5) for total cancer, 3.55 (2.94–4.28, I2 = 46%, n = 5) for all-cause mortality, and 1.57 (0.25–9.69, I2 = 79%, n = 2) for cardiovascular disease. Strong positive associations were observed between PSC and risk of CCA, hepatobiliary cancer, liver cancer, gastrointestinal cancer, pancreatic cancer, CRC, total cancer, and all-cause mortality, but not for cardiovascular disease.
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Cholangiocarcinoma (CCA) has poor prognosis due to late‐stage, symptomatic presentation. Altered DNA methylation markers may improve diagnosis of CCA. Reduced‐representation bisulfite sequencing was performed on DNA extracted from frozen CCA tissues and matched to adjacent benign biliary epithelia or liver parenchyma. Methylated DNA markers (MDMs) identified from sequenced differentially methylated regions were selected for biological validation on DNA from independent formalin‐fixed, paraffin‐embedded CCA tumors and adjacent hepatobiliary control tissues using methylation‐specific polymerase chain reaction. Selected MDMs were then blindly assayed on DNA extracted from independent archival biliary brushing specimens, including 12 perihilar cholangiocarcinoma, 4 distal cholangiocarcinoma cases, and 18 controls. Next, MDMs were blindly assayed on plasma DNA from patients with extrahepatic CCA (eCCA), including 54 perihilar CCA and 5 distal CCA cases and 95 healthy and 22 primary sclerosing cholangitis controls, balanced for age and sex. From more than 3,600 MDMs discovered in frozen tissues, 39 were tested in independent samples. In the clinical pilot of 16 MDMs on cytology brushings, methylated EMX1 (empty spiracles homeobox 1) had an area under the curve (AUC) of 0.98 (95% confidence interval [CI], 0.95‐1.0). In the clinical pilot on plasma, a cross‐validated recursive partitioning tree prediction model from nine MDMs was accurate for de novo eCCA (AUC, 0.88 [0.81‐0.95]) but not for primary sclerosing cholangitis–associated eCCA (AUC, 0.54 [0.35‐0.73]). Conclusion: Next‐generation DNA sequencing yielded highly discriminant methylation markers for CCA. Confirmation of these findings in independent tissues, cytology brushings, and plasma supports further development of DNA methylation to augment diagnosis of CCA.
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Background Resection for perihilar cholangiocarcinoma (pCCA) in primary sclerosing cholangitis (PSC) has been reported to lead to worse outcomes than resection for non-PSC pCCA. The aim of this study was to compare prognostic factors and outcomes after resection in patients with PSC-associated pCCA and non-PSC pCCA. Methods The international retrospective cohort comprised patients resected for pCCA from 21 centres (2000-2020). Patients operated with hepatobiliary resection, with pCCA verified by histology and with data on PSC status, were included. The primary outcome was overall survival. Secondary outcomes were disease-free survival and postoperative complications. Results Of 1128 pCCA patients, 34 (3.0%) had underlying PSC. Median overall survival after resection was 33 months for PSC patients and 29 months for non-PSC patients (p = .630). Complications (Clavien-Dindo grade ≥ 3) were more frequent in PSC pCCA (71% versus 44%, p = .003). The rate of posthepatectomy liver failure (21% versus 17%, p = .530) and 90-day mortality (12% versus 13%, p = 1.000) was similar for PSC and non-PSC patients. Discussion Median overall survival after resection for pCCA was similar in patients with underlying PSC and non-PSC patients. Complications were more frequent after resection for PSC-associated pCCA, with no difference in postoperative mortality.
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Background and Aims To influence host and disease phenotype, compositional microbiome changes, which have been demonstrated in patients with primary sclerosing cholangitis (PSC), must be accompanied by functional changes. We therefore aimed to characterize the genetic potential of the gut microbiome in PSC compared to healthy controls (HCs) and inflammatory bowel disease (IBD). Methods Fecal DNA from two cohorts (one Norwegian and one German), in total comprising 136 patients with PSC (58% with IBD), 158 HCs and 93 IBD patients without PSC were subjected to metagenomic shotgun sequencing, generating 17 billion paired end sequences, which were processed using HUMAnN2 and MetaPhlAn2, and analyzed using generalized linear models and random effects meta-analyses. Results PSC patients had fewer microbial genes compared to HC (P<.0001). Compared to HC, PSC patients showed enrichment and increased prevalence of Clostridium species, and a depletion of e.g., Eubacterium spp. and Ruminococcus obeum. Patients with PSC showed marked differences in the abundance of genes related to vitamin B6 synthesis and branched chain amino acid (BCAA) synthesis (Qfdr<.05). Targeted metabolomics of plasma from an independent set of PSC patients and controls found reduced concentrations of vitamin B6 and BCAAs in PSC (P<.0001), which strongly associated with reduced liver transplantation-free survival (log-rank P<.001). No taxonomic or functional differences were detected between PSC patients with and without IBD. Conclusion The gut microbiome of PSC patients exhibits large functional differences compared to HC, including microbial metabolism of essential nutrients. Alterations in related circulating metabolites associated with disease course, suggesting that microbial functions may be relevant for the disease process in PSC.
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Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease with no approved treatments. C‐C chemokine receptor types 2 and 5 (CCR2/CCR5) play an important role in inflammation and fibrosis and are potential therapeutic targets for PSC. We evaluated the efficacy and safety of cenicriviroc (CVC), a dual antagonist of CCR2 and CCR5, for the treatment of PSC. This was a single‐arm, open‐label, exploratory study of CVC in adults with a clinical diagnosis of PSC, serum alkaline phosphatase (ALP) ≥1.5 times the upper limit of normal (ULN), with or without inflammatory bowel disease, across eight sites in the United States and Canada. The primary endpoint was percent change in ALP over 24 weeks; key secondary efficacy endpoints were proportion of participants who achieved ALP normalization and overall response (decrease to
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Simple Summary Cancers affecting the bile duct may occur in different anatomic regions of the bile duct and are called cholangiocarcinomas. A subset of these cancers involve the bile ducts just below the liver in a region named the hepatic hilum and are referred to as perihilar cholangiocarcinomas. These small cancers are often unresectable (cannot be taken apart by surgery), as they include crucial blood vessels and other bile ducts of the liver. Herein, we report on the role of liver transplant in these patients, which can lead to long term disease free survival. Abstract Selected patients with unresectable perihilar cholangiocarcinoma (pCCA) derive long-term benefits from liver transplantation. Between 1993–2019, our group at Mayo Clinic performed 237 transplants for pCCA. With this experience, we note that two distinct patient populations comprise this group of pCCA patients: those with underlying primary sclerosing cholangitis (PSC) and those without identifiable risk factors termed sporadic or de novo pCCA. Long-term survival after transplant is better in PSC patients (74% five-year survival) than in those with de novo pCCA (58% five-year survival). Herein, we review the likely clinical factors contributing to the divergence in outcomes for these two patient populations. We also offer our insights on how further advances may improve patient selection and survival, focusing on the de novo pCCA patient population.
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Background: Primary sclerosing cholangitis (PSC) is associated with progressive liver disease and cholangiocarcinoma. Although risk stratification is crucial for making clinical decisions, it is hindered by a scarcity of proven prognostic markers. Aims: To assess the value of novel anti-glycoprotein 2 (anti-GP2) and anti-neutrophil cytoplasmic antibodies to serine proteinase 3 (PR3-ANCA) in combination with PSC-specific clinical and laboratory markers as predictors of quality of life, disease severity, and cholangiocarcinoma in two large, independent cohorts of PSC patients METHODS: Discovery (338 Polish patients) and validation (178 German patients) cohorts with PSC were evaluated. Anti-GP2 (isoforms 1/4) was detected by ELISAs and PR3-ANCA by chemiluminescence immunoassay. Clinical and laboratory data were collected and analysed. The outcome was defined as liver transplantation-free survival and occurrence of cholangiocarcinoma during follow-up. Results: In the discovery group, anti-GP21/4 IgA and PR3-ANCA were associated with liver dysfunction, anti-GP21/4 IgA with risk scores for PSC and anti-GP24 IgA with cirrhosis. All cholangiocarcinoma patients were positive for PR3-ANCA and/or anti-GP24 IgA. The association between anti-GP2 IgA and liver biochemistry, risk scores, cirrhosis, impaired survival, and cholangiocarcinoma was confirmed in the validation cohort. Cox proportional-hazards regression indicated anti-GP21 IgA as an independent variable of poor outcome in both study cohorts. Analysis of the combined data showed that anti-GP24 IgA and PR3-ANCA were independent predictors for cholangiocarcinoma, while anti-GP21 IgA and PR3-ANCA were indicators for poor survival. Conclusions: Anti-GP2 and PR3-ANCA are prognostic antibodies in PSC as they identify patients at risk of severe disease, poor survival and biliary cancer.
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Background: Liver transplantation (LT) has been performed in a select group of patients presenting with unresectable or primary sclerosing cholangitis (PSC)-associated perihilar cholangiocarcinoma (pCCA) in the Mayo Clinic with a reported 5-year overall survival (OS) of 53% on intention-to-treat analysis. The objective of this study was to estimate eligibility for LT in a cohort of pCCA patients in two tertiary referral centers. Methods: Patients diagnosed with pCCA between 2002 and 2014 were included from two tertiary referral centers in the Netherlands. The selection criteria used by the Mayo Clinic were retrospectively applied to determine the proportion of patients that would have been eligible for LT. Results: A total of 732 consecutive patients with pCCA were identified, of whom 24 (4%) had PSC-associated pCCA. Overall, 154 patients had resectable disease on imaging and 335 patients were ineligible for LT because of lymph node or distant metastases. An age limit of 70 years led to the exclusion of 50 patients who would otherwise be eligible for LT. After applying the Mayo Clinic criteria, only 34 patients (5%) were potentially eligible for LT. Median survival from diagnosis for these 34 patients was 13 months (95% CI 3-23). Conclusion: Only 5% of all patients presenting with pCCA were potentially eligible for LT under the Mayo criteria. Without transplantation, a median OS of about 1 year was observed.
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Extensive research on human microbiomes has largely focused on the human gut and the contribution of microbiome dysbiosis (loss of key taxa, diversity and metabolic capacity) in the onset of diseases. Other studies have focused on additional compartments in the human body such as the biliary system. These compartments also have an autochthonous microbiome that undergoes changes depending on the conditions of the host and vice versa. However, comprehensive studies characterizing the human bile microbiome and its relationship to liver diseases are still scarce.
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Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are associated with decreased health‐related quality of life and debilitating symptoms. These experiences can be defined as patient‐reported outcome (PRO) concepts and measured using PRO instruments. We identified all PRO concepts and instruments used in the PBC and PSC literature. This systematic review identified PBC and/or PSC studies from January 1, 1990, to May 6, 2019, that measured at least one PRO concept. Study population, design, PRO concept, PRO instrument, and validation data for PRO instruments were investigated. We provided descriptive statistics of PRO concepts and instruments used, stratified by population type. Use of PRO concepts and instruments were assessed over time. The search yielded 318 articles (69% in PBC, 18% in PSC, 13% in both, and 24% in drug trials). Forty‐nine unique PRO concepts were identified. The five most common PRO concepts included pruritus (25%), fatigue (19%), broad health‐related quality of life (16%), gastrointestinal adverse events (6%), and physical adverse events (6%). Only 60% of PRO concepts were measured with a PRO instrument, most of which were nonvalidated visual analogue or numeric rating scales. Only three of 83 PRO instruments were developed with feedback from the target populations (one for PBC, one for PSC, and one for both), and only six documented any psychometric testing in the target populations. Use of PRO instruments increased over time from 30% in the 1990s to 67% by 2019. Conclusion: The overwhelming majority of PRO instruments used in PBC/PSC were nonspecific and lacked patient validation or empirical justification. Significant opportunities exist to use qualitative methods to better understand patient experiences, and translate this knowledge into meaningful, patient‐driven study outcomes.
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Background & Aims Serum alkaline phosphatase (ALP) and the enhanced liver fibrosis (ELF) score are used as endpoints in trials of patients with primary sclerosing cholangitis (PSC). We aimed to quantify inter- and intra-individual variation in levels of ALP and the ELF score over time, and evaluated their association with fibrosis progression. Methods We analyzed data from 234 patients with large-duct PSC enrolled in a 2-year, phase 2b placebo-controlled trial of simtuzumab. Participants were assessed by laboratory tests every 4 weeks, and liver biopsies collected at time of screening, week 48, and week 96. Results Serum levels of ALP and ELF scores did not differ significantly between simtuzumab and placebo groups, so the data were pooled. Median per-patient variations in ALP between clinic visits were approximately 12% over 12 weeks, 20% over 48 weeks, and 20% over 96 weeks. Reductions, unrelated to study intervention, of more than 40% in ALP were observed in 10.9% of patients with baseline activity greater than 2-fold the upper limit of normal (ULN) and 12.5% of patients with more than 3-fold the ULN at 1 year. At 2 years, reductions of more than 40% in ALP were observed in 15.8% of patients with baseline activity greater than 2-fold the ULN and 17.9% of patients with more than 3-fold the ULN. Among the 209 patients with Ishak fibrosis stage 0–4 at baseline, serum levels of ALP did not associate with development of cirrhosis or with a 2-point increase in fibrosis stage at 2 years. The median per-patient variation in ELF scores between clinic visits was approximately 3% over 12 weeks, 4% over 48 weeks, and 4% over 96 weeks. Increased ELF scores at baseline and at weeks 12, 24 and 48, each associated with development of cirrhosis at 2 years (odds ratio >2.75; P<.01 for all timepoints). ELF scores at baseline and weeks 12, 24 and 48, also associated with a 2-point increase in fibrosis stage at 2 years (odds ratios all greater than 2; P<.01 for all timepoints). Conclusions In an analysis of data from patients with large-duct PSC enrolled in a prospective trial, we found large variations in serum levels of ALP, within and among patients. Serum levels of ALP did not associate with disease progression over a 2-year period. Variations in ELF score were smaller, and scores determined at multiple timepoints associated with fibrosis progression and development of cirrhosis.
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Primary sclerosing cholangitis (PSC) is a common indication for liver transplantation (LT). Up to 25% of patients experience recurrence of PSC (rPSC) after LT, which is associated with significant morbidity and mortality. To date, it is not possible to predict which patients are at risk for rPSC. The aetiology of PSC is complex and is speculated to involve translocation of intestinal bacteria to the liver, because of its frequent co‐occurrence with inflammatory bowel diseases (IBD). Here, we investigate whether the mucosal intestinal microbiome of PSC patients (n=97) at time of first LT can identify those patients who will develop rPSC. 16S gene sequencing of bacterial DNA isolated from formalin fixed paraffin embedded biopsies showed that PSC patients with Crohn’s disease (n=15) have a reduced microbial diversity and that inflammation of the mucosa is associated with beta‐diversity changes and feature differences. No differences in alpha‐ or beta‐diversity were observed between patients with rPSC (n=14) and without rPSC (n=83). However, many over‐represented bacterial features were detected in patients with rPSC, while surprisingly, those without recurrence of disease were characterized by an increased presence of the Gammaproteobacteria Shigella. This pilot study warrants further investigation into bacterial differences between rPSC and non‐rPSC patients.
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Introduction The impact of living with Primary Sclerosing Cholangitis (PSC) on psychological wellbeing is not well-known. A recent scoping review by the authors found that both depression and anxiety frequently featured in the accounts of those living with the illness. However, less clear were the factors that led to such psychological distress, the impact that the illness had on families and how to best support those living or supporting someone living with the illness. In light of this, the aim of this study was to explore how the illness impacted the lives of both those diagnosed with the illness and those supporting them. Method and results This study adopted a phenomenological approach to understand the subjective experiences of individual participants. A total of 30 individuals took part in Asynchronous Virtual Focus Groups hosted on a Virtual Learning Environment for a four-week period. Chronological narratives of individuals’ lived experiences from diagnosis to post-transplant are presented below. These narratives centred upon individuals’ and families’ experiences of receiving a diagnosis, and adjusting to life post-diagnosis, particularly in regard to their relationships with health professionals and other family members, and in preparing for the possibility of transplant. Discussion The present article provides an in-depth look at how PSC can impact psychological wellbeing, how psychological distress arises and includes advice tailored to individuals, families and health professionals on how to best support each other.
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The overall objective of these guidelines is to provide evidence-based recommendations for the diagnosis and management of immunoglobulin G4 (IgG4)-related digestive disease in adults and children. IgG4-related digestive disease can be diagnosed only with a comprehensive work-up that includes histology, organ morphology at imaging, serology, search for other organ involvement, and response to glucocorticoid treatment. Indications for treatment are symptomatic patients with obstructive jaundice, abdominal pain, posterior pancreatic pain, and involvement of extra-pancreatic digestive organs, including IgG4-related cholangitis. Treatment with glucocorticoids should be weight-based and initiated at a dose of 0.6–0.8 mg/kg body weight/day orally (typical starting dose 30-40 mg/day prednisone equivalent) for 1 month to induce remission and then be tapered within two additional months. Response to initial treatment should be assessed at week 2–4 with clinical, biochemical and morphological markers. Maintenance treatment with glucocorticoids should be considered in multi-organ disease or history of relapse. If there is no change in disease activity and burden within 3 months, the diagnosis should be reconsidered. If the disease relapsed during the 3 months of treatment, immunosuppressive drugs should be added.
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Background: Rare diseases may be life-threatening or chronically debilitating conditions. Patient care needs are often complex and challenging to coordinate and deliver effectively. Rare diseases and their clinical management may therefore substantially impact on patients' health-related quality of life (HRQOL). The use of patient-reported outcome measures (PROMs) may complement clinical assessments by elucidating patients' perspectives on their health status and care priorities. This study explored the opinions of patients and clinicians on the use of PROMs in the management of patients with rare diseases in routine clinical practice. Methods: A total of 15 semi-structured one-to-one interviews were conducted with four patients with primary sclerosing cholangitis (PSC); five renal transplant recipients; and six PSC doctors from University Hospitals Birmingham (UHB) NHS Foundation Trust. A focus group session was also conducted with 10 clinical staff members (doctors, nurses and other allied health professionals from UHB). The suitability and acceptability of the Chronic Liver Disease Questionnaire (CLDQ) and the Short Form 12 (SF12) were assessed by patients with PSC and their doctors while the Paediatric quality of life inventory Transplant Module (PedsQL-TM) and the EuroQoL-5 dimensions (EQ. 5D) were evaluated by the renal transplant recipients and their doctors. The discussions were audio recorded and transcribed verbatim. Coding of the transcripts was done using the Nvivo 11 Plus software. Thematic analysis was conducted to identify the main themes and subthemes. Results: Four themes were identified, namely: (i) potential benefits of PROMs in the management of rare diseases; (ii) views on selected questionnaires; (iii) practical considerations for implementation; and (iv) potential facilitators and barriers of implementation. Patients and clinicians suggested that the use of ePROMs may facilitate patient-centred care by promoting patient-clinician communication, highlighting aspects of HRQOL that are important to patients and encouraging patient involvement in their care. They also felt that the disease-specific CLDQ and PedsQL-TM were more relevant than the generic SF12 and EQ-5D. Conclusions: Patients with rare diseases often experience impaired HRQOL. The use of an ePROM system may enhance the routine management of patients with rare diseases.
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PurposeTo evaluate the biliary tree and hepatic parenchymal findings on magnetic resonance imaging (MRI) and magnetic resonance cholangiopancreatography (MRCP) in small-duct primary sclerosing cholangitis (SD-PSC).Methods Thirty-nine patients with biopsy-proven primary sclerosing cholangitis (PSC) without any bile duct abnormality on MRCP (n = 15) or ERCP (n = 24) at the time of diagnosis were identified. Follow-up MRCP was available in 36/39 patients (12/15 Baseline MRCP group and 24 Baseline ERCP group). Two radiologists in consensus assessed the MRI/MRCP findings. The baseline MRI/MRCP of 15 SD-PSC patients was compared with MRI/MRCP of 15 normal healthy potential liver donors (Control group). Comparisons were made between SD-PSC patients and the Control group, and between baseline and follow-up MRI/MRCP findings in the SD-PSC patients.ResultsIn the 15 Baseline MRCP SD-PSC subjects, the biliary tree was normal with a trend of larger bile ducts compared to the Control group. Periductal enhancement (arterial phase: 70%, 7/10; delayed phase: 90%, 9/10), heterogeneous parenchymal signal on T2-weighted (53%, 8/15) and post contrast-enhanced images (70%, 7/10), and enlarged periportal lymph nodes (73%, 11/15) were frequently present in patients with SD-PSC. Eight (33%) of 24 SD-PSC patients who had normal MRCP at baseline MRCP or initial follow-up MRCP after normal baseline ERCP showed large-duct PSC (LD-PSC) features on follow-up and the 10-year cumulative incidence for progression to LD-PSC rate was 8.5%.ConclusionSD-PSC patients have a normal biliary tree but frequently have peribiliary enhancement, abnormal parenchymal signal intensity, and periportal lymphadenopathy. One-third shows progression to LD-PSC on follow-up.
Article
To expand on the work of previous meetings, a virtual Baveno VII workshop was organised for October 2021. Among patients with compensated cirrhosis or compensated advanced chronic liver disease (cACLD - defined at the Baveno VI conference), the presence or absence of clinically significant portal hypertension (CSPH) is associated with differing outcomes, including risk of death, and different diagnostic and therapeutic needs. Accordingly, the Baveno VII workshop was entitled "Personalized Care for Portal Hypertension". The main fields of discussion were the relevance and indications for measuring the hepatic venous pressure gradient as a gold standard, the use of non-invasive tools for the diagnosis of cACLD and CSPH, the impact of aetiological and non-aetiological therapies on the course of cirrhosis, the prevention of the first episode of decompensation, the management of an acute bleeding episode, the prevention of further decompensation, as well as the diagnosis and management of splanchnic vein thrombosis and other vascular disorders of the liver. For each of these 9 topics, a thorough review of the medical literature was performed, and a series of consensus statements/recommendations were discussed and agreed upon. A summary of the most important conclusions/recommendations derived from the workshop is reported here. The statements are classified as unchanged, changed, and new in relation to Baveno VI.
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Key messages • Liver disease is now the second leading cause of years of working life lost in Europe, after only ischaemic heart disease • The clinical focus in patients with liver disease is oriented towards cirrhosis and its complications, whereas early and reversible disease stages are frequently disregarded and overlooked • The dissociation between primary and secondary care and the considerable heterogeneity across clinical pathways and inconsistent models of care cause delays in diagnosis of both rare and common liver diseases • Stigma has a major impact on liver diseases in Europe, leading to discrimination, reduction in health-care seeking behaviour, and reduced allocation of resources, which all result in poor clinical outcomes • Europe has the highest level of alcohol consumption in the world, which, together with ultra-processed food consumption and high prevalence of obesity, are the major drivers of liver-related morbidity and mortality • A scarcity of consistent and efficient screening and vaccination programmes for viral hepatitis combined with the high costs of drugs due to variable European reimbursement systems result in reduced access to treatment and delays in elimination programmes • COVID-19, alongside imposing delays in diagnostic pathways of liver diseases, has brought overlapping metabolic risk factors and social inequities into the spotlight as crucial barriers to liver health for the next generation of Europeans • Liver diseases are generally avoidable or treatable if measures for prevention and early detection are properly implemented; achieving this would reduce premature morbidity and mortality, saving the lives of almost 300 000 people across Europe each year
Article
Recommendations 1 ESGE suggests performing segmental biopsies (at least two from each segment), which should be placed in different specimen containers (ileum, cecum, ascending, transverse, descending, and sigmoid colon, and rectum) in patients with clinical and endoscopic signs of colitis. Weak recommendation, low quality of evidence. 2 ESGE recommends taking two biopsies from the right hemicolon (ascending and transverse colon) and, in a separate container, two biopsies from the left hemicolon (descending and sigmoid colon) when microscopic colitis is suspected. Strong recommendation, low quality of evidence. 3 ESGE recommends pancolonic dye-based chromoendoscopy or virtual chromoendoscopy with targeted biopsies of any visible lesions during surveillance endoscopy in patients with inflammatory bowel disease. Strong recommendation, moderate quality of evidence. 4 ESGE suggests that, in high risk patients with a history of colonic neoplasia, tubular-appearing colon, strictures, ongoing therapy-refractory inflammation, or primary sclerosing cholangitis, chromoendoscopy with targeted biopsies can be combined with four-quadrant non-targeted biopsies every 10 cm along the colon. Weak recommendation, low quality of evidence. 5 ESGE recommends that, if pouch surveillance for dysplasia is performed, visible abnormalities should be biopsied, with at least two biopsies systematically taken from each of the afferent ileal loop, the efferent blind loop, the pouch, and the anorectal cuff. Strong recommendation, low quality of evidence. 6 ESGE recommends that, in patients with known ulcerative colitis and endoscopic signs of inflammation, at least two biopsies be obtained from the worst affected areas for the assessment of activity or the presence of cytomegalovirus; for those with no evident endoscopic signs of inflammation, advanced imaging technologies may be useful in identifying areas for targeted biopsies to assess histologic remission if this would have therapeutic consequences. Strong recommendation, low quality of evidence. 7 ESGE suggests not biopsying endoscopically visible inflammation or normal-appearing mucosa to assess disease activity in known Crohn’s disease. Weak recommendation, low quality of evidence. 8 ESGE recommends that adequately assessed colorectal polyps that are judged to be premalignant should be fully excised rather than biopsied. Strong recommendation, low quality of evidence. 9 ESGE recommends that, where endoscopically feasible, potentially malignant colorectal polyps should be excised en bloc rather than being biopsied. If the endoscopist cannot confidently perform en bloc excision at that time, careful representative images (rather than biopsies) should be taken of the potential focus of cancer, and the patient should be rescheduled or referred to an expert center. Strong recommendation, low quality of evidence. 10 ESGE recommends that, in malignant lesions not amenable to endoscopic excision owing to deep invasion, six carefully targeted biopsies should be taken from the potential focus of cancer. Strong recommendation, low quality of evidence.
Article
Background & Aims Although the association between inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC) is well recognised, uncertainties remain about the magnitude of this problem. We conducted a systematic review and meta-analysis assessing prevalence of PSC in IBD to investigate whether type of IBD, how presence of PSC was defined, sex, disease extent or location, time period, or geographical location influenced prevalence. Methods MEDLINE, EMBASE, and EMBASE Classic were searched (from inception to 10th April 2021) to identify observational studies recruiting ≥50 adult patients with IBD reporting prevalence of PSC. Data were extracted, and pooled prevalence, odds ratios (OR), and 95% confidence intervals (CIs) calculated. Results Of 1204 citations, 64 studies were eligible, containing 776,700 patients. Overall, pooled prevalence of PSC in IBD was 2.16%, and was highest in South America and lowest in Southeast Asia. Pooled prevalence in patients with UC, CD, or IBD-U was 2.47%, 0.96% and 5.01%, respectively. Pooled prevalence was significantly higher in UC versus CD (OR = 1.69; 95% CI 1.24-2.29). In subgroup analyses according to method used to define presence of PSC, the highest prevalence was 2.88% in studies performing both liver biochemistry and ERCP/MRCP, and the lowest was 1.79% in studies using a clinical diagnosis. Prevalence was generally higher in men, patients with more extensive, compared with left-sided, UC or ileocolonic or colonic, compared with ileal, CD. Conclusions Our findings provide the first pooled estimates of the burden of PSC in IBD, as well as potential risk factors, which may be important in establishing a prompt diagnosis and initiating appropriate surveillance for relevant gastrointestinal malignancies.
Article
Primary sclerosing cholangitis (PSC) is a chronic inflammatory disorder affecting the bile ducts and is characterized by biliary strictures, progressive liver parenchymal fibrosis, and an increased risk of hepatobiliary malignancies primarily cholangiocarcinoma (CCA). PSC may lead to portal hypertension, liver decompensation, and liver failure with the need for liver transplantation. Magnetic resonance imaging (MRI)/magnetic resonance cholangiopancreatography (MRCP) are considered the imaging standard for diagnosis and follow-up in patients with PSC. Currently, there are no universally accepted reporting standards and definitions for MRI/MRCP features. Controversies exist about the definition of a high-grade stricture and there is no widely agreed approach to their management. The members of the MRI working group of the International Primary Sclerosing Cholangitis Study Group (IPSCSG) sought to define terminologies and reporting standards for describing MRI/MRCP features that would be applied to diagnosis and surveillance of disease progression, and potentially for evaluating treatment response in clinical trials. In this extensive review, the technique of MRI/MRCP and assessment of image quality for the evaluation of PSC is briefly described. The definitions and terminologies for severity and length of strictures, duct wall thickening and hyperenhancement, and liver parenchyma signal intensity changes are outlined. As CCA is an important complication of PSC, standardized reporting criteria for CCA developing in PSC are summarized. Finally, the guidelines for reporting important changes in follow-up MRI/MRCP studies are provided. • Primary sclerosing cholangitis is a chronic inflammatory disorder affecting the bile ducts, causing biliary strictures and liver fibrosis and an increased risk of cholangiocarcinoma. • This consensus document provides definitions and suggested reporting standards for MRI and MRCP features of primary sclerosing cholangitis, which will allow for a standardized approach to diagnosis, assessment of disease severity, follow-up, and detection of complications. • Standardized definitions and reporting of MRI/MRCP features of PSC will facilitate comparison between studies, promote longitudinal assessment during management, reduce inter-reader variability, and enhance the quality of care and communication between health care providers.
Article
This is the first American Association for the Study of Liver Diseases (AASLD) Practice Guidance on the management of malnutrition, frailty, and sarcopenia in patients with cirrhosis. This guidance represents the consensus of a panel of experts after a thorough review and vigorous debate of the literature published to date, incorporating clinical experience and common sense to fill in the gaps when appropriate. Our goal was to offer clinicians pragmatic recommendations that could be implemented immediately in clinical practice to target malnutrition, frailty, and sarcopenia in this population.
Article
Objectives To study the association of MRCP+ parameters with biochemical scoring systems and MR elastography (MRE) in primary sclerosing cholangitis (PSC). To evaluate the incremental value of combining MRCP+ with morphological scores in associating with biochemical scores.Methods and materialsMRI images, liver stiffness measurements by MRE, and biochemical testing of 65 patients with PSC that were retrospectively enrolled between January 2014 and December 2015 were obtained. MRCP+ was used to post-process MRCP images to obtain quantitative measurements of the bile ducts and biliary tree. Linear regression analysis was used to test the associations. Bootstrapping was used as a validation method.ResultsThe total number of segmental strictures had the strongest association with Mayo Risk Score (R2 = 0.14), minimum stricture diameter had the highest association with Amsterdam Oxford Prognostic Index (R2 = 0.12), and the percentage of duct nodes with width 0–3 mm had the strongest association with PSC Risk Estimate Tool (R2 = 0.09). The presence of Ducts with medians > 9 mm had the highest association with MRE (R2= 0.21). The strength of association of MRCP+ to Mayo Risk Score was similar to ANALI2 and weaker than MRE (R2 = 0.23, 0.24, 0.38 respectively). MRCP+ enhanced the association of ANALI 2 and MRE with the Mayo Risk Score.ConclusionsMRCP+ demonstrated a significant association with biochemical scores and MRE. The association of MRCP+ with the biochemical scores was generally comparable to ANALI scores. MRCP+ enhanced the association of ANALI2 and MRE with the Mayo Risk Score.Key Points • MRCP+ has the potential to act as a risk stratfier in PSC. • MRE outperformed MRCP+ for risk stratifcation. • Combination of MRCP+ with MRE and ANALI scores improved overall performace as risk stratifiers.
Article
Primary sclerosing cholangitis (PSC) is a rare, inflammatory cholestatic liver disease that causes biliary strictures which can lead to secondary complications. About 30-50% of PSC patients develop dominant strictures (DS) in the biliary tree, which are both the cause of jaundice and bacterial cholangitis as well as predilection spots for development of neoplastic development. Cancer is the most common cause of death in PSC. A central concern is to distinguish malignant from benign strictures, which eventually is done by invasive methods to obtain a brush cytology or biopsy sample, in most cases via endoscopic retrograde cholangiography-pancreatography (ERCP). Since medical therapies, like ursodesoxycholic acid or immunosuppressive drugs have no proven effect, therapeutic ERCP has become the primary management strategy to improve symptoms and in some patients may slow down disease progression. This article aims at outlining the current and emerging methods in ERCP in PSC patients.