Ulcerative colitis with low-grade dysplasia

Primary sclerosing cholangitis (PSC) is a chronic progressive inflammatory disease of the bile ducts that is surrounded by much uncertainty. First of all, it is a rare disease, with reported prevalence between 0 and 31.7 per 100,000 individuals,1Boonstra K. Beuers U. Ponsioen C.Y. Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: a systematic review.J Hepatol. 2012; 56: 1181-1188Abstract Full Text Full Text PDF PubMed Scopus (457) Google Scholar,2Barner-Rasmussen N. Pukkala E. Jussila A. et al.Epidemiology, risk of malignancy and patient survival in primary sclerosing cholangitis: a population-based study in Finland.Scand J Gastroenterol. 2020; 55: 74-81Crossref PubMed Scopus (31) Google Scholar and establishing a diagnosis can be difficult. The primary pathology is hidden deep in the liver, and there is no specific and easy noninvasive diagnostic test for PSC. Histologic features of fibrosing cholangiopathy are present in <20% of liver biopsy specimens obtained from patients with PSC and can also be seen in cases of secondary sclerosing cholangitis. Current US and European guidelines do not recommend liver biopsy for making a diagnosis of PSC except for suspected cases of small duct PSC and pediatric cases.3Lindor K.D. Kowdley K.V. Harrison M.E. ACG clinical guideline: primary sclerosing cholangitis.Am J Gastroenterol. 2015; 110: 646-659Crossref PubMed Scopus (358) Google Scholar,4European Association for the Study of the LiverEASL clinical practice guidelines: management of cholestatic liver diseases.J Hepatol. 2009; 51: 237-267Abstract Full Text Full Text PDF PubMed Scopus (1433) Google Scholar In addition, biliary tract abnormalities can be found on magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiography (ERC) in a wide array of conditions (see Supplementary Table 1). Furthermore, the course of PSC can be variable. Liver transplant–free survival ranges between 14.5 and 21.3 years in large cohorts.5Weismüller T.J. Trivedi P.J. Bergquist A. et al.Patient age, sex, and inflammatory bowel disease phenotype associate with course of primary sclerosing cholangitis.Gastroenterology. 2017; 152: 1975-1984Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar,6Boonstra K. Weersma R.K. van Erpecum K.J. et al.Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis.Hepatology. 2013; 58: 2045-2055Crossref PubMed Scopus (460) Google Scholar An important risk factor affecting survival is the development of cholangiocarcinoma (CCA). This has a cumulative incidence of approximately 20% at 20 years after diagnosis, but one third of CCA cases become manifest within 1 year after the diagnosis of PSC.5Weismüller T.J. Trivedi P.J. Bergquist A. et al.Patient age, sex, and inflammatory bowel disease phenotype associate with course of primary sclerosing cholangitis.Gastroenterology. 2017; 152: 1975-1984Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar,6Boonstra K. Weersma R.K. van Erpecum K.J. et al.Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis.Hepatology. 2013; 58: 2045-2055Crossref PubMed Scopus (460) Google Scholar Last but not least, the cause of PSC is still enigmatic, and consequently, there is no therapy that has been proven to modify disease progression. In recent years, there has been an upsurge of pilot studies and phase 2 clinical trials. Phase 2 and 3 trials are hampered by the lack of established surrogate endpoints for clinical outcome, the heterogeneity of the disease course, and the lack of clear definitions for many key clinical disease characteristics.7Ponsioen C.Y. Chapman R.W. Chazouillères O. et al.Surrogate endpoints for clinical trials in primary sclerosing cholangitis: review and results from an International PSC Study Group consensus process.Hepatology. 2016; 63: 1357-1367Crossref PubMed Scopus (124) Google Scholar While the available national and international clinical practice guidelines predominantly focus on clinical management, the International PSC Study Group (IPSCSG) has recognized that there is a vital need for clinical trials to use uniform definitions for the diagnosis of PSC and for assessing disease severity and outcomes.3Lindor K.D. Kowdley K.V. Harrison M.E. ACG clinical guideline: primary sclerosing cholangitis.Am J Gastroenterol. 2015; 110: 646-659Crossref PubMed Scopus (358) Google Scholar,4European Association for the Study of the LiverEASL clinical practice guidelines: management of cholestatic liver diseases.J Hepatol. 2009; 51: 237-267Abstract Full Text Full Text PDF PubMed Scopus (1433) Google Scholar,8Chapman M.H. Thorburn D. Hirschfield G.M. et al.British Society of Gastroenterology and UK-PSC guidelines for the diagnosis and management of primary sclerosing cholangitis.Gut. 2019; 68: 1356-1378Crossref PubMed Scopus (135) Google Scholar Therefore, the IPSCSG has commissioned a consensus process among its experts to issue a set of definitions to aid clinical trialists designing much needed clinical trials. To this end, an extensive consensus process was initiated, applying a hybrid between a Delphi process and a nominal group process, as was previously used by the IPSCSG and the European Crohn's and Colitis Organization.7Ponsioen C.Y. Chapman R.W. Chazouillères O. et al.Surrogate endpoints for clinical trials in primary sclerosing cholangitis: review and results from an International PSC Study Group consensus process.Hepatology. 2016; 63: 1357-1367Crossref PubMed Scopus (124) Google Scholar,9Dignass A. Eliakim R. Magro F. et al.Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 1: definitions and diagnosis.J Crohns Colitis. 2012; 6: 965-990Abstract Full Text Full Text PDF PubMed Scopus (675) Google Scholar Where necessary, an additional survey was conducted among all IPSCSG members (see the Supplementary Methods for details). Results are presented as a comprehensive set of consensus statements (CSs) and diagnostic criteria for PSC. Although patients with PSC are increasingly diagnosed at earlier stages of disease based on asymptomatic serum liver enzyme abnormalities, at least 45% of patients PSC present with symptoms on either a constant or intermittent basis, which significantly reduces quality of life.10Broome U. Olsson R. Lööf L. et al.Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis.Gut. 1996; 38: 610-615Crossref PubMed Google Scholar Furthermore, more than 22% of asymptomatic patients may develop symptoms within 5 years. The most common clinical symptoms associated with PSC are fatigue; pruritus; right upper quadrant (RUQ) abdominal pain; and emotional distress, which may include anxiety and depression symptoms. Pruritus and abdominal pain can fluctuate dramatically, and this may be suddenly worsened because of the development of a biliary obstruction or acute bacterial cholangitis. Therefore, clinical evaluation with laboratory testing and imaging may be necessary in the event of the sudden appearance or worsening of symptoms. Emotional distress for many patients is attributable to chronic anxiety about the uncertain etiology of the disease, the lack of effective therapy, and the risk of malignancy, among others.11Ranieri V. Kennedy E. Walmsley M. et al.The Primary Sclerosing Cholangitis (PSC) Wellbeing study: understanding psychological distress in those living with PSC and those who support them.PLoS One. 2020; 15e0234624Crossref PubMed Scopus (10) Google Scholar The incorporation of clearly defined patient-reported symptoms into the design of clinical trials is both desirable from a patient-centered perspective and highly encouraged by regulatory agencies12Ponsioen C.Y. Lindor K.D. Mehta R. et al.Design and endpoints for clinical trials in primary sclerosing cholangitis.Hepatology. 2018; 68: 1174-1188Crossref PubMed Scopus (43) Google Scholar (Box 1, CS 1.1). Recently, 2 such tools have emerged. One patient-reported outcome (PRO) dedicated to PSC showed excellent reliability and was able to discern patients with cirrhosis and those with a history of depression.13Younossi Z.M. Afendy A. Stepanova M. et al.Development and validation of a primary sclerosing cholangitis-specific patient-reported outcomes instrument: the PSC PRO.Hepatology. 2018; 68: 155-165Crossref PubMed Scopus (21) Google Scholar A more recently developed tool to assess patient-reported symptoms, the Simple Cholestatic Complaints Score, was developed through digital surveys of patients and showed good criterion and construct validity and a very high test-retest reproducibility.14Munster K.N. Dijkgraaf M.G.W. Gennep S. et al.The Simple Cholestatic Complaints Score is a valid and quick patient-reported outcome measure in primary sclerosing cholangitis.Liver Int. 2020; 40: 2758-2766Crossref PubMed Scopus (0) Google Scholar Further validation of these tools in larger and more diverse cohorts is needed.Box 1Consensus StatementsTabled 11.Clinical symptoms1.1.Assessment of symptoms in patients with PSC for clinical trial purposes should be performed through disease-specific and validated quantitative tools.1.2.Assessment of symptoms in patients with PSC should take into consideration and be distinguished from symptoms attributable to active inflammatory bowel disease and other coexistent conditions.2.Laboratory markers2.1.The presence of significant elevations of serum aminotransferase activity (>5 × ULN) and/or IgG (>2 × ULN) can be indicative of features of coexisting autoimmune hepatitis and should trigger consideration of liver biopsy for diagnostic and stratification purposes when considering enrolling a subject in a clinical trial.2.2.Serum IgG4 concentrations can be elevated in patients with PSC, in the absence of classical features of IgG4-related disease, but IgG4 elevations are not validated markers of disease diagnosis, severity, prognosis, or treatment.3.Imaging3.1.The pattern of PSC can be defined according to the appearances of cholangiography using high-quality magnetic resonance cholangiography (MRC) (at least 1.5 T):3.1.1.Small duct when a recent cholangiogram (not older than 1 year) is normal3.1.2.Intrahepatic when there are intrahepatic changes but the common ducts and first-order ducts are normal3.1.3.Extrahepatic disease when the common ducts and/or the first-order ducts are involved4.Histology4.1.Histologic findings in a liver biopsy sample from patient suspected to have PSC can be defined (classified) as follows:4.1.1.Typical of PSC: features of fibrosing cholangiopathy present (periductal fibrosis, fibro-obliterative duct lesions)4.1.2.Compatible with PSC: features of chronic biliary disease present (see text for further details) without typical bile duct lesions4.1.3.Atypical for PSC: features atypical for PSC present. Examples include•unusually prominent inflammatory activity suggesting the possibility of PSC-AIH overlap syndrome•features suggesting an alternative diagnosis, such as fatty liver disease, or IgG4-associated cholangitis.4.2.A liver biopsy specimen showing typical or compatible histologic features is required to establish a diagnosis of small duct PSC.4.3.In a person with PSC, a liver biopsy specimen showing at least moderate interface hepatitis in addition to features compatible with or diagnostic of PSC is required to establish a diagnosis of PSC with features of AIH or PSC-AIH overlap syndrome.4.4.The histologic features that indicate disease progression (staging) in PSC include fibrosis, bile duct loss, and evidence of chronic cholestasis (demonstrated by deposition of copper-associated protein in periportal hepatocytes).5.Concurrent IBD5.1.The definition and description of IBD in PSC should follow the European Crohn's and Colitis Organization (ECCO) guidelines and Montreal classification. Any patient with established PSC should undergo a full ileocolonoscopy with histology before concurrent IBD may be excluded.5.2.When assessing the existence of backwash ileitis, it is recommended that the ECCO definition be followed. This defines backwash ileitis as continuous extension of macroscopic or histologic inflammation from the cecum into the most distal ileum.6.Staging6.1.Disease staging of PSC is defined as the histologic progression from initial disease onset to cirrhosis.6.2.A clinically significant change in disease stage is defined by a 1-point change in the Ludwig or Nakanuma system or a 2-point change in the Ishak system.6.3.Histologic cirrhosis is a clinically significant endpoint.6.4.Cirrhosis (stage 5–6 by Ishak) in PSC can be defined by an LS of >14.4 kPa measured by VCTE.6.5.Cirrhosis (stage 5–6 or greater by Ishak) in PSC can be defined by an ELF score of >9.8 or FibroTest of >7.3.7.Clinical endpoints7.1.Liver transplant:Liver transplant is an appropriate endpoint in PSC clinical trials. However, divergent indications for transplant listing (end-stage disease, dysplasia, CCA, symptoms, intractable cholangitis) and method of transplantation (deceased vs living donation) should not be grouped into a single endpoint because of the wide heterogeneity of clinical practice.7.2.Liver-related death:Liver-related death in the setting of PSC is defined as death from clinically significant portal hypertension, synthetic liver dysfunction, or specific complications from biliary disease such as hepatobiliary infections.8.Cancer development8.1.Cholangiocarcinoma:8.1.1.CCA in PSC requires pathologic confirmation and is classified according to CCA in general.8.1.2.Dysplastic changes considered precursors to CCA in PSC are defined by standard criteria.8.2.Colorectal carcinoma:8.2.1.CRC in the setting of PSC is defined according to standard criteria.9.Pediatric PSC9.1.Pediatric PSC is not a specific disease phenotype. PSC in children should be described in terms of small vs large duct involvement, whether features of overlap with AIH are present or absent, and whether IBD is present or absent, as in adult patients.9.2.Terms such as juvenile sclerosing cholangitis and autoimmune sclerosing cholangitis should be avoided.9.3.When gGT is substituted for ALP, the consensus definitions in this document are applicable to children.10.Recurrent PSC10.1.The diagnosis of rPSC is based on the presence of compatible radiologic changes (using high-quality MR) with/or without histologic findings, along with the exclusion of other causes of similar findings. Open table in a new tab Tabled 11.Clinical symptoms1.1.Assessment of symptoms in patients with PSC for clinical trial purposes should be performed through disease-specific and validated quantitative tools.1.2.Assessment of symptoms in patients with PSC should take into consideration and be distinguished from symptoms attributable to active inflammatory bowel disease and other coexistent conditions.2.Laboratory markers2.1.The presence of significant elevations of serum aminotransferase activity (>5 × ULN) and/or IgG (>2 × ULN) can be indicative of features of coexisting autoimmune hepatitis and should trigger consideration of liver biopsy for diagnostic and stratification purposes when considering enrolling a subject in a clinical trial.2.2.Serum IgG4 concentrations can be elevated in patients with PSC, in the absence of classical features of IgG4-related disease, but IgG4 elevations are not validated markers of disease diagnosis, severity, prognosis, or treatment.3.Imaging3.1.The pattern of PSC can be defined according to the appearances of cholangiography using high-quality magnetic resonance cholangiography (MRC) (at least 1.5 T):3.1.1.Small duct when a recent cholangiogram (not older than 1 year) is normal3.1.2.Intrahepatic when there are intrahepatic changes but the common ducts and first-order ducts are normal3.1.3.Extrahepatic disease when the common ducts and/or the first-order ducts are involved4.Histology4.1.Histologic findings in a liver biopsy sample from patient suspected to have PSC can be defined (classified) as follows:4.1.1.Typical of PSC: features of fibrosing cholangiopathy present (periductal fibrosis, fibro-obliterative duct lesions)4.1.2.Compatible with PSC: features of chronic biliary disease present (see text for further details) without typical bile duct lesions4.1.3.Atypical for PSC: features atypical for PSC present. Examples include•unusually prominent inflammatory activity suggesting the possibility of PSC-AIH overlap syndrome•features suggesting an alternative diagnosis, such as fatty liver disease, or IgG4-associated cholangitis.4.2.A liver biopsy specimen showing typical or compatible histologic features is required to establish a diagnosis of small duct PSC.4.3.In a person with PSC, a liver biopsy specimen showing at least moderate interface hepatitis in addition to features compatible with or diagnostic of PSC is required to establish a diagnosis of PSC with features of AIH or PSC-AIH overlap syndrome.4.4.The histologic features that indicate disease progression (staging) in PSC include fibrosis, bile duct loss, and evidence of chronic cholestasis (demonstrated by deposition of copper-associated protein in periportal hepatocytes).5.Concurrent IBD5.1.The definition and description of IBD in PSC should follow the European Crohn's and Colitis Organization (ECCO) guidelines and Montreal classification. Any patient with established PSC should undergo a full ileocolonoscopy with histology before concurrent IBD may be excluded.5.2.When assessing the existence of backwash ileitis, it is recommended that the ECCO definition be followed. This defines backwash ileitis as continuous extension of macroscopic or histologic inflammation from the cecum into the most distal ileum.6.Staging6.1.Disease staging of PSC is defined as the histologic progression from initial disease onset to cirrhosis.6.2.A clinically significant change in disease stage is defined by a 1-point change in the Ludwig or Nakanuma system or a 2-point change in the Ishak system.6.3.Histologic cirrhosis is a clinically significant endpoint.6.4.Cirrhosis (stage 5–6 by Ishak) in PSC can be defined by an LS of >14.4 kPa measured by VCTE.6.5.Cirrhosis (stage 5–6 or greater by Ishak) in PSC can be defined by an ELF score of >9.8 or FibroTest of >7.3.7.Clinical endpoints7.1.Liver transplant:Liver transplant is an appropriate endpoint in PSC clinical trials. However, divergent indications for transplant listing (end-stage disease, dysplasia, CCA, symptoms, intractable cholangitis) and method of transplantation (deceased vs living donation) should not be grouped into a single endpoint because of the wide heterogeneity of clinical practice.7.2.Liver-related death:Liver-related death in the setting of PSC is defined as death from clinically significant portal hypertension, synthetic liver dysfunction, or specific complications from biliary disease such as hepatobiliary infections.8.Cancer development8.1.Cholangiocarcinoma:8.1.1.CCA in PSC requires pathologic confirmation and is classified according to CCA in general.8.1.2.Dysplastic changes considered precursors to CCA in PSC are defined by standard criteria.8.2.Colorectal carcinoma:8.2.1.CRC in the setting of PSC is defined according to standard criteria.9.Pediatric PSC9.1.Pediatric PSC is not a specific disease phenotype. PSC in children should be described in terms of small vs large duct involvement, whether features of overlap with AIH are present or absent, and whether IBD is present or absent, as in adult patients.9.2.Terms such as juvenile sclerosing cholangitis and autoimmune sclerosing cholangitis should be avoided.9.3.When gGT is substituted for ALP, the consensus definitions in this document are applicable to children.10.Recurrent PSC10.1.The diagnosis of rPSC is based on the presence of compatible radiologic changes (using high-quality MR) with/or without histologic findings, along with the exclusion of other causes of similar findings. Open table in a new tab A particular challenge in assessing clinical symptoms in patients with PSC is the frequent concurrence of inflammatory bowel disease (IBD), which itself can influence the clinical course of PSC and may also account for a significant proportion of symptoms, especially during periods of IBD exacerbations.15Cheung A.C. Patel H. Meza-Cardona J. et al.Factors that influence health-related quality of life in patients with primary sclerosing cholangitis.Dig Dis Sci. 2016; 61: 1692-1699Crossref PubMed Scopus (1) Google Scholar Existing tools, including the PSC PRO, do not specifically account for symptoms attributable to IBD. Although the Simple Cholestatic Complaints Score did not show a difference in PSC patient symptoms according to the presence or absence of IBD, a systematic evaluation of IBD symptoms in patients with PSC has not been performed, which can result in confounding findings. Therefore, assessment of PSC symptoms should be performed alongside specifically designed tools to detect symptoms from IBD in those with PSC-IBD or other relevant coexistent conditions (Box 1, CS 1.2) This is critically important for clinical trials that aim to use PRO measures as endpoints in PSC. Cholestatic serum liver tests are a characteristic, but nonspecific, feature of biliary disease irrespective of the nature of biliary involvement. Alkaline phosphatase (ALP) as the hallmark of cholestasis is elevated in the vast majority of patients with PSC.16Poupon R. Liver alkaline phosphatase: a missing link between choleresis and biliary inflammation.Hepatology. 2015; 61: 2080-2090Crossref PubMed Scopus (75) Google Scholar Previously, it was thought that to make a diagnosis of PSC, elevation of ALP, or gamma-glutamyl transpeptidase (gGT) in children (see the "Pediatric Primary Sclerosing Cholangitis" section) was a prerequisite. Recent studies have shown that elevated cholestatic serum parameters need not always be present. For more background, see the Supplementary Material. Aminotransferases are often moderately elevated, whereas at diagnosis, serum bilirubin and albumin levels are usually normal.3Lindor K.D. Kowdley K.V. Harrison M.E. ACG clinical guideline: primary sclerosing cholangitis.Am J Gastroenterol. 2015; 110: 646-659Crossref PubMed Scopus (358) Google Scholar Aminotransferase activity of more than 5 times the upper limit of normal (ULN) and a serum IgG of >2 × ULN should raise the suspicion of coexisting autoimmune hepatitis (AIH) and should trigger consideration of liver biopsy to identify histologic features that would support a diagnosis of AIH or PSC/AIH overlap, also called variant syndrome (Box 1, CS 2.1). This has management consequences, because patients with PSC/AIH commonly respond favorably to immunosuppressive medication such as corticoids and thiopurines, although not as well as patients with isolated AIH.17Boberg K.M. Chapman R.W. Hirschfield G.M. et al.Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue.J Hepatology. 2011; 54: 374-385Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar In contrast to primary biliary cholangitis (PBC) and AIH, there is no pattern of autoantibody reactivity in patients with PSC of relevance to diagnosis or treatment. Positive titers of autoantibodies are common in PSC, including antinuclear antibody (8%–77%), smooth muscle antibody (0%–83%), and atypical perinuclear antibody (26%–94%).18Prideaux L. De Cruz P. Ng S.C. et al.Serological antibodies in inflammatory bowel disease: a systematic review.Inflamm Bowel Dis. 2012; 18: 1340-1355Crossref PubMed Scopus (139) Google Scholar,19Moiseev S. Cohen Tervaert J.W. Arimura Y. et al.2020 International consensus on ANCA testing beyond systemic vasculitis.Autoimmun Rev. 2020; 19: 102618Crossref PubMed Scopus (18) Google Scholar However, these are also frequently present in AIH, and perinuclear antineutrophil cytoplasmic antibodies can be found in ulcerative colitis (UC) in 41%–73% and in Crohn's disease in 6%–38%.17Boberg K.M. Chapman R.W. Hirschfield G.M. et al.Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue.J Hepatology. 2011; 54: 374-385Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 18Prideaux L. De Cruz P. Ng S.C. et al.Serological antibodies in inflammatory bowel disease: a systematic review.Inflamm Bowel Dis. 2012; 18: 1340-1355Crossref PubMed Scopus (139) Google Scholar, 19Moiseev S. Cohen Tervaert J.W. Arimura Y. et al.2020 International consensus on ANCA testing beyond systemic vasculitis.Autoimmun Rev. 2020; 19: 102618Crossref PubMed Scopus (18) Google Scholar Serum IgG4 levels can be elevated in patients with PSC, but this has no validated bearing on diagnosis or disease severity (Box 1, CS 2.2). For distinction from IgG4-sclerosing cholangitis, see the Supplementary Material. Biliary imaging is integral to the diagnosis and classification of PSC. MRCP has been established as the noninvasive imaging of choice.3Lindor K.D. Kowdley K.V. Harrison M.E. ACG clinical guideline: primary sclerosing cholangitis.Am J Gastroenterol. 2015; 110: 646-659Crossref PubMed Scopus (358) Google Scholar,4European Association for the Study of the LiverEASL clinical practice guidelines: management of cholestatic liver diseases.J Hepatol. 2009; 51: 237-267Abstract Full Text Full Text PDF PubMed Scopus (1433) Google Scholar Regarding the utility of magnetic resonance imaging (MRI) in PSC, the reader is referred to a recent publication from the IPSCSG Working Group on MRI in PSC.20Schramm C. Eaton J. Ringe K.I. et al.Recommendations on the use of magnetic resonance imaging in PSC-A position statement from the International PSC Study Group.Hepatology. 2017; 66: 1675-1688Crossref PubMed Scopus Google Scholar A of features are described in large duct PSC, including or within the and/or biliary of the intrahepatic ducts with of the biliary of the and changes not of PSC, and from causes of secondary sclerosing cholangitis in the absence of can be difficult. in the bile ducts on cholangiography are thought to be highly specific for PSC. in the common and common bile the are usually seen in disease and are reported in of cases in a large of C.Y. et al.Natural history of primary sclerosing cholangitis and prognostic of cholangiography in a 51: PubMed Scopus (0) Google Scholar small duct PSC cholangiography is normal is an in PSC. recent have reported on the history of small cohorts of small duct PSC patients to large duct PSC was described in and after a of years of in K. Eaton et resonance imaging features of primary sclerosing 2020; PubMed Scopus Google K.I. Bergquist A. H. et features and MRI progression of small duct primary sclerosing cholangitis J 2020; Full Text Full Text PDF PubMed Scopus (0) Google Scholar (Box 1, CS was no with MRI findings and progression to large duct PSC in either in the bile ducts are a common and clinically relevant of the chronic inflammatory process that in the biliary in PSC. a of large duct PSC patients with the incidence of the development of can be to to approximately in patients with large duct A. P. et al.Development of bile duct in patients with primary sclerosing cholangitis with outcome after endoscopic Hepatol. Full Text Full Text PDF PubMed Scopus Google Scholar extensive in the Supplementary the a of criteria that into the definition of a as in of is called a when it the criteria before MRCP or with of in or first-order intrahepatic not and worsening of cholestatic symptoms within 2 biliary or and/or of × ULN and recent for × P. et of in primary sclerosing cholangitis: outcome after Full Text Full Text PDF PubMed Scopus Google and/or within for × or of >2 × ULN no within is

The Commensal Microbiota and Enteropathogens in the Pathogenesis of Inflammatory Bowel Diseases

We have reconstituted human mitochondrial transcription in vitro on DNA oligonucleotide templates representing the light strand and heavy strand-1 promoters using protein components (RNA polymerase and transcription factors A and B2) isolated from Escherichia coli. We show that 1 eq of each transcription factor and polymerase relative to the promoter is required to assemble a functional initiation complex. The light strand promoter is at least 2-fold more efficient than the heavy strand-1 promoter, but this difference cannot be explained solely by the differences in the interaction of the transcription machinery with the different promoters. In both cases, the rate-limiting step for production of the first phosphodiester bond is open complex formation. Open complex formation requires both transcription factors; however, steps immediately thereafter only require transcription factor B2. The concentration of nucleotide required for production of the first dinucleotide product is substantially higher than that required for subsequent cycles of nucleotide addition. In vitro, promoter-specific differences in post-initiation control of transcription exist, as well as a second rate-limiting step that controls conversion of the transcription initiation complex into a transcription elongation complex. Rate-limiting steps of the biochemical pathways are often those that are targeted for regulation. Like the more complex multisubunit transcription systems, multiple steps may exist for control of transcription in human mitochondria. The tools and mechanistic framework presented here will facilitate not only the discovery of mechanisms regulating human mitochondrial transcription but also interrogation of the structure, function, and mechanism of the complexes that are regulated during human mitochondrial transcription.

AGA Clinical Practice Update on Management of Inflammatory Bowel Disease in Elderly Patients: Expert Review

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Esophageal chromoendoscopy in Barrett's esophagus: “cons”

Other articles in this series concentrate on normal physiological and cellular functions of hyaluronan. In this article we discuss the influences of hyaluronan on disease progression. Alterations in hyaluronan metabolism, distribution, and function have been documented in many diseases, e.g. arthritis, immune and inflammatory disorders, pulmonary and vascular diseases, and cancer (see Refs. 1 and 2). In this article we will concentrate on cancer and vascular disease because our knowledge in these areas has advanced rapidly over the past several years and because work in these areas has highlighted the importance of hyaluronan-cell interactions in cell behavior.

Pulmonary Hypertension: From an Orphan Disease to a Public Health Problem

The multipotentiality and self-renewal ability of stem cells are controlled by intrinsic genetic pathways that are subject to regulation by extrinsic signals emanating from the stem cell niche. The stem cell niche provides a microenvironment composed of cellular structures or extracellular matrix in which stem cells are maintained as undifferentiated (1Li L. Xie T. Annu. Rev. Cell Dev. Biol. 2005; 21: 605-631Crossref PubMed Scopus (942) Google Scholar, 2Lin H. Nat. Rev. Genet. 2002; 3: 931-940Crossref PubMed Scopus (305) Google Scholar, 3Scadden D.T. Nature. 2006; 441: 1075-1079Crossref PubMed Scopus (1508) Google Scholar, 4Spradling A. Drummond-Barbosa D. Kai T. Nature. 2001; 414: 98-104Crossref PubMed Scopus (1215) Google Scholar, 5Watt F.M. Hogan B.L. Science. 2000; 287: 1427-1430Crossref PubMed Scopus (1474) Google Scholar, 6Fuchs E. Tumbar T. Guasch G. Cell. 2004; 116: 769-778Abstract Full Text Full Text PDF PubMed Scopus (1481) Google Scholar). The concept of "the stem cell niche" was first proposed in studies of the HSC 2The abbreviations used are:HSChematopoietic stem cellGSCgerm line stem cellBMbone marrowCARCXCL12-abundant reticularCBscystoblastsESCescort stem cellCPscyst progenitorsAng-1angiopoietin-1.2The abbreviations used are:HSChematopoietic stem cellGSCgerm line stem cellBMbone marrowCARCXCL12-abundant reticularCBscystoblastsESCescort stem cellCPscyst progenitorsAng-1angiopoietin-1. (7Schofield R. Blood Cells. 1978; 4: 7-25PubMed Google Scholar); however, in vivo evidence of its existence was first shown in the Drosophila GSC (8Cox D.N. Chao A. Baker J. Chang L. Qiao D. Lin H. Genes Dev. 1998; 12: 3715-3727Crossref PubMed Scopus (802) Google Scholar, 9King F.J. Lin H. Development (Camb.). 1999; 126: 1833-1844PubMed Google Scholar, 10Xie T. Spradling A.C. Science. 2000; 290: 328-330Crossref PubMed Scopus (620) Google Scholar). 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These advantages facilitated identification of the cellular components of the stem cell niche and definition of the molecular basis of physical interaction between stem cells and their niches (23Song X. Xie T. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 14813-14818Crossref PubMed Scopus (184) Google Scholar, 24Yamashita Y.M. Jones D.L. Fuller M.T. Science. 2003; 301: 1547-1550Crossref PubMed Scopus (595) Google Scholar) and revealed key niche signals involved in stem cell regulation (18Kiger A.A. Jones D.L. Schulz C. Rogers M.B. Fuller M.T. Science. 2001; 294: 2542-2545Crossref PubMed Scopus (538) Google Scholar, 25LaFever L. Drummond-Barbosa D. Science. 2005; 309: 1071-1073Crossref PubMed Scopus (248) Google Scholar, 26Szakmary A. Cox D.N. Wang Z. Lin H. Curr. Biol. 2005; 15: 171-178Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar, 27Xie T. Spradling A.C. Cell. 1998; 94: 251-260Abstract Full Text Full Text PDF PubMed Scopus (530) Google Scholar, 28Yamashita Y.M. 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Two HSC niches have been proposed in murine BM, an osteoblastic niche and a vascular niche, in which osteoblasts and vascular endothelial cells have been demonstrated as major components, respectively (34Zhang J. Niu C. Ye L. Huang H. He X. Tong W.G. Ross J. Haug J. Johnson T. Feng J.Q. Harris S. Wiedemann L.M. Mishina Y. Li L. Nature. 2003; 425: 836-841Crossref PubMed Scopus (2385) Google Scholar, 35Calvi L.M. Adams G.B. Weibrecht K.W. Weber J.M. Olson D.P. Knight M.C. Martin R.P. Schipani E. Divieti P. Bringhurst F.R. Milner L.A. Kronenberg H.M. Scadden D.T. Nature. 2003; 425: 841-846Crossref PubMed Scopus (2799) Google Scholar, 36Arai F. Hirao A. Ohmura M. Sato H. Matsuoka S. Takubo K. Ito K. Koh G.Y. Suda T. Cell. 2004; 118: 149-161Abstract Full Text Full Text PDF PubMed Scopus (1540) Google Scholar, 37Nilsson S.K. Johnston H.M. Whitty G.A. Williams B. Webb R.J. Denhardt D.T. Bertoncello I. Bendall L.J. Simmons P.J. Haylock D.N. 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Immunity. 2006; 25: 977-988Abstract Full Text Full Text PDF PubMed Scopus (1693) Google Scholar). Drosophila ovary and testis provide attractive models for stem cell niche studies. In Drosophila ovary, cap cells, a specific type of somatic cell located at the tip of the germarium in the ovary, function as the niche for GSCs. An E-cadherin/β-catenin-formed cell-cell adhesion junction mediates the physical interaction between GSCs and their niche cells (23Song X. Xie T. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 14813-14818Crossref PubMed Scopus (184) Google Scholar, 46Song X. Zhu C.H. Doan C. Xie T. Science. 2002; 296: 1855-1857Crossref PubMed Scopus (389) Google Scholar), ensuring stem cell control by niche signals. Normally, asymmetric division of stem cells results in two daughter cells with different fates: one daughter cell attaches to the niche and is maintained as a stem cell (self-renewal), whereas the other daughter cell leaves the niche and develops into a cystoblast (1Li L. Xie T. Annu. Rev. Cell Dev. Biol. 2005; 21: 605-631Crossref PubMed Scopus (942) Google Scholar, 4Spradling A. Drummond-Barbosa D. Kai T. Nature. 2001; 414: 98-104Crossref PubMed Scopus (1215) Google Scholar). CBs undergo four incomplete cell divisions to form an interconnected 2–16-cell germ line cyst. In addition to the GSC, another type of cell called the ESC also attaches to cap cells interspersed between the GSCs. Together with cap cells, ESCs encapsulate GSCs to separate GSCs from their differentiated daughter cells. When the GSCs divide and detach from the niche to produce CBs and cyst cells, the ESCs also proliferate and differentiate to produce more escort cells. The escort cells expand and continue to encapsulate CBs and cysts during the process of cyst formation and are finally replaced by follicle cells after the 16-cell germ line cyst stage (Fig. 1a). Interestingly, the newly formed cysts (prior to the eight-cell cyst stage, while still encapsulated by the escort cell) can revert to the stem cell state under certain circumstances, suggesting that they may still retain (albeit limited) stem cell properties (47Kai T. Spradling A. Nature. 2004; 428: 564-569Crossref PubMed Scopus (267) Google Scholar). A similar niche is also found in Drosophila testis and is composed of hub cells located at the end of the testis (48Le Bras S. Van Doren M. Dev. Biol. 2006; 294: 92-103Crossref PubMed Scopus (96) Google Scholar). Male GSCs surrounding the hub cells are interspersed with CPs (which are counterparts of ESCs in the ovary). Both GSCs and CPs are attached to the hub cells through an adhesion junction. Similar to ESCs in the ovary, proliferation and differentiation of CPs always accompany proliferation and differentiation of GSCs. CPs in the testis produce cyst cells, which encapsulate the gonialblasts (the immediate daughters of male GSCs) during spermatogonium formation (Fig. 1b). The newly formed gonialblasts can also revert to stem cells under certain circumstances, resembling their counterpart cells (CBs and cysts) in the ovary (49Brawley C. Matunis E. Science. 2004; 304: 1331-1334Crossref PubMed Scopus (326) Google Scholar). The role of cap and hub cells in GSC regulation has been well studied, but the contribution of ESCs and their offspring in the ovary and CPs and their progeny in the testis to GSC self-renewal, proliferation, and differentiation is largely unknown. However, it is known that a dialogue between the two types of cells is required for the coordination during organogenesis (30King F.J. Szakmary A. Cox D.N. Lin H. Mol. Cell. 2001; 7: 497-508Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar). Cap and hub cells provide an attachment point for anchoring GSCs to the niche; they also produce signals that inhibit differentiation but promote self-renewal of stem cells (17Tulina N. Matunis E. Science. 2001; 294: 2546-2549Crossref PubMed Scopus (506) Google Scholar). The stem cell niches in mammals are very complicated because of the complexity of cellular components of mammalian tissues, even though the mechanism for niche regulation is conserved from invertebrate to vertebrate. In mammals, BM tissue is composed of more than eight different hematopoietic cell lineages supported by a network of mesenchymal stromal cells and vascular endothelial cells. The two HSC niches, osteoblastic (34Zhang J. Niu C. Ye L. Huang H. He X. Tong W.G. Ross J. Haug J. Johnson T. Feng J.Q. Harris S. Wiedemann L.M. Mishina Y. Li L. Nature. 2003; 425: 836-841Crossref PubMed Scopus (2385) Google Scholar, 35Calvi L.M. Adams G.B. Weibrecht K.W. Weber J.M. Olson D.P. Knight M.C. Martin R.P. Schipani E. 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The concurrence of hematopoiesis and osteogenesis in BM suggests a close relationship between bone-forming cells and hematopoietic cells (57Patt H.M. Maloney M.A. Proc. Soc. Exp. Biol. Med. 1972; 140: 205-207Crossref PubMed Scopus (35) Google Scholar, 58Maloney M.A. Patt H.M. Proc. Soc. Exp. Biol. Med. 1975; 149: 94-97Crossref PubMed Scopus (12) Google Scholar). Early studies demonstrated that endosteal BM is more highly enriched with HSCs/progenitors compared with central BM (59Lord B.I. Testa N.G. Hendry J.H. Blood. 1975; 46: 65-72Crossref PubMed Google Scholar, 60Gong J.K. Science. 1978; 199: 1443-1445Crossref PubMed Scopus (195) Google Scholar). The facts that hematopoiesis recovery after myeloablative injury occurs on the endosteal bone surface (45Heissig B. Hattori K. Dias S. Friedrich M. Ferris B. Hackett N.R. Crystal R.G. Besmer P. Lyden D. Moore M.A. Werb Z. Rafii S. 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