Causal effects from inflammatory bowel disease on liver function and disease: a two-sample Mendelian randomization study.

Diagnosis and Management of Primary Sclerosing Cholangitis

This study aimed to explore the causal association between inflammatory bowel disease (IBD) and the risk of type 2 diabetes (T2D) based on a two-sample Mendelian randomization (MR) study. Summary single nucleotide polymorphism (SNP)-phenotype association data were obtained from published two genome-wide association studies (GWAS) including SNPs related to IBD, UC, or CD in European participants (n = 71,997) and East Asian participants (n = 16,805). Two GWAS including SNPs associated with T2D included 655,666 Europeans and 433,540 East Asians. A series of screening processes were performed to select qualified instrumental SNPs strongly related to exposure. We applied the inverse variance weighted (IVW), the MR-Egger regression, and the weighted median to estimate the causal effects of IBD, ulcerative colitis (UC) or Crohn' disease (CD) on T2D. Cochran's Q test was conducted to evaluate the statistical heterogeneity between SNPs in the IVW method. The leave-one-out analysis was employed to assess whether the results were caused by any single SNP associated with IBD, UC, or CD. Odds ratio (OR) and 95% confidence interval (CI) were calculated. The IVW results demonstrated that IBD could increase the risk of T2D in the European population (OR = 1.0230, 95%CI: 1.0073-1.0390). UC was positively associated with the risk of T2D according to the weighted median (OR = 1.0274, 95%CI: 1.0009-1.0546) and IVW (OR = 1.0244, 95%CI: 1.0071-1.0421) results in the European population. The IVW results indicated that the CD was positively associated with the risk of T2D in the European population (OR = 1.0187, 95%CI: 1.0045-1.0330). In the East Asian population, there are no associations between the IBD, UC, or CD and the risk of T2D (all P > 0.05). MVMR results revealed that the causal effect UC on T2D was still statistically significant after including body mass index (BMI) or low-density lipoprotein (LDL). IBD, UC, or CD had causal effects on the risk of T2D in the European population, which might provide evidence for the prevention of T2D in patients with IBD, UC, or CD.

: The objective of the present study was to quantify the national pediatric inpatient inflammatory bowel disease (IBD) burden in terms of the number of IBD-related hospitalizations, the number of days spent in the hospital, and hospitalization costs. : Hospitalizations for children and adolescents 20 years and younger with a primary diagnosis of either Crohn disease (CD) or ulcerative colitis (UC) were selected from the 2006 Kids' Inpatient Database (KID). Length of the hospital stay in days (LOS) and charges for the hospitalization were found directly in the Kids' Inpatient Database, and cost was calculated using the hospital's cost-to-charge ratio. Predictor variables included patient characteristics, such as age and severity of illness, and hospital characteristics. Ordinary-least-squares regressions were developed and estimated to explain hospitalization costs. : In 2006, there were 10,777 IBD-related hospitalizations. The total and mean costs for CD were $66.3 million and $10,176 (95% confidence interval [CI] $9647-$10,705), and for UC were $48.6 million and $11,836 (95% CI $10,760-$12,912). For CD, 0- to 5-year-old patients had the highest mean LOS (8.10, 95% CI 5.53-10.67, days) and mean cost ($13,894, 95% CI $9053-$18,735), whereas, for UC, 11- to 15-year-old patients had the highest mean LOS (7.49, 95% CI 6.88-8.10, 95% CI 5.53-10.67, days) and mean cost ($13,407, 95% CI $11,704-$15,110). : For a pediatric disease with a rather low prevalence rate, the estimated annual inpatient pediatric burden of IBD is a sizeable $152.4 million (2010 US$) and 64,985 days spent in the hospital. As medications and outpatient treatments improve for the treatment of IBD, there is an opportunity for significant reduction in inpatient burden.

State of Research in Pediatric Gastroenterology, Hepatology, and Nutrition: 2010 and Beyond

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

Beyond Gene Discovery in Inflammatory Bowel Disease: The Emerging Role of Epigenetics

In order to elucidate the correlation and its pathways between liver diseases and vascular dementia (VaD). We performed two-sample Mendelian randomization (MR) study. We performed a two-sample MR study using summary-level genome-wide association study (GWAS) data for 4 liver diseases (nonalcoholic fatty liver disease [NAFLD], nonalcoholic steatohepatitis [NASH], alcoholic liver disease [ALD], and fibrosis/cirrhosis [FACOL]) and VaD. Inverse variance weighted (IVW) served as the primary analysis, complemented by a suite of sensitivity analyses (Cochran Q test, MR-Egger regression and MR pleiotropy residual sum and outlier [MR-PRESSO]). Furthermore, multivariable MR (MVMR) was conducted to adjust for key metabolic traits, including fasting glucose and triglycerides. The IVW analysis indicated that no significant causal associations were found between any of the 4 liver diseases and the risk of VaD. Sensitivity analyses indicated that the results for NAFLD and FACOL may be affected by heterogeneity, and NAFLD may also be affected by horizontal pleiotropy. Crucially, after adjusting for genetic liability to elevated triglycerides or fasting glucose in MVMR analyses, the initially null association for NAFLD became significant, revealing a protective effect against VaD. Associations for other liver diseases remained null after adjustment. This MR study found no direct causal link between liver diseases and VaD. However, adjusting for glucose or triglycerides revealed a potential protective effect of NAFLD, suggesting metabolic factors may confound the association. Further research is warranted to disentangle the complex relationship between these health conditions.

Background: An association between inflammatory bowel disease (IBD) [which includes ulcerative colitis (UC) and Crohn's disease (CD)] and IgA nephropathy (IgAN) has been discovered in observational studies, but the causal relationship is still unknown. The aim of this study was to clarify the causal link between IBD (which includes UC and CD) and IgAN via a two-sample Mendelian randomization (MR) analysis. Methods: Eligible single-nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs) for analyses and were obtained from the publicly available genome-wide association study (GWAS) summary statistics. Inverse-variance weighting (IVW), Mendelian randomization-Egger (MR-Egger) regression, the Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) test, and the weighted median were utilized to obtain the results. The MR-PRESSO test and MR-Egger regression were also performed to detect and correct horizontal pleiotropy. The Cochran's Q test and "leave-one-out" analysis were also conducted to assess the stability and reliability of the MR results. Results: This study found that IBD, UC, and CD all had significant positive causal effects on IgAN risk (IBD: OR = 1.58, 95% CI 1.15-2.16, p = 4.53 × 10-3; UC: OR = 1.55, 95% CI 1.14-2.11, p = 4.88 × 10-3; CD: OR = 1.57, 95% CI 1.21-2.03, p = 5.97 × 10-4). No significant horizontal pleiotropic effect was found for the causal association between IBD, UC, CD, and the risk of IgAN. Cochran's Q test identified no evidence of heterogeneity for the IV estimates. The "leave-one-out" sensitivity analysis also revealed that the MR results were robust. Conclusion: The results of this two-sample MR analysis supported that IBD, UC, and CD were causally associated with the risk of IgAN, while there was no sufficient evidence for the causal effect of IgAN on IBD, UC, or CD. Our findings provide theoretical support and a new perspective for the diagnosis and treatment of these two diseases.

BackgroundExtraintestinal manifestations (EIMs) significantly affect the life quality of people with inflammatory bowel disease (IBD) and are crucial factors impacting occurrence rates and mortality among IBD patients. This study performed a Mendelian randomization (MR) analysis to investigate the causal relationships between genetically predicted IBD and the development of EIMs, including erythema nodosum (EN), episcleritis, scleritis, uveitis, primary sclerosing cholangitis (PSC), and spondyloarthritis. To further investigate differences between subtypes, separate analyses were conducted for ulcerative colitis (UC) and Crohn’s disease (CD).MethodsThe study was conducted based on genome-wide association studies (GWAS) data. We carefully selected SNPs associated with both exposure and outcome by comparing and integrating data from GWAS and relevant literature, and prioritizing studies with large sample sizes, high quality, and as much population homogeneity as possible. The SNPs associated with IBD, UC and CD were extracted from the International Inflammatory Bowel Disease Genetics Consortium. And the SNPs associated with EIMs were extracted from the UK Biobank, the International PSC Study Group and the FinnGen study. A series of quality control steps were taken in our analysis to select eligible instrumental SNPs which were strongly associated with exposure. The causal effects were estimated using a primary analysis that employed inverse-variance weighting (IVW) and complementary analysis that utilized MR-Egger weighted by the median. A sensitivity analysis was conducted using the Cochran Q statistic, a funnel plot, the MR-Egger intercept, and a leave-one-out approach. Reverse causality analysis was also performed to ensure the robustness of the findings. Furthermore, a fixed-effects meta-analysis was employed to combine MR outcomes from various data origins, bolstering the strength and dependability of our findings.ResultsOur findings indicated that genetically predicted IBD had a robust causal relationship with an increased risk of specific conditions, including EN (OR, 1.20; 95% CI, 1.09–1.32; p < 0.01), uveitis (OR, 1.15; 95% CI, 1.11–1.20; p < 0.01), PSC (OR, 1.21; 95% CI, 1.13–1.28; p < 0.01), and spondyloarthritis (OR, 1.19; 95% CI, 1.14–1.23; p < 0.01). In subgroup analyses, the causal effects of both UC and CD on EN, uveitis, PSC, and spondyloarthritis were also significant and robust. Additionally, no significant evidence of causality was observed between genetically predicted IBD, UC, and CD, and the occurrence of both episcleritis and scleritis. The results of reverse causality analysis indicated a robust causal association between genetically predicted PSC and the elevated risk of IBD (OR, 1.21; 95% CI, 1.15–1.29; p < 0.01), UC (OR, 1.27; 95% CI, 1.17–1.37; p < 0.01), and CD (OR, 1.10; 95% CI, 1.02–1.20; p < 0.01). Additionally, spondyloarthritis had a causal relationship with an increased risk of both IBD (OR, 1.03; 95% CI, 1.01–1.06; p < 0.01) and UC (OR, 1.05; 95% CI, 1.02–1.08; p < 0.01).Graphical abstract

Mendelian randomization (MR) was used to evaluate the bidirectional causal relationship between inflammatory bowel disease (IBD) and interleukins (ILs), chemokines. Genetic instruments and summary data of five ILs and six chemokines were obtained from a genome-wide association study database, and instrumental variables related to IBD were obtained from the FinnGen Consortium. Inverse variance weighting (IVW) was used as the main MR analysis method, and several other MR methods including MR-Egger and weighted median were used to confirm the reliability of the results. Sensitivity analyses such as heterogeneity and pleiotropy were also performed. The IVW method provided evidence to support that genetically predicted IL-16, IL-18, and CXCL10 significantly positively correlated with IBD, while IL-12p70 and CCL23 significantly negatively correlated with IBD. IL-16 and IL-18 had a suggestive association with an increased risk of ulcerative colitis (UC), and CXCL10 had a suggestive association with an increased risk of Crohn's disease (CD). However, there was no evidence to support that IBD and two main subtypes (UC and CD) are associated with changes in the levels of ILs and chemokines. The results of the sensitivity analyses were robust and no evidence of heterogeneity and horizontal pleiotropy was observed. The present study showed that some ILs and chemokines affect IBD, but IBD and its main subtypes (UC and CD) have no effect on the level changes of ILs and chemokines.

Inflammatory bowel disease (IBD) represents an immune-related inflammation of the gastrointestinal tract. Current research highlights the significant role of immune mechanisms and metabolic components on its development and progression. Nonetheless, the interplay between these factors remains inadequately explored. This study used Mendelian randomization (MR) to analyze the causality between immune cells, plasma metabolites, and IBD, and to identify potential mediation metabolites. This study used 2-sample MR analysis method to assess the associations between 731 immune cell types, 1400 plasma metabolites, and IBD, and subtypes ulcerative colitis (UC) and Crohn’s disease (CD). The inverse-variance weighted, Simple mode, Weighted median, and Weighted mode approaches confirmed the validity of the results. Horizontal pleiotropy was evaluated via MR-Egger regression, heterogeneity through Cochran’s Q test, and sensitivity using the leave-one-out method. Mediation analysis pinpointed potential mediation metabolites linking immune cells with IBD and its subtypes. MR analysis identified causal associations involving 17 immune cell phenotypes and 37 metabolites with IBD, 13 immune cell phenotypes and 15 metabolites with UC, and 11 immune cell phenotypes and 19 plasma metabolites with CD (P < .01). Mediation analysis demonstrated that the association between CD25 on IgD+ CD38br and IBD was mediated by the arachidonate (20:4n6) to oleate to vaccenate (18:1) ratio, with a mediation proportion of 7.42%. CD28+ CD45RA+ CD8dim absolute cell and HLA DR on B cells mediated the associations between 3-(4-hydroxyphenyl) lactate, carnitine C14 levels, and UC, with mediation proportions of 6.97% and 8.8%, respectively. CD27 on sw mem and CD3 on EM CD4+ mediated the associations between mannonate levels, 2-hydroxy-4-(methylthio) butanoic acid levels, and CD, with mediation proportions of 10.9% and 5.89%, respectively. The study demonstrates the causal association of immune cells and plasma metabolites with IBD, UC, and CD, providing novel insights in terms of the prevention, diagnosis, and management of these conditions.

Primary sclerosing cholangitis (PSC) is a chronic progressive disorder of unknown aetiology characterised by chronic inflammation and stricture formation of the biliary tree. Symptoms include itch and lethargy and in advanced cases cholangitis and end-stage liver disease, however increasing numbers of asymptomatic individuals are being identified. The disease is rare in the general population but is strongly associated with inflammatory bowel disease (IBD) affecting up to 5% of patients with ulcerative colitis, with a slightly lower prevalence (up to 3.6%) in Crohn's disease. The strength of this association means that the vast majority (> 90%) of patients with PSC also have IBD, although many may have only mild gastro-intestinal symptoms. Usually IBD presents before PSC, although vice-versa can occur and the onset of both conditions can be separated in some cases by many years. Mean age of diagnosis of PSC is in the fifth decade of life with a strong male predominance. Risk is increased in those with a family history of PSC, suggesting a genetic predisposition and the disease is almost exclusive to non-smokers. The ulcerative colitis associated with PSC is characteristically mild, runs a quiescent course, is associated with rectal sparing, more severe right sided disease, backwash ileitis and has a high risk of pouchitis post-colectomy. Most worrisome is the high risk of colorectal malignancy which necessitates routine colonoscopic surveillance. Cholangiocarcinoma is also a frequent complication of PSC with a 10%-15% lifetime risk of developing this condition. Treatment with high dose ursodeoxycholic acid offers some chemoprotective effects against colorectal malignancy and may decrease symptoms, biochemical and histological progression of liver disease. Small duct PSC patients characteristically have normal cholangiography, and liver biopsy is required for diagnosis, it appears to have a more favourable prognosis. Autoimmune Hepatitis (AIH) is also more prevalent in patients with IBD, with up to 16% of patients with AIH also having ulcerative colitis. A small subgroup of patients have a AIH-PSC overlap syndrome and the management of these patients depends on liver histology, serum IgM levels, autoantibodies, degree of biochemical cholestasis and cholangiography as some of these patients may respond to immunosuppression.

Reply

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

Deciphering the complex links between inflammatory bowel diseases and NAFLD through advanced statistical and machine learning analysis