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201. Dosimetric comparison of different algorithms in stereotactic body radiation therapy (SBRT) plan for non-small cell lung cancer (NSCLC)

Author

Zhang J, Jiang D, Su H, Dai Z, Dai J, Liu H, Xie C, and Yu H

Subjects
SBRT, AXB, NSCLC, AAA, PBC, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, lcsh:RC254-282, dosimetric difference
Abstract

Jun Zhang,1,* Dazhen Jiang,1,* Huanfan Su,2 Zhitao Dai,3 Jing Dai,1 Hui Liu,1 Conghua Xie,1 Haijun Yu11Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Hubei Cancer Clinical Study Center, Hubei 430072, People’s Republic of China; 2Jiangxi Medical College, Department of Medical Imaging, Shangrao, Jiangxi 334000, People’s Republic of China; 3School of Physics and Technology, Wuhan University, Wuhan 430071, People’s Republic of China*These authors contributed equally to this workPurposes: The main aim of the study was to investigate the dosimetric difference between acuros XB algorithm (AXB), anisotropic analytic algorithm (AAA), and pencil beam convolution (PBC) algorithm in stereotactic body radiation therapy (SBRT) plan for non-small cell lung cancer (NSCLC).Patients and Methods: Thirty-eight NSCLC patients were included. GTV, PTV, and organs at risk were delineated by the radiation oncologists. Three optimized SBRT plans for each patients were gained using three algorithms of AXB, AAA, and PBC with the identical plan parameters. Dosimetric endpoints were collected and compared among the three plans, including dosimetric criteria: V100%, V90%, PTV Dmin, Dmax, Dmean, homogeneity index (HI), and Paddick conformity index (CI).Results: AXB plan resulted in decreased V100% with a mean difference 6.14% compared with PBC plan (For V100%, AXB vs AAA vs PBC=93.44% vs 95.54% vs 99.58%, P0.05); and increased the Dmean of PTV in three algorithms with significant difference (For Dmean of PTV, AXB vs AAA vs PBC=5332cGy vs 5330Gy vs 5785Gy, P0.05).Conclusion: For SBRT plan of NSCLC, AAA and PBC algorithms overestimate target coverage, AXB algorithm is recommended for the SBRT plan of NSCLC.Keywords: NSCLC, SBRT, AXB, AAA, PBC, dosimetric difference

Published
2019

202. Evaluation of Lung Density and Its Dosimetric Impact on Lung Cancer Radiotherapy: A Simulation Study

Author

M.L.B. Bhatt, T Raj Verma, S Prasad Mishra, Nasheed I. Jamal, N Kumar Painuly, N. K. Singh, and SA Yoganathan

Subjects
lcsh:Medical physics. Medical radiology. Nuclear medicine, medicine.medical_treatment, lcsh:R895-920, Virtual Phantom, Bioengineering, Computed tomography, PBC, Computed Tomography, Variation in Lung Density, medicine, Radiology, Nuclear Medicine and imaging, Radiation treatment planning, Lung cancer, Physics, Lung, Radiological and Ultrasound Technology, medicine.diagnostic_test, business.industry, medicine.disease, Monte Carlo Code FLUKA, Lung density, Radiation therapy, medicine.anatomical_structure, Homogeneous, Monte carlo code, Original Article, Nuclear medicine, business
Abstract

Background: The dosimetric parameters required in lung cancer radiation therapy are taken from a homogeneous water phantom; however, during treatment, the expected results are being affected because of its inhomogeneity. Therefore, it becomes necessary to quantify these deviations. Objective: The present study has been undertaken to find out inter- and intra- lung density variations and its dosimetric impact on lung cancer radiotherapy using Monte Carlo code FLUKA and PBC algorithms. Material and Methods: Density of 100 lungs was recorded from their CT images along with age. Then, after PDD calculated by FLUKA MC Code and PBC algorithm for virtual phantom having density 0.2 gm/cm3 and 0.4 gm/cm3 (density range obtained from CT images of 100 lungs) using Co-60 10 x10 cm2 beams were compared. Results: Average left and right lung densities were 0.275±0.387 and 0.270±0.383 respectively. The deviation in PBC calculated PDD were (+)216%, (+91%), (+)45%, (+)26.88%, (+)14%, (-)1%, (+)2%, (-)0.4%, (-)1%, (+)1%, (+)4%, (+)4.5% for 0.4 gm/cm3 and (+)311%, (+)177%, (+)118%, (+)90.95%, (+)72.23%, (+)55.83% ,(+)38.85%, (+)28.80%, (+)21.79%, (+)15.95%, (+)1.67%, (-) 2.13%, (+)1.27%, (+)0.35%, (-)1.79%, (-)2.75% for 0.2 gm/cm3 density mediums at depths of 1mm, 2mm, 3mm, 4mm, 5mm, 6 mm, 7 mm, 8mm, 9mm,10mm, 15mm, 30mm, 40mm, 50mm, 80mm and 100 mm, respectively. Conclusion: Large variations in inter- and intra- lung density were recorded. PBC overestimated the dose at air/lung interface as well as inside lung. The results of Monte Carlo simulation can be used to assess the performance of other treatment planning systems used in lung cancer radiotherapy.

Published
2019

203. NFKB1 and MANBA Confer Disease Susceptibility to Primary Biliary Cholangitis via Independent Putative Primary Functional VariantsSummary

Author

Nao Nishida, Kaname Kojima, Ken Nakatani, Yuki Hitomi, Yosuke Kawai, Masao Nagasaki, Katsushi Tokunaga, Minoru Nakamura, Yoshihiro Aiba, and Minae Kawashima

Subjects
0301 basic medicine, EMSA, electrophoretic mobility shift assay, Genome-wide association study, PBC, Linkage Disequilibrium, Pathogenesis, Jurkat Cells, PCR, polymerase chain reaction, 0302 clinical medicine, Risk Factors, Chromosome Segregation, GWAS, Association mapping, Original Research, Genetics, education.field_of_study, Liver Cirrhosis, Biliary, Gastroenterology, Hep G2 Cells, e-QTL, 3. Good health, 1KJPN, whole-genome sequence reference panel of 1070 Japanese individuals, 030211 gastroenterology & hepatology, CRISPR/Cas9, clustered regularly interspaced short palindromic repeat, SNP, single-nucleotide polymorphism, LD, linkage disequilibrium, Population, NF-κB, nuclear factor-κB, Locus (genetics), Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Disease Susceptibility Gene, 03 medical and health sciences, Asian People, Humans, SNP, PDC-E2, E2 component of the pyruvate dehydrogenase complex, Genetic Predisposition to Disease, lcsh:RC799-869, GWAS, genome-wide association study, education, CRISPR/Cas9, Alleles, Hepatology, LEF-1, lymphoid enhancer-binding factor 1, beta-Mannosidase, NF-kappa B p50 Subunit, Th, T-helper type, RXRα, retinoid X receptor α, 030104 developmental biology, Amino Acid Substitution, Gene Expression Regulation, Genetic Loci, lcsh:Diseases of the digestive system. Gastroenterology, PBC, primary biliary cholangitis, Imputation (genetics), Transcription Factors
Abstract

Background & Aims Primary biliary cholangitis (PBC) is a chronic and cholestatic liver disease that eventually leads to cirrhosis and hepatic failure. We recently identified several susceptibility genes included NFKB1 and MANBA for PBC in the Japanese population by genome-wide association study. However, the primary functional variants in the NFKB1/MANBA region and the molecular mechanism for conferring disease susceptibility to PBC have not yet been clarified. Methods We performed high-density association mapping based on a single-nucleotide polymorphism (SNP) imputation analysis, using data from a whole-genome sequence reference panel of 1070 Japanese individuals and the previous genome-wide association study (1389 PBC patients, 1508 healthy controls). Among SNPs (P < 5.0 × 10-7) in the NFKB1/MANBA region, putative primary functional variants and the molecular mechanism for conferring disease susceptibility to PBC were identified by in silico/in vitro functional analysis. Results Among the SNPs in the NFKB1/MANBA region, rs17032850 and rs227361, which changed the binding of transcription factors lymphoid enhancer-binding factor 1 (LEF-1) and retinoid X receptor α (RXRα), respectively, were identified as putative primary functional variants that regulate gene expression. In addition, expression-quantitative trait locus data and gene editing using a clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system supported the potential role of rs17032850 and rs227361 in regulating NFKB1 and MANBA expression, respectively. Conclusions We identified independent putative primary functional variants in NFKB1/MANBA and showed the distinct molecular mechanism by which each putative primary functional variant conferred susceptibility to PBC. Our approach was useful to dissect the pathogenesis not only of PBC, but also other digestive diseases in which NFKB1/MANBA has been reported as a susceptibility locus., Graphical abstract

Published
2019

204. Development and adaptation of patient-reported outcome measures for patients who experience itch associated with primary biliary cholangitis

Author

Ashish V. Joshi, Mona L. Martin, David Jones, Larissa Stassek, and Steven I. Blum

Subjects
Evening, Health Informatics, PBC, Itch, 03 medical and health sciences, 0302 clinical medicine, Health Information Management, Medicine, Medical diagnosis, Cognitive interview, skin and connective tissue diseases, North American English, Patient-reported outcomes, Recall, business.industry, Research, 030503 health policy & services, Pruritus, lcsh:Public aspects of medicine, Primary biliary cholangitis, Cognition, lcsh:RA1-1270, language.human_language, digestive system diseases, 030220 oncology & carcinogenesis, language, Itching, Patient-reported outcome, medicine.symptom, 0305 other medical science, business, Qualitative, Clinical psychology
Abstract

Purpose To conduct qualitative interviews to evaluate and refine the Itch Diary (ID) and weekly version of the PBC-40 in patients with itching associated with primary biliary cholangitis (PBC). Methods Twenty adults with self-reported PBC diagnoses and recent/ongoing itching of at least moderate intensity participated in face-to-face qualitative combined concept elicitation (CE) interviews and cognitive interviews after completing the morning and evening versions of the ID and weekly version of the PBC-40. These questionnaires were evaluated to confirm saturation of concepts of interest and cognitively test the English language versions of the measures in patients with PBC in the US and Canada. Transcripts were organized into descriptions of PBC-related symptoms and symptom-related impacts using a structured coding framework. Two waves of interviews were conducted; revisions made after wave 1 were further tested in wave 2. Results Interview results confirmed the relevance of concepts presented in the PBC-40 and ID to patients’ experiences. Saturation of concept was achieved. Itching-related signs and symptoms (46%) were the most commonly expressed symptom concept in the CE interviews followed by energy-related (14%) and additional signs/symptoms (13%). Several changes to the ID were made in response to cognitive interview results. Changes to the PBC-40 included adaptations from British to North American English, and the appropriateness of a 7-day recall period was confirmed. Conclusions Relevance of the symptom and impact concepts in the ID to measure PBC-related itch were confirmed. Adaptation of the PBC-40 to a weekly recall period and for North American English was successful.

Published
2019

208. Identification of the Representative Primary Biliary Cholangitis Cohort in Taiwan: A Comparison of Four Nationwide Cohorts

Author

Ming-Ling Chang, Hsin-Ping Ku, Rong-Nan Chien, Jing-Hong Hu, Cheng-Yu Lin, Chun-Wen Huang, Cheng-Jen Chen, Jur-Shan Cheng, Wei-Ting Chen, Ming-Yu Chang, and Haw-En Wang

Subjects
medicine.medical_specialty, medicine.medical_treatment, Population, prevalence, Prevalence, Liver transplantation, PBC, Gastroenterology, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, education, 030304 developmental biology, 0303 health sciences, education.field_of_study, business.industry, Mortality rate, Incidence (epidemiology), General Medicine, medicine.disease, digestive system diseases, Cohort, incidence, outcome, Medicine, 030211 gastroenterology & hepatology, business, Dyslipidemia, Cohort study, ICD-9
Abstract

Background/Purpose: The rates and outcomes of primary biliary cholangitis (PBC) in Taiwan remain unclear. Methods: A nationwide population-based cohort study (Taiwan National Health Insurance Research Database, 2002–2015) was conducted. Data from four PBC cohorts with various definitions were compared (cohort 1 (C1): ICD-9-CM (571.6), C2: alkaline phosphatase (Alk-P) and antimitochondrial antibody (AMA) measurements, C3: Alk-p and AMA measurements and ursodeoxycholic acid (UDCA) treatment, C4: ICD-9-CM (571.6), Alk-p and AMA measurements and UDCA treatment). Results: The average prevalence rate ranged from 9.419/105 (C4) to 307.658/105 (C2), and the female-to-male ratio ranged from 1.192 (C1) to 3.66 (C4). Prevalence rates increased over time in all cohorts. The average incidence rates ranged from 1.456/105 (C4) to 66.386/105 (C2). Incidence rates decreased over time in C1 (−9.09%, p &lt, 0.0001) and C4 (−6.68%, p &lt, 0.0001) and remained steady in the others. C4 had the lowest prevalence and incidence rates and highest female-to-male ratio. Cirrhosis rates ranged from 7.21% (C2) to 39.34% (C4), hepatoma rates ranged from 2.77%(C2) to 6.66%(C1), liver transplantation (LT) rates ranged from 1.07% (C2) to 6.77% (C4), and mortality rates ranged from 18.24% (C2) to 47.36% (C1). C4 had the highest LT (6.77%), osteoporosis (13.87%) and dyslipidemia rates (17.21%). Conclusions: Based on the reported ranges of reasonable rates, female predominance and characteristic outcomes, C4 was the most representative Taiwanese PBC cohort, with average prevalence and incidence rates of 9.419/105 and 1.456/105, respectively, and a female-to-male ratio of 3.66. In a 14-year period, cirrhosis, hepatoma, LT, and mortality were noted in 39.34%, 5.52%, 6.77%, and 34.22% of C4 patients, respectively.

Published
2021
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209. Bacterial and metabolic phenotypes associated with inadequate response to ursodeoxycholic acid treatment in primary biliary cholangitis.

Author

Martinez-Gili L, Pechlivanis A, McDonald JAK, Begum S, Badrock J, Dyson JK, Jones R, Hirschfield G, Ryder SD, Sandford R, Rushbrook S, Thorburn D, Taylor-Robinson SD, Crossey MME, Marchesi JR, Mells G, Holmes E, and Jones D

Subjects
Humans, Ursodeoxycholic Acid therapeutic use, Dehydrocholic Acid therapeutic use, RNA, Ribosomal, 16S genetics, Cholagogues and Choleretics therapeutic use, Bile Acids and Salts therapeutic use, Biomarkers, Phenotype, Bacteria genetics, Liver Cirrhosis, Biliary drug therapy, Gastrointestinal Microbiome
Abstract

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease with ursodeoxycholic acid (UDCA) as first-line treatment. Poor response to UDCA is associated with a higher risk of progressing to cirrhosis, but the underlying mechanisms are unclear. UDCA modulates the composition of primary and bacterial-derived bile acids (BAs). We characterized the phenotypic response to UDCA based on BA and bacterial profiles of PBC patients treated with UDCA. Patients from the UK-PBC cohort ( n  = 419) treated with UDCA for a minimum of 12-months were assessed using the Barcelona dynamic response criteria. BAs from serum, urine, and feces were analyzed using Ultra-High-Performance Liquid Chromatography-Mass Spectrometry and fecal bacterial composition measured using 16S rRNA gene sequencing. We identified 191 non-responders, 212 responders, and a subgroup of responders with persistently elevated liver biomarkers ( n  = 16). Responders had higher fecal secondary and tertiary BAs than non-responders and lower urinary bile acid abundances, with the exception of 12-dehydrocholic acid, which was higher in responders. The sub-group of responders with poor liver function showed lower alpha-diversity evenness, lower abundance of fecal secondary and tertiary BAs than the other groups and lower levels of phyla with BA-deconjugation capacity ( Actinobacteriota / Actinomycetota , Desulfobacterota , Verrucomicrobiota ) compared to responders. UDCA dynamic response was associated with an increased capacity to generate oxo-/epimerized secondary BAs. 12-dehydrocholic acid is a potential biomarker of treatment response. Lower alpha-diversity and lower abundance of bacteria with BA deconjugation capacity might be associated with an incomplete response to treatment in some patients.

Published
2023
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210. Recurrence of post burn contractures of the elbow and shoulder joints: experience from a ugandan hospital.

Author

Balumuka, Deo Darius, Galiwango, George William, and Alenyo, Rose

Subjects
BURNS & scalds, CONTRACTURE (Pathology), DUPUYTREN'S contracture, SCARS, ELBOW injuries
Abstract

Background: Recurrence of post-burn contractures, following inadequate management of post-burn contractures (PBC), is under reported. It is associated with multiple operations and an increased cost to patients and their families. The purpose of this study was to determine the frequency of recurrence of PBC of the shoulder and the elbow joint three months after surgical intervention and the associated risk-factors. Methods: This was a prospective cohort study conducted at CoRSU hospital from March 2012 to November 2014. All patients with PBC of the elbow and/or shoulder joint who consented to be in the study and met the inclusion criteria were enrolled. Data was collected using a pretested, coded questionnaire. A goniometer was used to measure the active range of motion of the involved joint. The measurements were recorded in degrees. The data was analysed with STATA version 12.1. Results: 58 patients were enrolled consecutively in the study. There were 36 females and 22 males, with a female to male ratio of 1.6:1. The age range was 0.75-45 years, with a median age of 5 years. The average age at the time of injury was 3.4 years. The most common cause of initial burn injury was scalding. The average number of joints involved per patient was two. There was a high incidence of recurrence of PBC (52 %) among the participants. The shoulder had the highest frequency of recurrence at 67 %. The elbow joint had a frequency of recurrence of 27 %. All participants with both elbow and shoulder joint involvement had PBC recur. The risk factors for recurrence were flame burn (p = 0.007), duration of PBC of more than 1 year (p = 0.018), and incomplete release of the contracture (p = 0.002). The presence of keloids, hypertrophic scars, ulcers and the occurrence of complications at the contracture site were not associated with recurrence of PBC. Conclusion: Recurrence of PBC of the elbow and shoulder joint is a common problem. The risk factors should be kept in mind during management of PBC to reduce the recurrence rate. [ABSTRACT FROM AUTHOR]

Published
2015
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211. The TALE face of Hox proteins in animal evolution.

Author

Merabet, Samir, Galliot, Brigitte, Braasch, Ingo, and Martinez, Pedro

Subjects
HOMEOBOX genes, HEXAPEPTIDES, BIOLOGICAL evolution
Abstract

Hox genes are major regulators of embryonic development. One of their most conserved functions is to coordinate the formation of specific body structures along the anterior-posterior (AP) axis in Bilateria. This architectural role was at the basis of several morphological innovations across bilaterian evolution. In this review, we traced the origin of the Hox patterning system by considering the partnership with PBC and Meis proteins. PBC and Meis belong to the TALE-class of homeodomain-containing transcription factors and act as generic cofactors of Hox proteins for AP axis patterning in Bilateria. Recent data indicate that Hox proteins acquired the ability to interact with their TALE partners in the last common ancestor of Bilateria and Cnidaria. These interactions relied initially on a short peptide motif called hexapeptide (HX), which is present in Hox and non-Hox protein families. Remarkably, Hox proteins can also recruit the TALE cofactors by using specific PBC Interaction Motifs (SPIMs).We describe how a functional Hox/TALE patterning system emerged in eumetazoans through the acquisition of SPIMs. We anticipate that interaction flexibility could be found in other patterning systems, being at the heart of the astonishing morphological diversity observed in the animal kingdom. [ABSTRACT FROM AUTHOR]

Published
2015
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212. A case report of osteomalacia unmasking primary biliary cirrhosis.

Author

Pawlowska, M., Kapeluto, J., and Kendler, D.

Subjects
*AUTOIMMUNE diseases, *BLOOD testing, *CELIAC disease, *HYPERPARATHYROIDISM, *ISOTOPES, *CIRRHOSIS of the liver, *MEDICAL screening, *OSTEOMALACIA, *PHYSICAL diagnosis, *VITAMIN D deficiency
Abstract

Osteomalacia, a metabolic bone disease characterized by the inability to mineralize new osteoid, can be caused by vitamin D deficiency. We report a patient with symptomatic, biochemical, and imaging evidence of osteomalacia due to vitamin D deficiency, who as a result of work up for bone disease was diagnosed with early primary biliary cirrhosis. Osteomalacia was treated with high-dose vitamin D and serial bone density scans showed evidence of increasing bone mineral density suggesting osteoid mineralization in response to treatment. The diagnosis of cholestatic liver disease should be considered in all patients presenting with osteomalacia due to vitamin D deficiency, particularly if other cholestatic liver enzymes are elevated in addition to alkaline phosphatase. [ABSTRACT FROM AUTHOR]

Published
2015
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213. Extrahepatic Autoimmune Conditions Associated with Primary Biliary Cirrhosis.

Author

Floreani, Annarosa, Franceschet, Irene, Cazzagon, Nora, Spinazzè, Alice, Buja, Alessandra, Furlan, Patrizia, Baldo, Vincenzo, and Gershwin, M.

Abstract

There is a paucity of information on extrahepatic autoimmune (EHA) conditions associated with primary biliary cirrhosis (PBC) and on the impact of EHA conditions on PBC patients' survival. Our goal was to assess the association between PBC and other autoimmune diseases and the impact of EHA conditions on the natural history of PBC. We took advantage of 361 consecutive PBC patients enrolled between 1975 and 2012 (22 males, 339 females; mean follow-up 8 ± 6.9 years). Any associated EHA conditions, PBC histological stage at diagnosis, biochemical data, physiological history, and extrahepatic malignancies developing during the follow-up were recorded. Survival was analyzed by means of Kaplan-Meier curves. Importantly, 221 patients (61.2 %) had at least one EHA conditions: 45 patients (20.4 %) had Hashimoto thyroiditis; 7 (3.2 %) had Graves' thyroiditis; 65 (29.4 %) had Raynaud's phenomenon; 124 (56.1 %) had Sjogren's syndrome; 8 (3.6 %) had systemic lupus erythematosus; 22 (9.9 %) had scleroderma; 22 (9.9 %) had rheumatoid arthritis; 18 (8.1 %) had cutaneous autoimmune diseases; 8 (3.6 %) had vasculitis; 5 (1.4 %) had celiac disease; and 25 (13.1 %) had other EHA conditions. The proportion of patients with associated EHA conditions enrolled during representative periods (1975-1980, 1981-1990, 1991-2000, 2001-2010, 2011-2012) remained stable. No differences emerged between patients with versus without EHA conditions in terms of mean age at PBC diagnosis, antimitochondrial antibody (AMA), or antinuclear antibody (ANA) positivity, histological stage at diagnosis, smoking habits, alcohol consumption, or BMI >25. Multiple logistic regression analysis showed that only female gender was significantly associated with positivity for EHA conditions (OR 4.8; 95 % CI 1.6-13.7, p = 0.004). The mean survival after the diagnosis of PBC was much the same in patients with and without EHA conditions. In conclusion, EHA conditions are often associated with PBC, especially in female patients, but they do not reduce patient survival. [ABSTRACT FROM AUTHOR]

Published
2015
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214. Extrahepatic Malignancies in Primary Biliary Cirrhosis: A Comparative Study at Two European Centers.

Author

Floreani, Annarosa, Spinazzè, Alice, Caballeria, Llorenc, Reig, Ana, Cazzagon, Nora, Franceschet, Irene, Buja, Alessandra, Furlan, Patrizia, Harada, Kenichi, Leung, Patrick, Gershwin, M., and Pares, Albert

Abstract

Limited information and divergent results are available on the prevalence/incidence, survival, and risk factors for developing extrahepatic malignancies (EMs) in primary biliary cirrhosis (PBC). The aim of the study was to analyze the epidemiology and survival rates for EM in PBC patients. The study was conducted on two series of patients followed up at two European centers (361 in Padova, Italy, and 397 in Barcelona, Spain) for a mean 7.7 ± 7 and 12.2 ± 7 years, respectively. The cancer incidence was compared with the standardized incidence ratios (SIRs) calculated using the Cancer Registry of the Veneto Region (Italy) and the Cancer Registry of Tarragona (Spain). Seventy-two patients developed EM. The prevalence of cases was similar in Padova (9.7 %) and Barcelona (9.4 %). The overall cancer incidence was similar to the expected incidence for the general population in the same geographical area (SIR = 1.2), and so was the crude EM rate (855.01 vs 652.86 per 100,000 patient-years, respectively, RR = 1.3). Logistic regression analysis showed that advanced histological stage and extrahepatic autoimmune diseases were significantly associated with the onset of EM. Survival was similar for PBC patients with and without EM ( p = n.s.), and actual survival was similar to the one predicted by the Mayo model. The incidence of EM in PBC patients was found similar in Italy and Spain and no different from that of the general population. Advanced histological stage and extrahepatic autoimmune disease were risk factors significantly associated with EM developing in PBC. The onset of cancer in PBC patients does not influence the natural history of their liver disease. [ABSTRACT FROM AUTHOR]

Published
2015
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215. A Review of Tools for Project Financial Assessments

Author

Queiroz, Cesar, Mladenović, Goran, Queiroz, Cesar, and Mladenović, Goran

Abstract

Governments not always have the funds to build transport and other infrastructure projects that are economically justified and environmentally and socially sound. Under certain circumstances, projects meeting such conditions can be implemented by involving private financing, through public-private partnerships (PPP), which is a means to get projects completed by leveraging scarce public resources. In a PPP project, the sources of revenue to the private partner (or concessionaire) may include (i) the users of the facility (e.g., road tolling), (ii) the government (e.g. through availability payments, capital grants and shadow tolls), and (iii) both users and government, which is usually called a hybrid concession. As a key step in considering attracting private investors for such projects, decision makers and practitioners need to assess their financial viability, an endeavor that can be greatly facilitated by relatively simple tools now available. This paper reviews and provides case studies of two existing tools for assessing the financial viability of: (i) hybrid road PPP projects, which involve both tolls and availability payments; and (ii) output- and performance-based road contracts (OPBRC), which involves payments by the government. The main output generated by both models include the project’s internal rate of return, equity internal rate of return, annual debt service coverage ratio and the present value of the government’s cash flow.

Published
2020

217. Long-term impact of preventive UDCA therapy after transplantation for primary biliary cholangitis

Author

Corpechot, C, Chazouilleres, O, Belnou, P, Montano-Loza, A, Mason, A, Ebadi, M, Eurich, D, Chopra, S, Jacob, D, Schramm, C, Sterneck, M, Bruns, T, Reuken, P, Rauchfuss, F, Roccarina, D, Thorburn, D, Gerussi, A, Trivedi, P, Hirschfield, G, Mcdowell, P, Nevens, F, Boillot, O, Bosch, A, Giostra, E, Conti, F, Poupon, R, Pares, A, Reig, A, Donato, M, Malinverno, F, Floreani, A, Russo, F, Cazzagon, N, Verhelst, X, Goet, J, Harms, M, van Buuren, H, Hansen, B, Carrat, F, Dumortier, J, Corpechot C., Chazouilleres O., Belnou P., Montano-Loza A. J., Mason A., Ebadi M., Eurich D., Chopra S., Jacob D., Schramm C., Sterneck M., Bruns T., Reuken P., Rauchfuss F., Roccarina D., Thorburn D., Gerussi A., Trivedi P., Hirschfield G., McDowell P., Nevens F., Boillot O., Bosch A., Giostra E., Conti F., Poupon R., Pares A., Reig A., Donato M. F., Malinverno F., Floreani A., Russo F. P., Cazzagon N., Verhelst X., Goet J., Harms M., van Buuren H., Hansen B., Carrat F., Dumortier J., Corpechot, C, Chazouilleres, O, Belnou, P, Montano-Loza, A, Mason, A, Ebadi, M, Eurich, D, Chopra, S, Jacob, D, Schramm, C, Sterneck, M, Bruns, T, Reuken, P, Rauchfuss, F, Roccarina, D, Thorburn, D, Gerussi, A, Trivedi, P, Hirschfield, G, Mcdowell, P, Nevens, F, Boillot, O, Bosch, A, Giostra, E, Conti, F, Poupon, R, Pares, A, Reig, A, Donato, M, Malinverno, F, Floreani, A, Russo, F, Cazzagon, N, Verhelst, X, Goet, J, Harms, M, van Buuren, H, Hansen, B, Carrat, F, Dumortier, J, Corpechot C., Chazouilleres O., Belnou P., Montano-Loza A. J., Mason A., Ebadi M., Eurich D., Chopra S., Jacob D., Schramm C., Sterneck M., Bruns T., Reuken P., Rauchfuss F., Roccarina D., Thorburn D., Gerussi A., Trivedi P., Hirschfield G., McDowell P., Nevens F., Boillot O., Bosch A., Giostra E., Conti F., Poupon R., Pares A., Reig A., Donato M. F., Malinverno F., Floreani A., Russo F. P., Cazzagon N., Verhelst X., Goet J., Harms M., van Buuren H., Hansen B., Carrat F., and Dumortier J.

Abstract

Background & Aims: Recurrence of primary biliary cholangitis (PBC) after liver transplantation (LT) is frequent and can impair graft and patient survival. Ursodeoxycholic acid (UDCA) is the current standard therapy for PBC. We investigated the effect of preventive exposure to UDCA on the incidence and long-term consequences of PBC recurrence after LT. Methods: We performed a retrospective cohort study in 780 patients transplanted for PBC, between 1983–2017 in 16 centers (9 countries), and followed-up for a median of 11 years. Among them, 190 received preventive UDCA (10–15 mg/kg/day). The primary outcome was histological evidence of PBC recurrence. The secondary outcomes were graft loss, liver-related death, and all-cause death. The association between preventive UDCA and outcomes was quantified using multivariable-adjusted Cox and restricted mean survival time (RMST) models. Results: While recurrence of PBC significantly shortened graft and patient survival, preventive exposure to UDCA was associated with reduced risk of PBC recurrence (adjusted hazard ratio [aHR] 0.41; 95% CI 0.28–0.61; p <0.0001), graft loss (aHR 0.33; 95% CI 0.13–0.82; p <0.05), liver-related death (aHR 0.46; 95% CI 0.22–0.98; p <0.05), and all-cause death (aHR 0.69; 95% CI 0.49–0.96; p <0.05). On RMST analysis, preventive UDCA led to a survival gain of 2.26 years (95% CI 1.28–3.25) over a period of 20 years. Exposure to cyclosporine rather than tacrolimus had a complementary protective effect alongside preventive UDCA, reducing the cumulative incidence of PBC recurrence and all-cause death. Conclusions: Preventive UDCA after LT for PBC is associated with a reduced risk of disease recurrence, graft loss, and death. A regimen combining cyclosporine and preventive UDCA is associated with the lowest risk of PBC recurrence and mortality. Lay summary: Recurrence of primary biliary cholangitis after liver transplantation is frequent and can impair graft and patient survival. We perform

Published
2020

219. Evaluation of circulating cell-free DNA in cholestatic liver disease using liver-specific methylation markers

Author

Konstantinos N. Lazaridis, Sohan Punia, Ahmad H. Ali, Erik M. Schlicht, Brian D. Juran, Zhifu Sun, and Raymond Moore

Subjects
0301 basic medicine, medicine.medical_specialty, Cholangitis, Sclerosing, Pilot Projects, PBC, Gastroenterology, Methylation, Primary sclerosing cholangitis, 03 medical and health sciences, Liver disease, 0302 clinical medicine, Cholestasis, PSC, Internal medicine, medicine, Humans, lcsh:RC799-869, business.industry, Liver Cirrhosis, Biliary, CfDNA, General Medicine, Hepatology, medicine.disease, Circulating Cell-Free DNA, 030104 developmental biology, CpG site, Liver, Alkaline phosphatase, 030211 gastroenterology & hepatology, lcsh:Diseases of the digestive system. Gastroenterology, business, Cell-Free Nucleic Acids, Biomarkers, Research Article
Abstract

Background Quantification of circulating organ-specific cell-free DNA (cfDNA) provides a sensitive measure of ongoing cell death that could benefit evaluation of the cholestatic liver diseases primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), which lack reliable non-invasive biomarkers. Our goal in this pilot study was to determine whether liver-specific cfDNA levels are increased in PBC and PSC patients relative to controls and in advanced versus early disease, to evaluate their potential as novel disease biomarkers. Methods Peripheral blood derived bisulfite-treated DNA was PCR amplified from patients with PBC (n = 48), PSC (n = 48) and controls (n = 96) to evaluate methylation status at 16 CpG sites reported to be specifically unmethylated in liver tissue near the genes IGF2R, ITIH4 and VTN. Amplicons were used to prepare paired end libraries which were sequenced on a MiSeq sequencer. Trimmed reads were aligned and used to determine unmethylation ratios and to calculate concentration of liver-specific cfDNA. Comparisons between groups were performed using the two-tailed Mann–Whitney Test and relationships between variables were evaluated using Pearson’s Correlation. Results Levels of liver-specific cfDNA, as measured at the 3 genetic loci, were increased in PBC and PSC patients relative to controls and in late-stage relative to early-stage patients. As well, cfDNA levels were correlated with levels of alkaline phosphatase, a commonly used biochemical test to evaluate disease severity in liver disease, in patients, but not in controls. Conclusions cfDNA offers promise as a non-invasive liquid-biopsy to evaluate liver-specific cell-death in patients with cholestatic liver diseases.

Published
2021

220. Old and novel prognostic biomarkers in primary biliary cholangitis

Author

Pietro Invernizzi, Andrea Palermo, Marco Carbone, Giacomo Mulinacci, Mulinacci, G, Palermo, A, Invernizzi, P, and Carbone, M

Subjects
medicine.medical_specialty, Primary (chemistry), business.industry, Health Policy, risk stratification, medicine.disease, Chronic liver disease, PBC, Gastroenterology, digestive system diseases, 03 medical and health sciences, 0302 clinical medicine, Cholestasis, 030220 oncology & carcinogenesis, Internal medicine, Risk stratification, medicine, biomarker, Pharmacology (medical), business, Pharmacology, Toxicology and Pharmaceutics (miscellaneous), 030217 neurology & neurosurgery, prognosi
Abstract

Introduction: Primary Biliary Cholangitis (PBC) is a chronic liver disease characterized by intrahepatic biliary destruction and progressive cholestasis potentially leading to end-stage liver disease and its associated complications. As for many chronic disorders, the risk of disease progression in PBC varies between patients. This has fostered the identification of disease tags defining the trajectory of the disease course. Areas covered: In this review, authors report the evidence-based parameters associated with outcomes in PBC, after an extensive literature search of the PubMed electronic database. Expert opinion: Several prognostic tools including clinical and biochemical disease parameters have been proposed. In the era of the omics science and digital innovation, biomarker discovery has sped up. Extensive data and sample collection of well-phenotyped cohorts of patients with longitudinal follow-up will guarantee an extraordinary opportunity to integrate molecular phenotyping into the clinic, thus promoting a personalized care of patients with PBC. Finally, we emphasize the need to leverage a therapeutic window of opportunity in PBC bringing a paradigm shift toward early intervention with combination therapies in individuals with a more severe phenotype to reach a deeper disease control and halt disease progression.

Published
2021

221. Cholangiocyte senescence in primary sclerosing cholangitis is associated with disease severity and prognosis

Author

Annarosa Floreani, Maria Guido, Giorgia Corrà, Francesco Paolo Russo, Vincenza Guzzardo, Samantha Sarcognato, Sara De Martin, and Nora Cazzagon

Subjects
ductular reaction, Cirrhosis, ALT, medicine.medical_treatment, HA, PT, p16, RC799-869, Liver transplantation, PBC, SASP, Gastroenterology, UDCA, hazard ratio, PSC, HR, odds ratio, TGFβ, transforming growth factor beta, HCC, transforming growth factor beta, p21WAF1/Cip1, IBD, inflammatory bowel disease, p21, primary biliary cholangitis, INR, international normalized ratio, OR, Diseases of the digestive system. Gastroenterology, Prognosis, γ-glutamyltranspeptidase, senescence-associated secretory phenotype, portal tract, SMA, smooth muscle actin, INR, medicine.medical_specialty, CCA, cholangiocarcinoma, CK7, γGT, CS, cellular senescence, MH, metaplastic hepatocytes, SASP, senescence-associated secretory phenotype, LT, liver transplantation, UDCA, ursodeoxycholic acid, inflammatory bowel disease, cholangitis activity, Decompensation, CCA, ALP, alkaline phosphatase, autoimmune hepatitis, international normalized ratio, medicine.disease, HR, hazard ratio, GBCA, PSC, primary sclerosing cholangitis, p16INK4A, smooth muscle actin, alanine transaminase, CA, cholangitis activity, IHC, NBD, PT, portal tract, Autoimmune hepatitis, native bile duct, DR, AIH, LT, Immunology and Allergy, cellular senescence, SMA, CA, biology, liver transplantation, primary sclerosing cholangitis, hepatocellular carcinoma, Senescent cholangiocytes, ursodeoxycholic acid, Hepatocellular carcinoma, cholangiocarcinoma, CS, alkaline phosphatase, Research Article, ALT, alanine transaminase, BDL, IBD, IHC, immunohistochemical, bile duct loss, Cholangiocyte, Primary sclerosing cholangitis, Fibrosing cholangiopathy, TGFβ, Internal medicine, Internal Medicine, medicine, DR, ductular reaction, p16, p16INK4A, MH, Hepatology, business.industry, hepatitis activity, AIH, autoimmune hepatitis, cytokeratin 7, metaplastic hepatocytes, p21, p21WAF1/Cip1, HA, hepatitis activity, NBD, native bile duct, GBCA, gallbladder carcinoma, γGT, γ-glutamyltranspeptidase, OR, odds ratio, Alanine transaminase, immunohistochemical, biology.protein, ALP, BDL, bile duct loss, PBC, primary biliary cholangitis, gallbladder carcinoma, business, CK7, cytokeratin 7, HCC, hepatocellular carcinoma
Abstract

Background & Aims Primary sclerosing cholangitis (PSC) is a rare cholangiopathy of unknown aetiopathogenesis. The aim of this study was to evaluate cellular senescence (CS) marker expression in cholangiocytes of patients with PSC and their correlation with clinical–pathological features and prognosis. Methods Thirty-five patients with PSC with at least 1 available liver sampling were included. Clinical laboratory data at the time of liver sampling were collected. The endpoints were survival without liver transplantation (LT), time to LT, and survival without LT or cirrhosis decompensation. Histological grading and staging were assessed according to Nakanuma. Immunohistochemical stains for CS markers, p16INK4A (p16) and p21WAF1/Cip1 (p21), were performed and scored by a 3-tier scale based on positivity extent in native bile duct (NBD) and ductular reaction (DR). Results: p16 expression in NBD and DR was directly correlated with fibrosis (p ≤0.001 for both) and stage (p = 0.006 and p, Graphical abstract, Highlights • Cholangiocyte senescence was previously described in end-stage PSC. • Cholangiocyte senescence is present in all stages of PSC and may represent an early pathogenic event. • Cholangiocyte senescence is associated with histological and clinical severity in patients with PSC. • Cholangiocyte senescence is independently associated with patients’ outcome in PSC.

Published
2021

222. Reply to: 'A spotlight on natural killer cells in primary biliary cholangitis'

Author

Vincenzo Ronca, Pietro Invernizzi, Marco Carbone, Carbone, M, Ronca, V, and Invernizzi, P

Subjects
medicine.medical_specialty, Primary (chemistry), Hepatology, business.industry, Cholangitis, Liver Cirrhosis, Biliary, Biliary cirrhosi, Biliary cirrhosis, Biliary fibrosis, Autoimmunity, medicine.disease_cause, medicine.disease, PBC, Gastroenterology, Killer Cells, Natural, Cholestasis, Cholestasi, Internal medicine, medicine, Biliary fibrosi, Humans, business
Published
2021

223. Accuracy of Transient Elastography in Assessing Fibrosis at Diagnosis in Naïve Patients With Primary Biliary Cholangitis: A Dual Cut-Off Approach

Author

Cristina Rigamonti, Rosanna Venere, Carla De Benedittis, Guido Carpino, Pietro Invernizzi, Italian Pbc Registry, Elisabetta Degasperi, Giacomo Mulinacci, Marco Carbone, Sarah Elisabeth O’Donnell, Diletta Overi, Sara Labanca, Vito Di Marco, A. Ciaccio, Vincenzo Cardinale, Mauro Viganò, Andrea Palermo, Annarosa Floreani, Daphne D’Amato, Nora Cazzagon, Vincenzo Ronca, Donatella Barisani, Laura Cristoferi, Federica Malinverno, Marco Marzioni, Domenico Alvaro, Clara Mancuso, Vincenza Calvaruso, Anna Fichera, Martina Lucà, Federica Cerini, Alessandra Nardi, Eugenio Gaudio, Antonino Picciotto, Nicola Zucchini, Monica Leutner, Alessio Gerussi, Laura Cristoferi, Vincenza Calvaruso, Diletta Overi 5 , Mauro Viganò 6 , Cristina Rigamonti 7 , Elisabetta Degasperi 8 , Vincenzo Cardinale 9 , Sara Labanca 10 , Nicola Zucchini 11 , Anna Fichera, Vito Di Marco, Monica Leutner 12 , Rosanna Venere 13 , Antonino Picciotto 10 , Martina Lucà 1 2 , Giacomo Mulinacci 1 2 , Andrea Palermo 1 2 , Alessio Gerussi 1 2 , Daphne D'Amato 1 2 , Sarah Elisabeth O'Donnell 1 2 , Federica Cerini 6 , Carla De Benedittis 7 , Federica Malinverno 1 2 , Vincenzo Ronca 1 2 , Clara Mancuso 1 2 , Nora Cazzagon 14 , Antonio Ciaccio 1 2 , Donatella Barisani 1 , Marco Marzioni 15 , Annarosa Floreani 16 17 , Domenico Alvaro 9 , Eugenio Gaudio 5 , Pietro Invernizzi 1 2 , Guido Carpino # 18 , Alessandra Nardi # 19 , Marco Carbone, Cristoferi, L, Calvaruso, V, Overi, D, Viganò, M, Rigamonti, C, Degasperi, E, Cardinale, V, Labanca, S, Zucchini, N, Fichera, A, Di Marco, V, Leutner, M, Venere, R, Picciotto, A, Lucà, M, Mulinacci, G, Palermo, A, Gerussi, A, D'Amato, D, O'Donnell, S, Cerini, F, De Benedittis, C, Malinverno, F, Ronca, V, Mancuso, C, Cazzagon, N, Ciaccio, A, Barisani, D, Marzioni, M, Floreani, A, Alvaro, D, Gaudio, E, Invernizzi, P, Carpino, G, Nardi, A, and Carbone, M

Subjects
area under curve, 0301 basic medicine, medicine.medical_specialty, liver cirrhosis, Diagnostic accuracy, risk stratification, PBC, Gastroenterology, primary biliary cholangiti, elasticity imaging techniques, female, humans, biliary, male, middle aged, ROC curve, sensitivity and specificity, Therapy naive, 03 medical and health sciences, 0302 clinical medicine, Fibrosis, Internal medicine, medicine, Hepatology, Receiver operating characteristic, medicine.diagnostic_test, Liver Cirrhosis, Biliary, business.industry, Original Articles, medicine.disease, transient elastography, Autoimmune, Cholestatic and Biliary Disease, 030104 developmental biology, Liver biopsy, Cohort, Original Article, 030211 gastroenterology & hepatology, diagnostic accuracy, Cut-off, Transient elastography, business, fibrosi
Abstract

Background & aims Liver fibrosis holds a relevant prognostic meaning in primary biliary cholangitis (PBC). Non-invasive fibrosis evaluation using vibration-controlled transient elastography (VCTE) is routinely performed. However, there is limited evidence on its accuracy at diagnosis in PBC. We aimed to estimate the diagnostic accuracy of VCTE in assessing advanced fibrosis at disease presentation in PBC. Approach & results We collected data from 167 consecutive treatment-naive PBC patients who underwent liver biopsy(LB) at diagnosis at six Italian centers. VCTE examinations were completed within 12 weeks of LB. Biopsies were scored by two blinded expert pathologists, according to Ludwig system. Diagnostic accuracy was estimated using the area under the receiver operating characteristic curves(AUROCs) for advanced fibrosis (Ludwig stage≥III). The effects of biochemical and clinical parameters on liver stiffness measurement (LSM) were appraised. Derivation cohort consisted of 126 patients with valid LSM and LB, VCTE identified patients with advanced fibrosis with AUROC of 0.89. LSM cut-offs ≤6.5kPa and >11.0kPa enabled to exclude and confirm, respectively, advanced fibrosis (negative predictive value[NPV]=0.94, positive predictive value[PPV]=0.89, error rate=5.6%). These values were externally validated in an independent cohort of 91 PBC patients(NPV=0.93, PPV=0.89, error rate=8.6%). Multivariable analysis found the only parameter affecting LSM was fibrosis stage. No association was found with BMI and liver biochemistry. Conclusions In a multicenter study of treatment-naive PBC patients, we identified two cut-offs (LSM≤6.5kPa and>11.0kPa) able to discriminate at diagnosis the presence or the absence, respectively, of advanced fibrosis in PBC patients, with external validation. In patients with LSM between these two cut-offs, VCTE is not reliable and liver biopsy should be evaluated for accurate disease staging. BMI and liver biochemistry did not affect LSMs.

Published
2021

224. Primary biliary cholangitis associated with SARS-CoV-2 infection

Author

Alessandra Bartoli, Pamela Sighinolfi, Carmela Cursaro, Stefano Gitto, and Pietro Andreone

Subjects
2019-20 coronavirus outbreak, Hepatology, medicine.diagnostic_test, Guillain-Barre syndrome, business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), COVID-19, PBC, Guillain-Barré syndrome, medicine.disease, medicine.disease_cause, Autoimmunity, auto-immune disease triggers, Biopsy, Immunology, medicine, Hashimoto Disease, auto-immune diseases, Liver function tests, business, Letter to the Editor, Liver pathology
Published
2021

225. Real-world experience with obeticholic acid in patients with primary biliary cholangitis

Author

Anna Morgando, Mauro Viganò, Ana Lleo, Maurizio Pompili, Elisabetta De Gasperi, Daphne D’Amato, Alessandro Mussetto, Nora Cazzagon, Pietro Invernizzi, Francesca Colapietro, Vincenzo Ronca, Sara Labanca, Ester Vanni, M.R. Cannavò, Francesco Losito, Ernesto Claar, G. Scifo, Giovanni Galati, Umberto Vespasiani-Gentilucci, Silvia Storato, Alessio Gerussi, Grazia Anna Niro, Antonio Izzi, Barbara Omazzi, Antonio De Vincentis, Valentina Feletti, Giuseppe Grassi, Valeria Pace Palitti, Clara Mancuso, Vincenza Calvaruso, Evelise Frazzetto, Roberto Boldizzoni, Marco Marzioni, Floriano Rosina, Andrea Palermo, Antonino Picciotto, Valentina Bellia, Gaetano Bertino, Italian Pbc Registry, Guido Poggi, Rodolfo Sacco, Domenico Alvaro, Luigi Muratori, Maria Vinci, Marie Graciella Pigozzi, Raffaele Cozzolongo, Natalia Terreni, Annarosa Floreani, Maurizio Russello, Marco Distefano, Rinaldo Pellicano, Maria D'Antò, Marco Carbone, Rosanna Venere, R. Fontana, Antonio Picardi, Silvia Casella, S. E. O'Donnell, Federica Malinverno, Stefano Fagiuoli, Laura Cristoferi, Luchino Chessa, Giacomo Mulinacci, Pietro Pozzoni, Antonino Castellaneta, Giulia Marconi, Adriano M. Pellicelli, Francesca Romana Ponziani, Leonardo Baiocchi, D'Amato, D, De Vincentis, A, Malinverno, F, Vigano, M, Alvaro, D, Pompili, M, Picciotto, A, Palitti, V, Russello, M, Storato, S, Pigozzi, M, Calvaruso, V, De Gasperi, E, Lleo, A, Castellaneta, A, Pellicelli, A, Cazzagon, N, Floreani, A, Muratori, L, Fagiuoli, S, Niro, G, Feletti, V, Cozzolongo, R, Terreni, N, Marzioni, M, Pellicano, R, Pozzoni, P, Baiocchi, L, Chessa, L, Rosina, F, Bertino, G, Vinci, M, Morgando, A, Vanni, E, Scifo, G, Sacco, R, D'Anto, M, Bellia, V, Boldizzoni, R, Casella, S, Omazzi, B, Poggi, G, Cristoferi, L, Gerussi, A, Ronca, V, Venere, R, Ponziani, F, Cannavo, M, Mussetto, A, Fontana, R, Losito, F, Frazzetto, E, Distefano, M, Colapietro, F, Labanca, S, Marconi, G, Grassi, G, Galati, G, O'Donnell, S, Mancuso, C, Mulinacci, G, Palermo, A, Claar, E, Izzi, A, Picardi, A, Invernizzi, P, Carbone, M, Vespasiani-Gentilucci, U, D'Amato D, De Vincentis A, Malinverno F, Viganò M, Alvaro D, Pompili M, Picciotto A, Palitti VP, Russello M, Storato S, Pigozzi MG, Calvaruso V, De Gasperi E, Lleo A, Castellaneta A, Pellicelli A, Cazzagon N, Floreani A, Muratori L, Fagiuoli S, Niro GA, Feletti V, Cozzolongo R, Terreni N, Marzioni M, Pellicano R, Pozzoni P, Baiocchi L, Chessa L, Rosina F, Bertino G, Vinci M, Morgando A, Vanni E, Scifo G, Sacco R, D'Antò M, Bellia V, Boldizzoni R, Casella S, Omazzi B, Poggi G, Cristoferi L, Gerussi A, Ronca V, Venere R, Ponziani F, Cannavò M, Mussetto A, Fontana R, Losito F, Frazzetto E, Distefano M, Colapietro F, Labanca S, Marconi G, Grassi G, Galati G, O'Donnell SE, Mancuso C, Mulinacci G, Palermo A, Claar E, Izzi A, Picardi A, Invernizzi P, Carbone M, Vespasiani-Gentilucci U, and Italian PBC Registry and the Club Epatologi Ospedalieri (CLEO)/Associazione Italiana Gastroenterologi ed Endoscopisti Digestivi Ospedalieri (AIGO) PBC Study Group.

Subjects
upper limit of normal, Cirrhosis, ALT, AMA, Autoimmunity, antinuclear antibodies, ULN, PBC, Gastroenterology, UDCA, Settore MED/12, ULN, upper limit of normal, obeticholic acid, aRR, adjusted risk ratio, CRFs, case record form, AST, aspartate transferase, Clinical endpoint, GGT, gamma-glutamyl transferase, QC, primary biliary cholangitis, Ursodeoxycholic acid, ANA, TCC, Cholestasi, TIPS, Treatment Completer Cohort, ANA, antinuclear antibodie, medicine.medical_specialty, RR, UDCA, ursodeoxycholic acid, TIPS, transjugular intrahepatic portosystemic shunt, OCA, Cirrhosi, ALP, alkaline phosphatase, autoimmune hepatitis, medicine.disease, digestive system diseases, Discontinuation, Keywords: AIH, autoimmune hepatiti, QC, quality control, chemistry, gamma-glutamyl transferase, randomised controlled trial, electronic data capture, antimitochondrial antibodies, aspartate transferase, Autoimmune hepatitis, chemistry.chemical_compound, AIH, CRFs, Immunology and Allergy, adjusted risk ratio, ANA, antinuclear antibodies, RR, risk ratio, Overall cohort, ALT, alanine transferase, AMA, antimitochondrial antibodie, Cholestasis, CRFs, case record forms, Obeticholic acid, Overlap PBC-AIH, ursodeoxycholic acid, OCA, obeticholic acid, Tolerability, alkaline phosphatase, RCT, Research Article, medicine.drug, case record forms, Context (language use), AMA, antimitochondrial antibodies, Internal medicine, EDC, electronic data capture, transjugular intrahepatic portosystemic shunt, Internal Medicine, medicine, RCT, randomised controlled trial, OC, lcsh:RC799-869, quality control, alanine transferase, AST, aRR, Hepatology, business.industry, AIH, autoimmune hepatitis, TCC, Treatment Completer Cohort, PBC, primary biliary cholangiti, GGT, risk ratio, OC, Overall cohort, ALP, lcsh:Diseases of the digestive system. Gastroenterology, PBC, primary biliary cholangitis, business, EDC
Abstract

Background & aims Obeticholic acid (OCA) is the second-line treatment approved for patients with primary biliary cholangitis (PBC) and an inadequate response or intolerance to ursodeoxycholic acid. We aimed to evaluate the effectiveness and safety of OCA under real-world conditions. Methods Patients were recruited into the Italian PBC Registry, a multicentre, observational cohort study that monitors patients with PBC at national level. The primary endpoint was the biochemical response according to Poise criteria; the secondary endpoint was the biochemical response according to normal range criteria, defined as normal levels of bilirubin, alkaline phosphatase (ALP), and alanine aminotransferase (ALT) at 12 months. Safety and tolerability were also assessed. Results We analysed 191 patients until at least 12 months of follow-up. Median age was 57 years, 94% female, 61 (32%) had cirrhosis, 28 (15%) had histologically proven overlap with autoimmune hepatitis (PBC-AIH). At 12 months, significant median reductions of ALP (-32.3%), ALT (-31.4%), and bilirubin (-11.2%) were observed. Response rates were 42.9% according to Poise criteria, and 11% by normal range criteria. Patients with cirrhosis had lower response than patients without cirrhosis (29.5% vs. 49.2%, p = 0.01), owing to a higher rate of OCA discontinuation (30% vs. 12%, p = 0.004), although with similar ALP reduction (29.4% vs. 34%, p = 0.53). Overlap PBC-AIH had a similar response to pure PBC (46.4% vs. 42.3%, p = 0.68), with higher ALT reduction at 6 months (-38% vs. -29%, p = 0.04). Thirty-three patients (17%) prematurely discontinued OCA because of adverse events, of whom 11 experienced serious adverse events. Treatment-induced pruritus was the leading cause of OCA discontinuation (67%). Conclusions Effectiveness and safety of OCA under real-world conditions mirror those in the Poise trial. Patients with cirrhosis had lower tolerability. Overlap PBC-AIH showed higher ALT reduction at 6 months compared with patients with pure PBC. Lay summary Obeticholic acid (OCA) was shown to be effective in more than one-third of patients not responding to ursodeoxycholic acid in a real-world context in Italy. Patients with cirrhosis had more side effects with OCA, and this led to suspension of the drug in one-third of patients. OCA was also effective in patients who had overlap between autoimmune hepatitis and primary biliary cholangitis., Graphical abstract, Highlights • Under real-world conditions, OCA was effective in ~43% of patients who were non-responders to UDCA, according to Poise criteria. • Patients with cirrhosis showed lower efficacy (29.5%), mainly attributed to reduced tolerability and higher discontinuation rate. • Patients with overlap AIH-PBC showed a comparable efficacy to pure PBC, with a higher ALT reduction at 6 months. • Most patients with PBC are still in need of additional therapy if aiming to normalise liver biochemistry.

Published
2021

226. X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis

Author

S. Abiru, John F. Dillon, Yasuhiro Miyake, Piero Portincasa, Giancarlo Spinzi, R. Harvey, T. Ngatchu, Agostino Colli, M. Taniai, K. Flahive, Masanori Abe, B. Hoeroldt, S. Holder, Howard Curtis, María Isabel Colombo, C. MacNicol, Gang Xie, Andrew Chilton, H. Hussaini, Cristina Rigamonti, M. Kato, Shintaro Yagi, G. Abouda, D. Tyrer, Chris D. Evans, Christopher I. Amos, K. Koss, Kazuaki Chayama, P. Premchand, K. Migita, Simon Panter, Marco Marzioni, Silvia Colombo, Konstantinos N. Lazaridis, M. Yagura, Ashley Brown, D. Gocher, Domenico Alvaro, K. Murata, Mark Wright, Piero Luigi Almasio, C. Healey, A. Ciaccio, N. Wheatley, Vincenzo Cardinale, T. Delahooke, Chiara Milani, T. Shewan, W. Stableforth, S. Levi, Mark L. Green, James V. Jones, Y. Baird, Aftab Ala, Burroughs Ak, D. Williams, K. Ario, P. Sanghi, Hemant Gupta, P. Southern, L. Farrington, M. Hamilton, Andrew D. Higham, I. Yabuuchi, H. Yatsuhashi, Lorenzo Morini, T. Yamamoto, Douglas Thorburn, M. Carnahan, N. Nishida, Susan Slininger, M. Koga, K. Honda, Annarosa Floreani, Andrew Douglass, K. Netherton, M. Yasunami, Hirohito Tsubouchi, F. Donato, K. Walker, U. Shmueli, Paolo Muratori, Ray Mathew, J. Maiden, E. Dungca, Subramaniam Ramakrishnan, S. Vyas, Helen Sweeting, Subrata Saha, T. Komeda, T. Komatsu, H. J. Lee, Maria Consiglia Bragazzi, T. Komura, C. Thomas, C. Shallcross, C. Duggan, J. Kordula, F. Muscariu, Lourdes Cumlat, Imran Patanwala, Giulia Cardamone, L. Morgan, J. Brighton, Masao Honda, H. Nakamura, David Jones, Raj Srirajaskanthan, M. E. Gershwin, T. Muro, L. Stafford, N. Fukushima, Graham P. Butcher, Andrea Crosignani, George Lipscomb, K. Hirata, Y. Nagaoki, S. Mann, Paul G. Richardson, David A Elphick, M. Mupudzi, Y. Ohara, E. Grieve, Gayle Clifford, Claudio Tiribelli, M. Quinn, G. Van Duyvenvoorde, E. Archer, Tatsuki Ichikawa, J. Maltby, T. Arinaga-Hino, Simon Williams, A. King, Yasuni Nakanuma, H. Doyle, A. Brind, Nora Cazzagon, H. Ota, Daphne D’Amato, K. Hogben, H. Wooldridge, J. Wilkins, Shuichi Kaneko, L. Hankey, Gordon Wood, Andrew Fraser, K. Martin, A. Naqvi, M. Ninkovic, M. Patel, Yoshihiko Maehara, Kapil Kapur, I. Amey, Vincenza Calvaruso, Kenichi Harada, T. Yamashita, James Neuberger, N. Taylor, T. Lee, J. Featherstone, C. Lawlor, K. Seward, Satoshi Yamagiwa, Andrea Galli, L. Tan, Kentaro Kikuchi, K. Furuta, Mark A. Ainsworth, Hiromasa Ohira, Esther Unitt, Yosuke Kawai, N. Lancaster, D. Simpson, R. Shidrawi, I. Salam, A.J. Bell, Pietro Andreone, J. Ishida, Voi Shim Wong, N Fisher, Andrew C. Douds, R. Penn, Matthew Foxton, A. Watson, Andrew Mason, S. Walsh, Hiromi Ishibashi, Daniel M. Forton, Giovanni Casella, H. Takaki, K. Yamauchi, Pietro Lampertico, Osamu Yokosuka, M. Koda, M. Davies, H. Mitchison, P. Gyawali, G. Bird, M. Hughes, L. Jones, C. Hamilton, A. Hynes, R. Galaska, Fabio Marra, Debasish Das, C. Cowley, A. Fouracres, Yasuhiko Sugawara, E. Mita, T. Saoshiro, Akinobu Taketomi, Robert P. Myers, R. Przemioslo, F. Wright, L. Hobson, L. Currie, J. Allison, J. Hails, Noriyo Yamashiki, Massimo Zuin, C. Grimley, Alessio Gerussi, S. Besley, Stefano Duga, A. Piotrowicz, H. Kouno, L. Dali-kemmery, H. Sakai, M. Mizokami, Stefano Fagiuoli, Amy Davis, Pier Maria Battezzati, Masao Nagasaki, Luigi Muratori, A. Mori, S. Desmennu, S. Jones, R. Abrahams, Keith George, F. Makita, J. Brown, D. Gorard, Satoru Joshita, M. Mills, Pierluigi Toniutto, S. Campbell, J. Butterworth, S. Dyer, Filomena Morisco, Norihiro Kokudo, T. Yapp, C. Shorrock, Floriano Rosina, E. Walker, Shinji Uemoto, H. Takahashi, Simon M. Rushbrook, K. Amor, E. Marshall, J. Browning, S. Batham, Luca Fabris, Paul R. Banim, Meenakshi Narain, M. Harada, Dermot Gleeson, N. Hirashima, M. Kikuchi, T. Nikami, Gideon M. Hirschfield, Carlo Ferrari, G. Prasad, O. Chirag, Katsushi Tokunaga, M. Nasseri, Rosanna Asselta, Y. Lu, Ken Shirabe, D. Sirdefield, George F. Mells, K. Sugi, R. Ayres, G. Whatley, A. Singhal, M. Leoni, N. Sivaramakrishnan, T. Harding, Rupert Ransford, Anton V J Gunasekera, C. Mulvaney-Jones, D. Ramanaden, M. Mendall, Muhammad F. Dawwas, Dave Jones, Luca Valenti, Earl J. Williams, Markus Gess, Peter Bramley, A. McNair, E. Hashimoto, P. Townshend, C. Ford, Mario Strazzabosco, Luca Miele, Matthew J Brookes, J. Colley, Mark Wilkinson, H. Dewhurst, Charles Millson, E. Shpuza, Shinji Shimoda, T. Himoto, P. Kitchen, M. Nakamuta, Hiroaki Nishimura, Martin Lombard, Kevork M. Peltekian, M. Pitcher, G. Lim, L. Graves, C. Palmer, S. Lord, S. Katsushima, S. Tripoli, Andrew Austin, N. White, B. Grover, S. Congreave, M. Prince, Rebecca Jones, K. Hirano, A. Shepherd, Y. Mano, Michael A. Heneghan, Richard Sandford, L. O'Donohoe, Marco Carbone, S. A. Rolls, Patrick Goggin, M. L. Cowan, M. Crossey, A. Loftus, K. Young, Mesbah Rahman, Cameron N. Ghent, E. Nambela, M. Xiong, L. Grellier, Sunil Dolwani, Antonio Picciotto, Gill Watts, Alberto Mattalia, Elvezia Maria Paraboschi, J. Orpe, Takeji Umemura, Yuki Hitomi, Fiona H. 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D., Collier, J., Klass, H., Ninkovic, M., Cramp, M., Sharer, N., Aspinall, R., Goggin, P., Ghosh, D., Douds, A., Hoeroldt, B., Booth, J., Williams, E., Hussaini, H., Stableforth, W., Ayres, R., Thorburn, D., Marshall, E., Burroughs, A., Mann, S., Lombard, M., Richardson, P., Patanwala, I., Maltby, J., Brookes, M., Mathew, R., Vyas, S., Singhal, S., Gleeson, D., Misra, S., Butterworth, J., George, K., Harding, T., Douglass, A., Panter, S., Shearman, J., Bray, G., Butcher, G., Forton, D., Mclindon, J., Cowan, M., Whatley, G., Mandal, A., Gupta, H., Sanghi, P., Jain, S., Pereira, S., Prasad, G., Watts, G., Wright, M., Neuberger, J., Gordon, F., Unitt, E., Grant, A., Delahooke, T., Higham, A., Brind, A., Cox, M., Ramakrishnan, S., King, A., Collins, C., Whalley, S., Li, A., Fraser, J., Bell, A., Wong, V. 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Battezzati P.M., Crosignani A., Zuin M., Mattalia A., Calvaruso V., Colombo S., Benedetti A., Marzioni M., Galli A., Marra F., Tarocchi M., Picciotto A., Morisco F., Fabris L., Croce L.S., Tiribelli C., Toniutto P., Strazzabosco M., Ch'ng C.L., Rahman M., Yapp T., Sturgess R., Healey C., Czajkowski M., Gunasekera A., Gyawali P., Premchand P., Kapur K., Marley R., Foster G., Watson A., Dias A., Subhani J., Harvey R., McCorry R., Ramanaden D., Gasem J., Evans R., Mathialahan T., Shorrock C., Lipscomb G., Southern P., Tibble J., Gorard D., Palegwala A., Jones S., Dawwas M., Alexander G., Dolwani S., Prince M., Foxton M., Elphick D., Mitchison H., Gooding I., Karmo M., Saksena S., Mendall M., Patel M., Ede R., Austin A., Sayer J., Hankey L., Hovell C., Fisher N., Carter M., Koss K., Piotrowicz A., Grimley C., Neal D., Lim G., Levi S., Ala A., Broad A., Saeed A., Wood G., Brown J., Wilkinson M., Gordon H., Ramage J., Ridpath J., Ngatchu T., Grover B., Shaukat S., Shidrawi R., Abouda G., Ali F., Rees I., Salam I., Narain M., Brown A., Taylor-Robinson S., Williams S., Grellier L., Banim P., Das D., Chilton A., Heneghan M., Curtis H., Gess M., Drake I., Aldersley M., Davies M., Jones R., McNair A., Srirajaskanthan R., Pitcher M., Sen S., Bird G., Barnardo A., Kitchen P., Yoong K., Chirag O., Sivaramakrishnan N., MacFaul G., Jones D., Shah A., Evans C., Saha S., Pollock K., Bramley P., Mukhopadhya A., Fraser A., Mills P., Shallcross C., Campbell S., Bathgate A., Shepherd A., Dillon J., Rushbrook S., Przemioslo R., Macdonald C., Metcalf J., Shmueli U., Davis A., Naqvi A., Lee T., Ryder S.D., Collier J., Klass H., Ninkovic M., Cramp M., Sharer N., Aspinall R., Goggin P., Ghosh D., Douds A., Hoeroldt B., Booth J., Williams E., Hussaini H., Stableforth W., Ayres R., Thorburn D., Marshall E., Burroughs A., Mann S., Lombard M., Richardson P., Patanwala I., Maltby J., Brookes M., Mathew R., Vyas S., Singhal S., Gleeson D., Misra S., Butterworth J., George K., Harding T., Douglass A., Panter S., Shearman J., Bray G., Butcher G., Forton D., Mclindon J., Cowan M., Whatley G., Mandal A., Gupta H., Sanghi P., Jain S., Pereira S., Prasad G., Watts G., Wright M., Neuberger J., Gordon F., Unitt E., Grant A., Delahooke T., Higham A., Brind A., Cox M., Ramakrishnan S., King A., Collins C., Whalley S., Li A., Fraser J., Bell A., Wong V.S., Singhal A., Gee I., Ang Y., Ransford R., Gotto J., Millson C., Bowles J., Thomas C., Harrison M., Galaska R., Kendall J., Whiteman J., Lawlor C., Gray C., Elliott K., Mulvaney-Jones C., Hobson L., Van Duyvenvoorde G., Loftus A., Seward K., Penn R., Maiden J., Damant R., Hails J., Cloudsdale R., Silvestre V., Glenn S., Dungca E., Wheatley N., Doyle H., Kent M., Hamilton C., Braim D., Wooldridge H., Abrahams R., Paton A., Lancaster N., Gibbins A., Hogben K., Desousa P., Muscariu F., Musselwhite J., McKay A., Tan L., Foale C., Brighton J., Flahive K., Nambela E., Townshend P., Ford C., Holder S., Palmer C., Featherstone J., Nasseri M., 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G., Archer E., Hamilton M., Curtis J., Shewan T., Walsh S., Warner K., Netherton K., Mupudzi M., Gunson B., Gitahi J., Gocher D., Batham S., Pateman H., Desmennu S., Conder J., Clement D., Gallagher S., Orpe J., Chan P., Currie L., O'Donohoe L., Oblak M., Morgan L., Quinn M., Amey I., Baird Y., Cotterill D., Cumlat L., Winter L., Greer S., Spurdle K., Allison J., Dyer S., Sweeting H., Kordula J., Aiba Y., Nakamura H., Abiru S., Nagaoka S., Komori A., Yatsuhashi H., Ishibashi H., Ito M., Kawai Y., Kohn S.-S., Gervais O., Migita K., Katsushima S., Naganuma A., Sugi K., Komatsu T., Mannami T., Matsushita K., Yoshizawa K., Makita F., Nikami T., Nishimura H., Kouno H., Ota H., Komura T., Nakamura Y., Shimada M., Hirashima N., Komeda T., Ario K., Nakamuta M., Yamashita T., Furuta K., Kikuchi M., Naeshiro N., Takahashi H., Mano Y., Tsunematsu S., Yabuuchi I., Shimada Y., Yamauchi K., Sugimoto R., Sakai H., Mita E., Koda M., Tsuruta S., Kamitsukasa H., Sato T., Masaki N., Kobata T., Fukushima N., Higuchi N., Ohara Y., Muro T., Takesaki E., Takaki H., Yamamoto T., Kato M., Nagaoki Y., Hayashi S., Ishida J., Watanabe Y., Kobayashi M., Koga M., Saoshiro T., Yagura M., Hirata K., Takikawa H., Ohira H., Zeniya M., Abe M., Onji M., Kaneko S., Honda M., Arai K., Arinaga-Hino T., Hashimoto E., Taniai M., Umemura T., Joshita S., Nakao K., Ichikawa T., Shibata H., Yamagiwa S., Seike M., Honda K., Sakisaka S., Takeyama Y., Harada M., Senju M., Yokosuka O., Kanda T., Ueno Y., Kikuchi K., Ebinuma H., Himoto T., Yasunami M., Murata K., Mizokami M., Shimoda S., Miyake Y., Takaki A., Yamamoto K., Hirano K., Ichida T., Ido A., Tsubouchi H., Chayama K., Harada K., Nakanuma Y., Maehara Y., Taketomi A., Shirabe K., Soejima Y., Mori A., Yagi S., Uemoto S., Tanaka T., Yamashiki N., Tamura S., Sugawara Y., Kokudo N., Carbone M., Cardamone G., Duga S., Gershwin M.E., Seldin M.F., Invernizzi P., Asselta, R, Paraboschi, E, Gerussi, A, Cordell, H, Mells, G, Sandford, R, Jones, D, Nakamura, M, Ueno, K, Hitomi, Y, Kawashima, M, Nishida, N, Tokunaga, K, Nagasaki, M, Tanaka, A, Tang, R, Li, Z, Shi, Y, Liu, X, Xiong, M, Hirschfield, G, Siminovitch, K, Walker, E, Xie, G, Mason, A, Myers, R, Peltekian, K, Ghent, C, Atkinson, E, Juran, B, Lazaridis, K, Lu, Y, Gu, X, Jing, K, Amos, C, Affronti, A, Brunetto, M, Coco, B, Spinzi, G, Elia, G, Ferrari, C, Lleo, A, Muratori, L, Muratori, P, Portincasa, P, Colli, A, Bruno, S, Colloredo, G, Azzaroli, F, Andreone, P, Bragazzi, M, Alvaro, D, Cardinale, V, Cazzagon, N, Rigamonti, C, Floreani, A, Rosina, F, Ciaccio, A, Cristoferi, L, D'Amato, D, Malinverno, F, Mancuso, C, Massironi, S, Milani, C, O'Donnell, S, Ronca, V, Barisani, D, Lampertico, P, Donato, F, Fagiuoli, S, Almasio, P, Giannini, E, Cursaro, C, Colombo, M, Valenti, L, Miele, L, Andriulli, A, Niro, G, Grattagliano, I, Morini, L, Casella, G, Vinci, M, Battezzati, P, Crosignani, A, Zuin, M, Mattalia, A, Calvaruso, V, Colombo, S, Benedetti, A, Marzioni, M, Galli, A, Marra, F, Tarocchi, M, Picciotto, A, Morisco, F, Fabris, L, Croce, L, Tiribelli, C, Toniutto, P, Strazzabosco, M, Ch'Ng, C, Rahman, M, Yapp, T, Sturgess, R, Healey, C, Czajkowski, M, Gunasekera, A, Gyawali, P, Premchand, P, Kapur, K, Marley, R, Foster, G, Watson, A, Dias, A, Subhani, J, Harvey, R, Mccorry, R, Ramanaden, D, Gasem, J, Evans, R, Mathialahan, T, Shorrock, C, Lipscomb, G, Southern, P, Tibble, J, Gorard, D, Palegwala, A, Jones, S, Dawwas, M, Alexander, G, Dolwani, S, Prince, M, Foxton, M, Elphick, D, Mitchison, H, Gooding, I, Karmo, M, Saksena, S, Mendall, M, Patel, M, Ede, R, Austin, A, Sayer, J, Hankey, L, Hovell, C, Fisher, N, Carter, M, Koss, K, Piotrowicz, A, Grimley, C, Neal, D, Lim, G, Levi, S, Ala, A, Broad, A, Saeed, A, Wood, G, Brown, J, Wilkinson, M, Gordon, H, Ramage, J, Ridpath, J, Ngatchu, T, Grover, B, Shaukat, S, Shidrawi, R, Abouda, G, Ali, F, Rees, I, Salam, I, Narain, M, Brown, A, Taylor-Robinson, S, Williams, S, Grellier, L, Banim, P, Das, D, Chilton, A, Heneghan, M, Curtis, H, Gess, M, Drake, I, Aldersley, M, Davies, M, Jones, R, Mcnair, A, Srirajaskanthan, R, Pitcher, M, Sen, S, Bird, G, Barnardo, A, Kitchen, P, Yoong, K, Chirag, O, Sivaramakrishnan, N, Macfaul, G, Shah, A, Evans, C, Saha, S, Pollock, K, Bramley, P, Mukhopadhya, A, Fraser, A, Mills, P, Shallcross, C, Campbell, S, Bathgate, A, Shepherd, A, Dillon, J, Rushbrook, S, Przemioslo, R, Macdonald, C, Metcalf, J, Shmueli, U, Davis, A, Naqvi, A, Lee, T, Ryder, S, Collier, J, Klass, H, Ninkovic, M, Cramp, M, Sharer, N, Aspinall, R, Goggin, P, Ghosh, D, Douds, A, Hoeroldt, B, Booth, J, Williams, E, Hussaini, H, Stableforth, W, Ayres, R, Thorburn, D, Marshall, E, Burroughs, A, Mann, S, Lombard, M, Richardson, P, Patanwala, I, Maltby, J, Brookes, M, Mathew, R, Vyas, S, Singhal, S, Gleeson, D, Misra, S, Butterworth, J, George, K, Harding, T, Douglass, A, Panter, S, Shearman, J, Bray, G, Butcher, G, Forton, D, Mclindon, J, Cowan, M, Whatley, G, Mandal, A, Gupta, H, Sanghi, P, Jain, S, Pereira, S, Prasad, G, Watts, G, Wright, M, Neuberger, J, Gordon, F, Unitt, E, Grant, A, Delahooke, T, Higham, A, Brind, A, Cox, M, Ramakrishnan, S, King, A, Collins, C, Whalley, S, Li, A, Fraser, J, Bell, A, Wong, V, Singhal, A, Gee, I, Ang, Y, Ransford, R, Gotto, J, Millson, C, Bowles, J, Thomas, C, Harrison, M, Galaska, R, Kendall, J, Whiteman, J, Lawlor, C, Gray, C, Elliott, K, Mulvaney-Jones, C, Hobson, L, Van Duyvenvoorde, G, Loftus, A, Seward, K, Penn, R, Maiden, J, Damant, R, Hails, J, Cloudsdale, R, Silvestre, V, Glenn, S, Dungca, E, Wheatley, N, Doyle, H, Kent, M, Hamilton, C, Braim, D, Wooldridge, H, Abrahams, R, Paton, A, Lancaster, N, Gibbins, A, Hogben, K, Desousa, P, Muscariu, F, Musselwhite, J, Mckay, A, Tan, L, Foale, C, Brighton, J, Flahive, K, Nambela, E, Townshend, P, Ford, C, Holder, S, Palmer, C, Featherstone, J, Nasseri, M, Sadeghian, J, Williams, B, Rolls, S, Hynes, A, Duggan, C, Crossey, M, Stansfield, G, Macnicol, C, Wilkins, J, Wilhelmsen, E, Raymode, P, Lee, H, Durant, E, Bishop, R, Ncube, N, Tripoli, S, Casey, R, Cowley, C, Miller, R, Houghton, K, Ducker, S, Wright, F, Bird, B, Baxter, G, Keggans, J, Hughes, M, Grieve, E, Young, K, Williams, D, Ocker, K, Hines, F, Martin, K, Innes, C, Valliani, T, Fairlamb, H, Thornthwaite, S, Eastick, A, Tanqueray, E, Morrison, J, Holbrook, B, Browning, J, Walker, K, Congreave, S, Verheyden, J, Slininger, S, Stafford, L, O'Donnell, D, Ainsworth, M, Lord, S, Kent, L, March, L, Dickson, C, Simpson, D, Longhurst, B, Hayes, M, Shpuza, E, White, N, Besley, S, Pearson, S, Wright, A, Jones, L, Gunter, E, Dewhurst, H, Fouracres, A, Farrington, L, Graves, L, Marriott, S, Leoni, M, Tyrer, D, Dali-kemmery, L, Lambourne, V, Green, M, Sirdefield, D, Amor, K, Colley, J, Shinder, B, Jones, J, Mills, M, Carnahan, M, Taylor, N, Boulton, K, Tregonning, J, Brown, C, Clifford, G, Archer, E, Hamilton, M, Curtis, J, Shewan, T, Walsh, S, Warner, K, Netherton, K, Mupudzi, M, Gunson, B, Gitahi, J, Gocher, D, Batham, S, Pateman, H, Desmennu, S, Conder, J, Clement, D, Gallagher, S, Orpe, J, Chan, P, Currie, L, O'Donohoe, L, Oblak, M, Morgan, L, Quinn, M, Amey, I, Baird, Y, Cotterill, D, Cumlat, L, Winter, L, Greer, S, Spurdle, K, Allison, J, Dyer, S, Sweeting, H, Kordula, J, Aiba, Y, Nakamura, H, Abiru, S, Nagaoka, S, Komori, A, Yatsuhashi, H, Ishibashi, H, Ito, M, Kawai, Y, Kohn, S, Gervais, O, Migita, K, Katsushima, S, Naganuma, A, Sugi, K, Komatsu, T, Mannami, T, Matsushita, K, Yoshizawa, K, Makita, F, Nikami, T, Nishimura, H, Kouno, H, Ota, H, Komura, T, Nakamura, Y, Shimada, M, Hirashima, N, Komeda, T, Ario, K, Nakamuta, M, Yamashita, T, Furuta, K, Kikuchi, M, Naeshiro, N, Takahashi, H, Mano, Y, Tsunematsu, S, Yabuuchi, I, Shimada, Y, Yamauchi, K, Sugimoto, R, Sakai, H, Mita, E, Koda, M, Tsuruta, S, Kamitsukasa, H, Sato, T, Masaki, N, Kobata, T, Fukushima, N, Higuchi, N, Ohara, Y, Muro, T, Takesaki, E, Takaki, H, Yamamoto, T, Kato, M, Nagaoki, Y, Hayashi, S, Ishida, J, Watanabe, Y, Kobayashi, M, Koga, M, Saoshiro, T, Yagura, M, Hirata, K, Takikawa, H, Ohira, H, Zeniya, M, Abe, M, Onji, M, Kaneko, S, Honda, M, Arai, K, Arinaga-Hino, T, Hashimoto, E, Taniai, M, Umemura, T, Joshita, S, Nakao, K, Ichikawa, T, Shibata, H, Yamagiwa, S, Seike, M, Honda, K, Sakisaka, S, Takeyama, Y, Harada, M, Senju, M, Yokosuka, O, Kanda, T, Ueno, Y, Kikuchi, K, Ebinuma, H, Himoto, T, Yasunami, M, Murata, K, Mizokami, M, Shimoda, S, Miyake, Y, Takaki, A, Yamamoto, K, Hirano, K, Ichida, T, Ido, A, Tsubouchi, H, Chayama, K, Harada, K, Nakanuma, Y, Maehara, Y, Taketomi, A, Shirabe, K, Soejima, Y, Mori, A, Yagi, S, Uemoto, S, Tanaka, T, Yamashiki, N, Tamura, S, Sugawara, Y, Kokudo, N, Carbone, M, Cardamone, G, Duga, S, Gershwin, M, Seldin, M, Invernizzi, P, Asselta R, Paraboschi EM, Gerussi A, Cordell HJ, Mells GF, Sandford RN, Jones DE, Nakamura M, Ueno K, Hitomi Y, Kawashima M, Nishida N, Tokunaga K, Nagasaki M, Tanaka A, Tang R, Li Z, Shi Y, Liu X, Xiong M, Hirschfield G, Siminovitch KA, Canadian-US PBC Consortium, Italian PBC Genetics Study Group, UK-PBC Consortium, Japan PBC-GWAS Consortium, Carbone M, Cardamone G, Duga S, Gershwin ME, Seldin MF, Invernizzi P, and LiveR North

Subjects
Canadian-US PBC Consortium, 0301 basic medicine, Male, Linkage disequilibrium, Genome-wide association study, Disease, PBC, Settore MED/03 - GENETICA MEDICA, Linkage Disequilibrium, 0302 clinical medicine, UK-PBC Consortium, Genotype, Mitochondrial Precursor Protein Import Complex Proteins, Italian PBC Genetics Study Group, Odds Ratio, X-Wide Association Study, Japan PBC-GWAS Consortium, X chromosome, Genetics, Liver Cirrhosis, Biliary, Gastroenterology, Forkhead Transcription Factors, DNA-Binding Proteins, Shal Potassium Channels, 030211 gastroenterology & hepatology, Female, Adult, Monosaccharide Transport Proteins, Superenhancer, Locus (genetics), Single-nucleotide polymorphism, Biology, Protein Serine-Threonine Kinases, Polymorphism, Single Nucleotide, Article, White People, 03 medical and health sciences, Asian People, Proto-Oncogene Proteins, Endopeptidases, Humans, Cell Lineage, Genetic Predisposition to Disease, Meta-analysi, Genetic association, Chromosomes, Human, X, Gastroenterology & Hepatology, Hepatology, 1103 Clinical Sciences, Meta-analysis, 030104 developmental biology, Genetic Loci, 1114 Paediatrics and Reproductive Medicine, 1109 Neurosciences, Carrier Proteins, Genome-Wide Association Study
Abstract

Background & aims: Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease. Methods: We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals). Results: Single-marker association analyses found approximately 100 loci displaying P < 5 × 10-4, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10-6; odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028-1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09-1.26; P = 9.93 × 10-8), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 × 10-9; OR, 1.33; 95% CI, 1.21-1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively). Conclusions: This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus.

Published
2021

227. Primary branchiogenic carcinoma: malignant degeneration of a branchial cyst, a case report

Author

Gianpaolo Tartaro, Marco Montella, Giuseppe Colella, Immacolata Cozzolino, Chiara Spuntarelli, Davide De Cicco, Ciro Emiliano Boschetti, Colella, Giuseppe, Boschetti, Ciro Emiliano, Spuntarelli, Chiara, De Cicco, Davide, Cozzolino, Immacolata, Montella, Marco, and Tartaro, Gianpaolo

Subjects
Male, Cancer Research, medicine.medical_specialty, Neck mass, Case Report, Degeneration (medical), PBC, head and neck, surgery, Cervical masses, primary branchiogenic carcinoma, Positron Emission Tomography Computed Tomography, medicine, Neoplasm, Humans, Cyst, Branchiogenic carcinoma, branchial cyst, business.industry, Squamous Cell Carcinoma of Head and Neck, Branchial Cyst, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Lymphatic system, Treatment Outcome, Oncology, Head and Neck Neoplasms, Neck Dissection, Radiology, medicine.symptom, Branchioma, business
Abstract

Background Primary branchiogenic carcinoma (PBC) is an extremely rare and poorly documented disease developed from a brachial cleft cyst. Case A 51‐year‐old patient was referred to our unit for an upper neck mass. PBC was confirmed in accordance with Kahfif's diagnostic criteria. Prophylactic selective neck dissection was performed in a second‐stage surgery to ensure the complete removal of the neoplasm. Branchiogenic origin with lymphoid tissue was confirmed in the “host cyst” after histological examination and no other tumors were found elsewhere. Regular follow up documented no relapse 12 months after surgery. Conclusions Although rare, PBC must be suspected in presence of cervical masses, especially in patients older than 40 years. A standardized treatment algorithm still lacks, but prophylactic selective neck dissection could be considered as the first line choice after the diagnosis has been confirmed.

Published
2021

228. An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs

Author

Heather J. Cordell, James J. Fryett, Kazuko Ueno, Rebecca Darlay, Yoshihiro Aiba, Yuki Hitomi, Minae Kawashima, Nao Nishida, Seik-Soon Khor, Olivier Gervais, Yosuke Kawai, Masao Nagasaki, Katsushi Tokunaga, Ruqi Tang, Yongyong Shi, Zhiqiang Li, Brian D. Juran, Elizabeth J. Atkinson, Alessio Gerussi, Marco Carbone, Rosanna Asselta, Angela Cheung, Mariza de Andrade, Aris Baras, Julie Horowitz, Manuel A.R. Ferreira, Dylan Sun, David E. Jones, Steven Flack, Ann Spicer, Victoria L. Mulcahy, Jinyoung Byan, Younghun Han, Richard N. Sandford, Konstantinos N. Lazaridis, Christopher I. Amos, Gideon M. Hirschfield, Michael F. Seldin, Pietro Invernizzi, Katherine A. Siminovitch, Xiong Ma, Minoru Nakamura, George F. Mells, Andrew Mason, Catherine Vincent, Gang Xie, Jinyi Zhang, Andrea Affronti, Piero L. Almasio, Domenico Alvaro, Pietro Andreone, Angelo Andriulli, Francesco Azzaroli, Pier Maria Battezzati, Antonio Benedetti, MariaConsiglia Bragazzi, Maurizia Brunetto, Savino Bruno, Vincenza Calvaruso, Vincenzo Cardinale, Giovanni Casella, Nora Cazzagon, Antonio Ciaccio, Barbara Coco, Agostino Colli, Guido Colloredo, Massimo Colombo, Silvia Colombo, Laura Cristoferi, Carmela Cursaro, Lory Saveria Crocè, Andrea Crosignani, Daphne D’Amato, Francesca Donato, Gianfranco Elia, Luca Fabris, Stefano Fagiuoli, Carlo Ferrari, Annarosa Floreani, Andrea Galli, Edoardo Giannini, Ignazio Grattagliano, Pietro Lampertico, Ana Lleo, Federica Malinverno, Clara Mancuso, Fabio Marra, Marco Marzioni, Sara Massironi, Alberto Mattalia, Luca Miele, Chiara Milani, Lorenzo Morini, Filomena Morisco, Luigi Muratori, Paolo Muratori, Grazia A. Niro, Sarah O’Donnell, Antonio Picciotto, Piero Portincasa, Cristina Rigamonti, Vincenzo Ronca, Floriano Rosina, Giancarlo Spinzi, Mario Strazzabosco, Mirko Tarocchi, Claudio Tiribelli, Pierluigi Toniutto, Luca Valenti, Maria Vinci, Massimo Zuin, Hitomi Nakamura, Seigo Abiru, Shinya Nagaoka, Atsumasa Komori, Hiroshi Yatsuhashi, Hiromi Ishibashi, Masahiro Ito, Kiyoshi Migita, Hiromasa Ohira, Shinji Katsushima, Atsushi Naganuma, Kazuhiro Sugi, Tatsuji Komatsu, Tomohiko Mannami, Kouki Matsushita, Kaname Yoshizawa, Fujio Makita, Toshiki Nikami, Hideo Nishimura, Hiroshi Kouno, Hirotaka Kouno, Hajime Ota, Takuya Komura, Yoko Nakamura, Masaaki Shimada, Noboru Hirashima, Toshiki Komeda, Keisuke Ario, Makoto Nakamuta, Tsutomu Yamashita, Kiyoshi Furuta, Masahiro Kikuchi, Noriaki Naeshiro, Hironao Takahashi, Yutaka Mano, Seiji Tsunematsu, Iwao Yabuuchi, Yusuke Shimada, Kazuhiko Yamauchi, Rie Sugimoto, Hironori Sakai, Eiji Mita, Masaharu Koda, Satoru Tsuruta, Hiroshi Kamitsukasa, Takeaki Sato, Naohiko Masaki, Tatsuro Kobata, Nobuyoshi Fukushima, Yukio Ohara, Toyokichi Muro, Eiichi Takesaki, Hitoshi Takaki, Tetsuo Yamamoto, Michio Kato, Yuko Nagaoki, Shigeki Hayashi, Jinya Ishida, Yukio Watanabe, Masakazu Kobayashi, Michiaki Koga, Takeo Saoshiro, Michiyasu Yagura, Keisuke Hirata, Atsushu Tanaka, Hajime Takikawa, Mikio Zeniya, Masanori Abe, Morikazu Onji, Shuichi Kaneko, Masao Honda, Kuniaki Arai, Teruko Arinaga-Hino, Etsuko Hashimoto, Makiko Taniai, Takeji Umemura, Satoru Joshita, Kazuhiko Nakao, Tatsuki Ichikawa, Hidetaka Shibata, Satoshi Yamagiwa, Masataka Seike, Koichi Honda, Shotaro Sakisaka, Yasuaki Takeyama, Masaru Harada, Michio Senju, Osamu Yokosuka, Tatsuo Kanda, Yoshiyuki Ueno, Kentaro Kikuchi, Hirotoshi Ebinuma, Takashi Himoto, Michio Yasunami, Kazumoto Murata, Masashi Mizokami, Kazuhito Kawata, Shinji Shimoda, Yasuhiro Miyake, Akinobu Takaki, Kazuhide Yamamoto, Katsuji Hirano, Takafumi Ichida, Akio Ido, Hirohito Tsubouchi, Kazuaki Chayama, Kenichi Harada, Yasuni Nakanuma, Yoshihiko Maehara, Akinobu Taketomi, Ken Shirabe, Yuji Soejima, Akira Mori, Shintaro Yagi, Shinji Uemoto, Egawa H, Tomohiro Tanaka, Noriyo Yamashiki, Sumito Tamura, Yasuhiro Sugawara, Norihiro Kokudo, Naga Chalasani, Vel Luketic, Joseph Odin, Kapil Chopra, Goncalo Abecasis, Michael Cantor, Giovanni Coppola, Aris Economides, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Alan Shuldiner, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, Thomas D. Schleicher, Maria Sotiropoulos Padilla, Karina Toledo, Louis Widom, Sarah E. Wolf, Manasi Pradhan, Kia Manoochehri, Ricardo H. Ulloa, Xiaodong Bai, Suganthi Balasubramanian, Leland Barnard, Andrew Blumenfeld, Gisu Eom, Lukas Habegger, Alicia Hawes, Shareef Khalid, Evan K. Maxwell, William Salerno, Jeffrey C. Staples, Marcus B. Jones, Lyndon J. Mitnaul, Richard Sturgess, Christopher Healey, Andrew Yeoman, Anton VJ. Gunasekera, Paul Kooner, Kapil Kapur, V. Sathyanarayana, Yiannis Kallis, Javaid Subhani, Rory Harvey, Roger McCorry, Paul Rooney, David Ramanaden, Richard Evans, Thiriloganathan Mathialahan, Jaber Gasem, Christopher Shorrock, Mahesh Bhalme, Paul Southern, Jeremy A. Tibble, David A. Gorard, Susan Jones, George Mells, Victoria Mulcahy, Brijesh Srivastava, Matthew R. Foxton, Carole E. Collins, David Elphick, Mazn Karmo, Francisco Porras-Perez, Michael Mendall, Tom Yapp, Minesh Patel, Roland Ede, Joanne Sayer, James Jupp, Neil Fisher, Martyn J. Carter, Konrad Koss, Jayshri Shah, Andrzej Piotrowicz, Glyn Scott, Charles Grimley, Ian R. Gooding, Simon Williams, Judith Tidbury, Guan Lim, Kuldeep Cheent, Sass Levi, Dina Mansour, Matilda Beckley, Coral Hollywood, Terry Wong, Richard Marley, John Ramage, Harriet M. Gordon, Jo Ridpath, Theodore Ngatchu, Vijay Paul Bob Grover, Ray G. Shidrawi, George Abouda, L. Corless, Mark Narain, Ian Rees, Ashley Brown, Simon Taylor-Robinson, Joy Wilkins, Leonie Grellier, Paul Banim, Debasish Das, Michael A. Heneghan, Howard Curtis, Helen C. Matthews, Faiyaz Mohammed, Mark Aldersley, Raj Srirajaskanthan, Giles Walker, Alistair McNair, Amar Sharif, Sambit Sen, George Bird, Martin I. Prince, Geeta Prasad, Paul Kitchen, Adrian Barnardo, Chirag Oza, Nurani N. Sivaramakrishnan, Prakash Gupta, Amir Shah, Chris DJ. Evans, Subrata Saha, Katharine Pollock, Peter Bramley, Ashis Mukhopadhya, Stephen T. Barclay, Natasha McDonald, Andrew J. Bathgate, Kelvin Palmer, John F. Dillon, Simon M. Rushbrook, Robert Przemioslo, Chris McDonald, Andrew Millar, Cheh Tai, Stephen Mitchell, Jane Metcalf, Syed Shaukat, Mary Ninkovic, Udi Shmueli, Andrew Davis, Asifabbas Naqvi, Tom JW. Lee, Stephen Ryder, Jane Collier, Howard Klass, Matthew E. Cramp, Nichols Sharer, Richard Aspinall, Deb Ghosh, Andrew C. Douds, Jonathan Booth, Earl Williams, Hyder Hussaini, John Christie, Steven Mann, Douglas Thorburn, Aileen Marshall, Imran Patanwala, Aftab Ala, Julia Maltby, Ray Matthew, Chris Corbett, Sam Vyas, Saket Singhal, Dermot Gleeson, Sharat Misra, Jeff Butterworth, Keith George, Tim Harding, Andrew Douglass, Harriet Mitchison, Simon Panter, Jeremy Shearman, Gary Bray, Michael Roberts, Graham Butcher, Daniel Forton, Zahid Mahmood, Matthew Cowan, Debashis Das, Chin Lye Ch’ng, Mesbah Rahman, Gregory C.A. Whatley, Emma Wesley, Aditya Mandal, Sanjiv Jain, Stephen P. Pereira, Mark Wright, Palak Trivedi, Fiona H. Gordon, Esther Unitt, Altaf Palejwala, Andrew Austin, Vishwaraj Vemala, Allister Grant, Andrew D. Higham, Alison Brind, Ray Mathew, Mark Cox, Subramaniam Ramakrishnan, Alistair King, Simon Whalley, Jocelyn Fraser, S.J. Thomson, Andrew Bell, Voi Shim Wong, Richard Kia, Ian Gee, Richard Keld, Rupert Ransford, James Gotto, Charles Millson, Cordell, H. J., Fryett, J. J., Ueno, K., Darlay, R., Aiba, Y., Hitomi, Y., Kawashima, M., Nishida, N., Khor, S. -S., Gervais, O., Kawai, Y., Nagasaki, M., Tokunaga, K., Tang, R., Shi, Y., Li, Z., Juran, B. D., Atkinson, E. J., Gerussi, A., Carbone, M., Asselta, R., Cheung, A., de Andrade, M., Baras, A., Horowitz, J., Ferreira, M. A. R., Sun, D., Jones, D. E., Flack, S., Spicer, A., Mulcahy, V. L., Byan, J., Han, Y., Sandford, R. N., Lazaridis, K. N., Amos, C. I., Hirschfield, G. M., Seldin, M. F., Invernizzi, P., Siminovitch, K. A., Ma, X., Nakamura, M., Mells, G. F., Mason, A., Vincent, C., Xie, G., Zhang, J., Affronti, A., Almasio, P. L., Alvaro, D., Andreone, P., Andriulli, A., Azzaroli, F., Battezzati, P. M., Benedetti, A., Bragazzi, M., Brunetto, M., Bruno, S., Calvaruso, V., Cardinale, V., Casella, G., Cazzagon, N., Ciaccio, A., Coco, B., Colli, A., Colloredo, G., Colombo, M., Colombo, S., Cristoferi, L., Cursaro, C., Croce, L. S., Crosignani, A., D'Amato, D., Donato, F., Elia, G., Fabris, L., Fagiuoli, S., Ferrari, C., Floreani, A., Galli, A., Giannini, E., Grattagliano, I., Lampertico, P., Lleo, A., Malinverno, F., Mancuso, C., Marra, F., Marzioni, M., Massironi, S., Mattalia, A., Miele, L., Milani, C., Morini, L., Morisco, F., Muratori, L., Muratori, P., Niro, G. A., O'Donnell, S., Picciotto, A., Portincasa, P., Rigamonti, C., Ronca, V., Rosina, F., Spinzi, G., Strazzabosco, M., Tarocchi, M., Tiribelli, C., Toniutto, P., Valenti, L., Vinci, M., Zuin, M., Nakamura, H., Abiru, S., Nagaoka, S., Komori, A., Yatsuhashi, H., Ishibashi, H., Ito, M., Migita, K., Ohira, H., Katsushima, S., Naganuma, A., Sugi, K., Komatsu, T., Mannami, T., Matsushita, K., Yoshizawa, K., Makita, F., Nikami, T., Nishimura, H., Kouno, H., Ota, H., Komura, T., Nakamura, Y., Shimada, M., Hirashima, N., Komeda, T., Ario, K., Nakamuta, M., Yamashita, T., Furuta, K., Kikuchi, M., Naeshiro, N., Takahashi, H., Mano, Y., Tsunematsu, S., Yabuuchi, I., Shimada, Y., Yamauchi, K., Sugimoto, R., Sakai, H., Mita, E., Koda, M., Tsuruta, S., Kamitsukasa, H., Sato, T., Masaki, N., Kobata, T., Fukushima, N., Ohara, Y., Muro, T., Takesaki, E., Takaki, H., Yamamoto, T., Kato, M., Nagaoki, Y., Hayashi, S., Ishida, J., Watanabe, Y., Kobayashi, M., Koga, M., Saoshiro, T., Yagura, M., Hirata, K., Tanaka, A., Takikawa, H., Zeniya, M., Abe, M., Onji, M., Kaneko, S., Honda, M., Arai, K., Arinaga-Hino, T., Hashimoto, E., Taniai, M., Umemura, T., Joshita, S., Nakao, K., Ichikawa, T., Shibata, H., Yamagiwa, S., Seike, M., Honda, K., Sakisaka, S., Takeyama, Y., Harada, M., Senju, M., Yokosuka, O., Kanda, T., Ueno, Y., Kikuchi, K., Ebinuma, H., Himoto, T., Yasunami, M., Murata, K., Mizokami, M., Kawata, K., Shimoda, S., Miyake, Y., Takaki, A., Yamamoto, K., Hirano, K., Ichida, T., Ido, A., Tsubouchi, H., Chayama, K., Harada, K., Nakanuma, Y., Maehara, Y., Taketomi, A., Shirabe, K., Soejima, Y., Mori, A., Yagi, S., Uemoto, S., H, E., Tanaka, T., Yamashiki, N., Tamura, S., Sugawara, Y., Kokudo, N., Chalasani, N., Luketic, V., Odin, J., Chopra, K., Abecasis, G., Cantor, M., Coppola, G., Economides, A., Lotta, L. A., Overton, J. D., Reid, J. G., Shuldiner, A., Beechert, C., Forsythe, C., Fuller, E. D., Gu, Z., Lattari, M., Lopez, A., Schleicher, T. D., Padilla, M. S., Toledo, K., Widom, L., Wolf, S. E., Pradhan, M., Manoochehri, K., Ulloa, R. H., Bai, X., Balasubramanian, S., Barnard, L., Blumenfeld, A., Eom, G., Habegger, L., Hawes, A., Khalid, S., Maxwell, E. K., Salerno, W., Staples, J. C., Jones, M. B., Mitnaul, L. J., Sturgess, R., Healey, C., Yeoman, A., Gunasekera, A. V., Kooner, P., Kapur, K., Sathyanarayana, V., Kallis, Y., Subhani, J., Harvey, R., Mccorry, R., Rooney, P., Ramanaden, D., Evans, R., Mathialahan, T., Gasem, J., Shorrock, C., Bhalme, M., Southern, P., Tibble, J. A., Gorard, D. A., Jones, S., Mells, G., Mulcahy, V., Srivastava, B., Foxton, M. R., Collins, C. E., Elphick, D., Karmo, M., Porras-Perez, F., Mendall, M., Yapp, T., Patel, M., Ede, R., Sayer, J., Jupp, J., Fisher, N., Carter, M. J., Koss, K., Shah, J., Piotrowicz, A., Scott, G., Grimley, C., Gooding, I. R., Williams, S., Tidbury, J., Lim, G., Cheent, K., Levi, S., Mansour, D., Beckley, M., Hollywood, C., Wong, T., Marley, R., Ramage, J., Gordon, H. M., Ridpath, J., Ngatchu, T., Bob Grover, V. P., Shidrawi, R. G., Abouda, G., Corless, L., Narain, M., Rees, I., Brown, A., Taylor-Robinson, S., Wilkins, J., Grellier, L., Banim, P., Das, D., Heneghan, M. A., Curtis, H., Matthews, H. C., Mohammed, F., Aldersley, M., Srirajaskanthan, R., Walker, G., Mcnair, A., Sharif, A., Sen, S., Bird, G., Prince, M. I., Prasad, G., Kitchen, P., Barnardo, A., Oza, C., Sivaramakrishnan, N. N., Gupta, P., Shah, A., Evans, C. D., Saha, S., Pollock, K., Bramley, P., Mukhopadhya, A., Barclay, S. T., Mcdonald, N., Bathgate, A. J., Palmer, K., Dillon, J. F., Rushbrook, S. M., Przemioslo, R., Mcdonald, C., Millar, A., Tai, C., Mitchell, S., Metcalf, J., Shaukat, S., Ninkovic, M., Shmueli, U., Davis, A., Naqvi, A., Lee, T. J., Ryder, S., Collier, J., Klass, H., Cramp, M. E., Sharer, N., Aspinall, R., Ghosh, D., Douds, A. C., Booth, J., Williams, E., Hussaini, H., Christie, J., Mann, S., Thorburn, D., Marshall, A., Patanwala, I., Ala, A., Maltby, J., Matthew, R., Corbett, C., Vyas, S., Singhal, S., Gleeson, D., Misra, S., Butterworth, J., George, K., Harding, T., Douglass, A., Mitchison, H., Panter, S., Shearman, J., Bray, G., Roberts, M., Butcher, G., Forton, D., Mahmood, Z., Cowan, M., Ch'Ng, C. L., Rahman, M., Whatley, G. C. A., Wesley, E., Mandal, A., Jain, S., Pereira, S. P., Wright, M., Trivedi, P., Gordon, F. H., Unitt, E., Palejwala, A., Austin, A., Vemala, V., Grant, A., Higham, A. D., Brind, A., Mathew, R., Cox, M., Ramakrishnan, S., King, A., Whalley, S., Fraser, J., Thomson, S. J., Bell, A., Wong, V. S., Kia, R., Gee, I., Keld, R., Ransford, R., Gotto, J., Millson, C., Cordell H.J., Fryett J.J., Ueno K., Darlay R., Aiba Y., Hitomi Y., Kawashima M., Nishida N., Khor S.-S., Gervais O., Kawai Y., Nagasaki M., Tokunaga K., Tang R., Shi Y., Li Z., Juran B.D., Atkinson E.J., Gerussi A., Carbone M., Asselta R., Cheung A., de Andrade M., Baras A., Horowitz J., Ferreira M.A.R., Sun D., Jones D.E., Flack S., Spicer A., Mulcahy V.L., Byan J., Han Y., Sandford R.N., Lazaridis K.N., Amos C.I., Hirschfield G.M., Seldin M.F., Invernizzi P., Siminovitch K.A., Ma X., Nakamura M., Mells G.F., Mason A., Vincent C., Xie G., Zhang J., Affronti A., Almasio P.L., Alvaro D., Andreone P., Andriulli A., Azzaroli F., Battezzati P.M., Benedetti A., Bragazzi M., Brunetto M., Bruno S., Calvaruso V., Cardinale V., Casella G., Cazzagon N., Ciaccio A., Coco B., Colli A., Colloredo G., Colombo M., Colombo S., Cristoferi L., Cursaro C., Croce L.S., Crosignani A., D'Amato D., Donato F., Elia G., Fabris L., Fagiuoli S., Ferrari C., Floreani A., Galli A., Giannini E., Grattagliano I., Lampertico P., Lleo A., Malinverno F., Mancuso C., Marra F., Marzioni M., Massironi S., Mattalia A., Miele L., Milani C., Morini L., Morisco F., Muratori L., Muratori P., Niro G.A., O'Donnell S., Picciotto A., Portincasa P., Rigamonti C., Ronca V., Rosina F., Spinzi G., Strazzabosco M., Tarocchi M., Tiribelli C., Toniutto P., Valenti L., Vinci M., Zuin M., Nakamura H., Abiru S., Nagaoka S., Komori A., Yatsuhashi H., Ishibashi H., Ito M., Migita K., Ohira H., Katsushima S., Naganuma A., Sugi K., Komatsu T., Mannami T., Matsushita K., Yoshizawa K., Makita F., Nikami T., Nishimura H., Kouno H., Ota H., Komura T., Nakamura Y., Shimada M., Hirashima N., Komeda T., Ario K., Nakamuta M., Yamashita T., Furuta K., Kikuchi M., Naeshiro N., Takahashi H., Mano Y., Tsunematsu S., Yabuuchi I., Shimada Y., Yamauchi K., Sugimoto R., Sakai H., Mita E., Koda M., Tsuruta S., Kamitsukasa H., Sato T., Masaki N., Kobata T., Fukushima N., Ohara Y., Muro T., Takesaki E., Takaki H., Yamamoto T., Kato M., Nagaoki Y., Hayashi S., Ishida J., Watanabe Y., Kobayashi M., Koga M., Saoshiro T., Yagura M., Hirata K., Tanaka A., Takikawa H., Zeniya M., Abe M., Onji M., Kaneko S., Honda M., Arai K., Arinaga-Hino T., Hashimoto E., Taniai M., Umemura T., Joshita S., Nakao K., Ichikawa T., Shibata H., Yamagiwa S., Seike M., Honda K., Sakisaka S., Takeyama Y., Harada M., Senju M., Yokosuka O., Kanda T., Ueno Y., Kikuchi K., Ebinuma H., Himoto T., Yasunami M., Murata K., Mizokami M., Kawata K., Shimoda S., Miyake Y., Takaki A., Yamamoto K., Hirano K., Ichida T., Ido A., Tsubouchi H., Chayama K., Harada K., Nakanuma Y., Maehara Y., Taketomi A., Shirabe K., Soejima Y., Mori A., Yagi S., Uemoto S., H E., Tanaka T., Yamashiki N., Tamura S., Sugawara Y., Kokudo N., Chalasani N., Luketic V., Odin J., Chopra K., Abecasis G., Cantor M., Coppola G., Economides A., Lotta L.A., Overton J.D., Reid J.G., Shuldiner A., Beechert C., Forsythe C., Fuller E.D., Gu Z., Lattari M., Lopez A., Schleicher T.D., Padilla M.S., Toledo K., Widom L., Wolf S.E., Pradhan M., Manoochehri K., Ulloa R.H., Bai X., Balasubramanian S., Barnard L., Blumenfeld A., Eom G., Habegger L., Hawes A., Khalid S., Maxwell E.K., Salerno W., Staples J.C., Jones M.B., Mitnaul L.J., Sturgess R., Healey C., Yeoman A., Gunasekera A.V., Kooner P., Kapur K., Sathyanarayana V., Kallis Y., Subhani J., Harvey R., McCorry R., Rooney P., Ramanaden D., Evans R., Mathialahan T., Gasem J., Shorrock C., Bhalme M., Southern P., Tibble J.A., Gorard D.A., Jones S., Mells G., Mulcahy V., Srivastava B., Foxton M.R., Collins C.E., Elphick D., Karmo M., Porras-Perez F., Mendall M., Yapp T., Patel M., Ede R., Sayer J., Jupp J., Fisher N., Carter M.J., Koss K., Shah J., Piotrowicz A., Scott G., Grimley C., Gooding I.R., Williams S., Tidbury J., Lim G., Cheent K., Levi S., Mansour D., Beckley M., Hollywood C., Wong T., Marley R., Ramage J., Gordon H.M., Ridpath J., Ngatchu T., Bob Grover V.P., Shidrawi R.G., Abouda G., Corless L., Narain M., Rees I., Brown A., Taylor-Robinson S., Wilkins J., Grellier L., Banim P., Das D., Heneghan M.A., Curtis H., Matthews H.C., Mohammed F., Aldersley M., Srirajaskanthan R., Walker G., McNair A., Sharif A., Sen S., Bird G., Prince M.I., Prasad G., Kitchen P., Barnardo A., Oza C., Sivaramakrishnan N.N., Gupta P., Shah A., Evans C.D., Saha S., Pollock K., Bramley P., Mukhopadhya A., Barclay S.T., McDonald N., Bathgate A.J., Palmer K., Dillon J.F., Rushbrook S.M., Przemioslo R., McDonald C., Millar A., Tai C., Mitchell S., Metcalf J., Shaukat S., Ninkovic M., Shmueli U., Davis A., Naqvi A., Lee T.J., Ryder S., Collier J., Klass H., Cramp M.E., Sharer N., Aspinall R., Ghosh D., Douds A.C., Booth J., Williams E., Hussaini H., Christie J., Mann S., Thorburn D., Marshall A., Patanwala I., Ala A., Maltby J., Matthew R., Corbett C., Vyas S., Singhal S., Gleeson D., Misra S., Butterworth J., George K., Harding T., Douglass A., Mitchison H., Panter S., Shearman J., Bray G., Roberts M., Butcher G., Forton D., Mahmood Z., Cowan M., Ch'ng C.L., Rahman M., Whatley G.C.A., Wesley E., Mandal A., Jain S., Pereira S.P., Wright M., Trivedi P., Gordon F.H., Unitt E., Palejwala A., Austin A., Vemala V., Grant A., Higham A.D., Brind A., Mathew R., Cox M., Ramakrishnan S., King A., Whalley S., Fraser J., Thomson S.J., Bell A., Wong V.S., Kia R., Gee I., Keld R., Ransford R., Gotto J., Millson C., Medical Research Council (MRC), LiveR North, Cordell, H, Fryett, J, Ueno, K, Darlay, R, Aiba, Y, Hitomi, Y, Kawashima, M, Nishida, N, Khor, S, Gervais, O, Kawai, Y, Nagasaki, M, Tokunaga, K, Tang, R, Shi, Y, Li, Z, Juran, B, Atkinson, E, Gerussi, A, Carbone, M, Asselta, R, Cheung, A, de Andrade, M, Baras, A, Horowitz, J, Ferreira, M, Sun, D, Jones, D, Flack, S, Spicer, A, Mulcahy, V, Byan, J, Han, Y, Sandford, R, Lazaridis, K, Amos, C, Hirschfield, G, Seldin, M, Invernizzi, P, Siminovitch, K, Ma, X, Nakamura, M, Mells, G, Mason, A, Vincent, C, Xie, G, Zhang, J, Affronti, A, Almasio, P, Alvaro, D, Andreone, P, Andriulli, A, Azzaroli, F, Battezzati, P, Benedetti, A, Bragazzi, M, Brunetto, M, Bruno, S, Calvaruso, V, Cardinale, V, Casella, G, Cazzagon, N, Ciaccio, A, Coco, B, Colli, A, Colloredo, G, Colombo, M, Colombo, S, Cristoferi, L, Cursaro, C, Croce, L, Crosignani, A, D'Amato, D, Donato, F, Elia, G, Fabris, L, Fagiuoli, S, Ferrari, C, Floreani, A, Galli, A, Giannini, E, Grattagliano, I, Lampertico, P, Lleo, A, Malinverno, F, Mancuso, C, Marra, F, Marzioni, M, Massironi, S, Mattalia, A, Miele, L, Milani, C, Morini, L, Morisco, F, Muratori, L, Muratori, P, Niro, G, O'Donnell, S, Picciotto, A, Portincasa, P, Rigamonti, C, Ronca, V, Rosina, F, Spinzi, G, Strazzabosco, M, Tarocchi, M, Tiribelli, C, Toniutto, P, Valenti, L, Vinci, M, Zuin, M, Nakamura, H, Abiru, S, Nagaoka, S, Komori, A, Yatsuhashi, H, Ishibashi, H, Ito, M, Migita, K, Ohira, H, Katsushima, S, Naganuma, A, Sugi, K, Komatsu, T, Mannami, T, Matsushita, K, Yoshizawa, K, Makita, F, Nikami, T, Nishimura, H, Kouno, H, Ota, H, Komura, T, Nakamura, Y, Shimada, M, Hirashima, N, Komeda, T, Ario, K, Nakamuta, M, Yamashita, T, Furuta, K, Kikuchi, M, Naeshiro, N, Takahashi, H, Mano, Y, Tsunematsu, S, Yabuuchi, I, Shimada, Y, Yamauchi, K, Sugimoto, R, Sakai, H, Mita, E, Koda, M, Tsuruta, S, Kamitsukasa, H, Sato, T, Masaki, N, Kobata, T, Fukushima, N, Ohara, Y, Muro, T, Takesaki, E, Takaki, H, Yamamoto, T, Kato, M, Nagaoki, Y, Hayashi, S, Ishida, J, Watanabe, Y, Kobayashi, M, Koga, M, Saoshiro, T, Yagura, M, Hirata, K, Tanaka, A, Takikawa, H, Zeniya, M, Abe, M, Onji, M, Kaneko, S, Honda, M, Arai, K, Arinaga-Hino, T, Hashimoto, E, Taniai, M, Umemura, T, Joshita, S, Nakao, K, Ichikawa, T, Shibata, H, Yamagiwa, S, Seike, M, Honda, K, Sakisaka, S, Takeyama, Y, Harada, M, Senju, M, Yokosuka, O, Kanda, T, Ueno, Y, Kikuchi, K, Ebinuma, H, Himoto, T, Yasunami, M, Murata, K, Mizokami, M, Kawata, K, Shimoda, S, Miyake, Y, Takaki, A, Yamamoto, K, Hirano, K, Ichida, T, Ido, A, Tsubouchi, H, Chayama, K, Harada, K, Nakanuma, Y, Maehara, Y, Taketomi, A, Shirabe, K, Soejima, Y, Mori, A, Yagi, S, Uemoto, S, H, E, Tanaka, T, Yamashiki, N, Tamura, S, Sugawara, Y, Kokudo, N, Chalasani, N, Luketic, V, Odin, J, Chopra, K, Abecasis, G, Cantor, M, Coppola, G, Economides, A, Lotta, L, Overton, J, Reid, J, Shuldiner, A, Beechert, C, Forsythe, C, Fuller, E, Gu, Z, Lattari, M, Lopez, A, Schleicher, T, Padilla, M, Toledo, K, Widom, L, Wolf, S, Pradhan, M, Manoochehri, K, Ulloa, R, Bai, X, Balasubramanian, S, Barnard, L, Blumenfeld, A, Eom, G, Habegger, L, Hawes, A, Khalid, S, Maxwell, E, Salerno, W, Staples, J, Jones, M, Mitnaul, L, Sturgess, R, Healey, C, Yeoman, A, Gunasekera, A, Kooner, P, Kapur, K, Sathyanarayana, V, Kallis, Y, Subhani, J, Harvey, R, Mccorry, R, Rooney, P, Ramanaden, D, Evans, R, Mathialahan, T, Gasem, J, Shorrock, C, Bhalme, M, Southern, P, Tibble, J, Gorard, D, Jones, S, Srivastava, B, Foxton, M, Collins, C, Elphick, D, Karmo, M, Porras-Perez, F, Mendall, M, Yapp, T, Patel, M, Ede, R, Sayer, J, Jupp, J, Fisher, N, Carter, M, Koss, K, Shah, J, Piotrowicz, A, Scott, G, Grimley, C, Gooding, I, Williams, S, Tidbury, J, Lim, G, Cheent, K, Levi, S, Mansour, D, Beckley, M, Hollywood, C, Wong, T, Marley, R, Ramage, J, Gordon, H, Ridpath, J, Ngatchu, T, Bob Grover, V, Shidrawi, R, Abouda, G, Corless, L, Narain, M, Rees, I, Brown, A, Taylor-Robinson, S, Wilkins, J, Grellier, L, Banim, P, Das, D, Heneghan, M, Curtis, H, Matthews, H, Mohammed, F, Aldersley, M, Srirajaskanthan, R, Walker, G, Mcnair, A, Sharif, A, Sen, S, Bird, G, Prince, M, Prasad, G, Kitchen, P, Barnardo, A, Oza, C, Sivaramakrishnan, N, Gupta, P, Shah, A, Evans, C, Saha, S, Pollock, K, Bramley, P, Mukhopadhya, A, Barclay, S, Mcdonald, N, Bathgate, A, Palmer, K, Dillon, J, Rushbrook, S, Przemioslo, R, Mcdonald, C, Millar, A, Tai, C, Mitchell, S, Metcalf, J, Shaukat, S, Ninkovic, M, Shmueli, U, Davis, A, Naqvi, A, Lee, T, Ryder, S, Collier, J, Klass, H, Cramp, M, Sharer, N, Aspinall, R, Ghosh, D, Douds, A, Booth, J, Williams, E, Hussaini, H, Christie, J, Mann, S, Thorburn, D, Marshall, A, Patanwala, I, Ala, A, Maltby, J, Matthew, R, Corbett, C, Vyas, S, Singhal, S, Gleeson, D, Misra, S, Butterworth, J, George, K, Harding, T, Douglass, A, Mitchison, H, Panter, S, Shearman, J, Bray, G, Roberts, M, Butcher, G, Forton, D, Mahmood, Z, Cowan, M, Ch'Ng, C, Rahman, M, Whatley, G, Wesley, E, Mandal, A, Jain, S, Pereira, S, Wright, M, Trivedi, P, Gordon, F, Unitt, E, Palejwala, A, Austin, A, Vemala, V, Grant, A, Higham, A, Brind, A, Mathew, R, Cox, M, Ramakrishnan, S, King, A, Whalley, S, Fraser, J, Thomson, S, Bell, A, Wong, V, Kia, R, Gee, I, Keld, R, Ransford, R, Gotto, J, Millson, C, Cordell HJ, Fryett JJ, Ueno K, Darlay R, Aiba Y, Hitomi Y, Kawashima M, Nishida N, Khor SS, Gervais O, Kawai Y, Nagasaki M, Tokunaga K, Tang R, Shi Y, Li Z, Juran BD, Atkinson EJ, Gerussi A, Carbone M, Asselta R, Cheung A, de Andrade M, Baras A, Horowitz J, Ferreira MAR, Sun D, Jones DE, Flack S, Spicer A, Mulcahy VL, Byan J, Han Y, Sandford RN, Lazaridis KN, Amos CI, Hirschfield GM, Seldin MF, Invernizzi P, Siminovitch KA, Ma X, Nakamura M, Mells GF, PBC Consortia, Canadian PBC Consortium, Chinese PBC Consortium, Italian PBC Study Group, Japan-PBC-GWAS Consortium, US PBC Consortium, UK-PBC Consortium, and Calvaruso V. .

Subjects
Liver Cirrhosis, ALSPAC, ERN RARE-LIVER, Genomic co-localization, Network-based in silico drug efficacy screening, UK-PBC, 0301 basic medicine, Candidate gene, Genome-Wide Association Study, Humans, Liver Cirrhosis, Biliary, Italian PBC Study Group, LD SCORE REGRESSION, Japan-PBC-GWAS Consortium, Genome-wide association study, Locus (genetics), Disease, SUSCEPTIBILITY, PBC, Chronic liver disease, Bioinformatics, GENETIC ASSOCIATION, 1117 Public Health and Health Services, 03 medical and health sciences, 0302 clinical medicine, UK-PBC Consortium, Genotype, Medicine, Genetic association, Science & Technology, Gastroenterology & Hepatology, Hepatology, business.industry, Biliary, Chinese PBC Consortium, 1103 Clinical Sciences, medicine.disease, PBC Consortia, 030104 developmental biology, Meta-analysis, ERN RARE LIVER, 030211 gastroenterology & hepatology, US PBC Consortium, Canadian PBC Consortium, business, Life Sciences & Biomedicine, Human
Abstract

[BACKGROUND & AIMS] Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intra-hepatic bile ducts eventually leads to cirrhosis. Many patients have inadequate response to licensed medications, motivating the search for novel therapies. Previous genome-wide association studies (GWAS) and meta-analyses (GWMA) of PBC have identified numerous risk loci for this condition, providing insight into its aetiology. We undertook the largest GWMA of PBC to date, aiming to identify additional risk loci and prioritise candidate genes for in silico drug efficacy screening. [METHODS] We combined new and existing genotype data for 10, 516 cases and 20, 772 controls from five European and two East Asian cohorts. [RESULTS] We identified 56 genome-wide significant loci (20 novel) including 46 in European, 13 in Asian, and 41 in combined cohorts; and a 57th genome-wide significant locus (also novel) in conditional analysis of the European cohorts. Candidate genes at newly identified loci include FCRL3, INAVA, PRDM1, IRF7, CCR6, CD226, and IL12RB1, each having key roles in immunity. Pathway analysis reiterated the likely importance of pattern recognition receptor and TNF signalling, Jak-STAT signalling, and differentiation of TH1 and TH17 cells in the pathogenesis of this disease. Drug efficacy screening identified several medications predicted to be therapeutic in PBC, some well-established in the treatment of other autoimmune disorders. [CONCLUSIONS] This study has identified additional risk loci for PBC, provided a hierarchy of agents that could be trialled in this condition, and emphasised the value of genetic and genomic approaches to drug discovery in complex disorders. [Lay summary] Primary biliary cholangitis (PBC) is a chronic liver disease that eventually leads to cirrhosis. In this study, we analysed genetic information from 10, 516 people with PBC and 20, 772 healthy individuals recruited in Canada, China, Italy, Japan, UK, or USA. We identified several genetic regions associated with PBC. Each of these regions contains several genes. For each region, we used diverse sources of evidence to help us choose the gene most likely to be involved in causing PBC. We used these ‘candidate genes’ to help us identify medications that are currently used for treatment of other conditions, which might also be useful for treatment of PBC., 原発性胆汁性胆管炎のゲノムワイド関連解析 --国際メタ解析による新規疾患感受性遺伝子と治療薬候補の同定--. 京都大学プレスリリース. 2021-06-28.

Published
2021

229. Extrahepatic autoimmune diseases in primary biliary cholangitis: Prevalence and significance for clinical presentation and disease outcome

Author

Fredrik Rorsman, Ellina Lytvyak, Mårten Werner, Aldo J. Montano-Loza, Fatema Alalkim, Benedetta Terziroli Beretta-Piccoli, Paolo Muratori, Thomas Berg, Thomas D. Schiano, Emma Nilsson, Tugrul Purnak, Ida Henriksson, David Semela, Staffan Wahlin, Eric M. Yoshida, Luigi Muratori, Alan Bonder, Murat Kiyici, Kristina Önnerhag, Janett Fischer, Ersan Ozaslan, Maneerat Chayanupatkul, Hanns-Ulrich Marschall, Murat Torgutalp, Claudia Coppo, Alexandra Heurgué-Berlot, Hirsh D. Trivedi, Nurhan Demir, Cumali Efe, Fatih Eren, Efe C., Torgutalp M., Henriksson I., Alalkim F., Lytvyak E., Trivedi H., Eren F., Fischer J., Chayanupatkul M., Coppo C., Purnak T., Muratori L., Werner M., Muratori P., Rorsman F., Onnerhag K., Nilsson E., Heurgue-Berlot A., Demir N., Semela D., Kiyici M., Schiano T.D., Montano-Loza A.J., Berg T., Ozaslan E., Yoshida E.M., Bonder A., Marschall H.-U., Beretta-Piccoli B.T., Wahlin S., Bursa Uludağ Üniversitesi/Tıp Fakültesi/İç Hastalıkları Anabilim Dalı., CPU-6796-2022, and Eren, Fatih

Subjects
Male, Anti-nuclear antibody, PBC, Gastroenterology, Inflammatory bowel disease, 0302 clinical medicine, Lichen sclerosus et atrophicus, Antiphospholipid syndrome, Ascites, Undifferentiated connective tissue disease, Temporal arteritis, Myasthenia gravis, Hepatic encephalopathy, Hashimoto disease, Addison disease, Crohn disease, Pemphigus vulgaris, IgA nephropathy, Prognosis, Liver cell carcinoma, Management, Risk-factors, Retrospective study, Blood, Cirrhosis, Smooth muscle antibody, Biochemical response, Ursodeoxycholic acid, Primary biliary cirrhosis, 030220 oncology & carcinogenesis, Rheumatoid arthritis, Graves disease, Systemic sclerosis, 030211 gastroenterology & hepatology, Cohort analysis, Lichen planus, Anti-phospholipid syndrome, Human, Sex factor, medicine.medical_specialty, Cholangitis, Biliary Liver Cirrhosis, Obeticholic Acid, Sarcoidosis, Immunology, Major clinical study, Aspartate aminotransferase, Article, Dermatomyositis, Multiple sclerosis, 03 medical and health sciences, Humans, Clinical significance, Aspartate Aminotransferases, Autoimmune hemolytic anemia, Autoantibodies, Polymyositi, Ankylosing spondylitis, Bullous pemphigoid, Wegener granulomatosis, Medical record, Biliary cirrhosis, Follow up, medicine.disease, Event free survival, Ankylosing spondyliti, Ulcerative colitis, Pernicious anemia, Idiopathic thrombocytopenic purpura, Gastroenterology & hepatology, Complication, Biomarkers, Sarcoidosi, Autoantibody, Immunoglobulin A nephropathy, Autoimmune disease, Prevalence, Celiac disease, Middle aged, Variceal bleeding, Liver Cirrhosis, Biliary, Chronic urticaria, Mitochondria, Gastritis, Antibodies, Antinuclear, Female, medicine.symptom, Adult, Vitiligo, Autoimmune Diseases, Antinuclear antibody, Systemic lupus erythematosus, Sex Factors, Decompensated liver cirrhosis, Mitochondrion antibody, Internal medicine, Psoriasis, medicine, Multiple sclerosi, Collagenous colitis, Mitochondrion, Membranous glomerulonephritis, Hepatology, business.industry, Bleeding, Bilirubin, Polyarteritis nodosa, Alkaline Phosphatase, Polymyositis, Biological marker, business, Controlled study, Sjoegren syndrome
Abstract

Background and Aim: The prevalence and clinical significance of extrahepatic autoimmune diseases (EHAIDs) have not been evaluated in a large cohort of primary biliary cholangitis (PBC). Methods: The medical records of 1554 patients with PBC from 20 international centers were retrospectively reviewed. Development of decompensated cirrhosis (ascites, variceal bleeding, and/or hepatic encephalopathy) and hepatocellular carcinoma were considered clinical endpoints. Results: A total of 35 different EHAIDs were diagnosed in 440 (28.3%) patients with PBC. Patients with EHAIDs were more often female (92.5% vs 86.1%, P&nbsp

Published
2021

230. Predictors for incomplete response to ursodeoxycholic acid in primary biliary cholangitis. Data from a national registry of liver disease

Author

Helena Cortez‐Pinto, Rodrigo Liberal, Susana Lopes, Mariana V. Machado, Joana Carvalho, Teresa Dias, Arsénio Santos, Cláudia Agostinho, Pedro Figueiredo, Rafaela Loureiro, Alexandra Martins, Gonçalo Alexandrino, Isabel Cotrim, Carina Leal, José Presa, Mónica Mesquita, Joana Nunes, Catarina Gouveia, Ana Horta e Vale, Ana Luísa Alves, Mariana Coelho, Luís Maia, Isabel Pedroto, António Banhudo, João Sebastião Pinto, Marta Vargas Gomes, Joana Oliveira, Valeska Andreozzi, Filipe Calinas, null on behalf of Liver.pt, and Repositório da Universidade de Lisboa

Subjects
Male, Cirrhosis, PBC, Gastroenterology, Severity of Illness Index, UDCA, Liver disease, 0302 clinical medicine, Risk Factors, Registries, Treatment Failure, Liver Cirrhosis, Biliary, Score, Response, gamma-Glutamyltransferase, Middle Aged, Ursodeoxycholic acid, Oncology, 030220 oncology & carcinogenesis, Disease Progression, 030211 gastroenterology & hepatology, Female, Original Article, medicine.symptom, medicine.drug, Adult, Barcelona, medicine.medical_specialty, Paris, Asymptomatic, 03 medical and health sciences, Predictive Value of Tests, Internal medicine, medicine, Humans, GLOBE, Aged, Portugal, business.industry, Predictors, Disease progression, Primary biliary cholangitis, Odds ratio, medicine.disease, Alkaline Phosphatase, Confidence interval, Logistic Models, Multivariate Analysis, National registry, Hepatobiliary, business
Abstract

Background The current standard of treatment in primary biliary cholangitis (PBC) is ursodeoxycholic acid (UDCA), although a considerable proportion of patients show incomplete response resulting in disease progression. Objective This study aimed to assess the prevalence of incomplete response to UDCA and determine associated patients' characteristics. Methods Patients with PBC as main diagnosis were included from a national multicentric patient registry—Liver.pt. Main endpoints included incomplete response to UDCA treatment according to Barcelona, Paris I and Paris II criteria, Globe and UK PBC scores and the association between baseline characteristics and incomplete response according to Paris II criteria. Results A total of 434 PBC patients were identified, with a mean age of 55 years and 89.2% females. Nearly half of patients were asymptomatic at diagnosis and 93.2% had positive anti‐mitochondrial antibodies. Almost all patients (95.6%) had been prescribed at least one drug for PBC treatment. At the last follow‐up visit, 93.3% were under treatment of which 99.8% received UDCA. Incomplete response to UDCA was observed in 30.7%, 35.3%, 53.7% and 36.4% of patients according to Barcelona, Paris I, Paris II criteria and Globe score, respectively. After adjusting for age and sex, and accordingly to Paris II criteria, the risk for incomplete biochemical response was 25% higher for patients with cirrhosis at diagnosis (odds ratio [OR] = 1.25; 95% confidence interval [95%CI]: 1.02–1.54; p = 0.033) and 35% (95%CI:1.06–1.72; p = 0.016) and 5% (OR = 1.05; 95%CI:1.01–1.10; p = 0.013) for those with elevated gamma‐glutamyl transferase (GGT) and alkaline phosphatase (ALP). Conclusion A considerable proportion of patients showed incomplete biochemical response to UDCA treatment according to Paris II criteria. Cirrhosis, elevated GGT and ALP at diagnosis were identified as associated risk factors for incomplete response. Early identification of patients at risk of incomplete response could improve treatment care and guide clinical decision to a more careful patient monitorization., Key summary Summarise the established knowledge on this subject Primary biliary cholangitis is a liver disease that can progress to end‐stage liver disease, with premature death or need for liver transplantation.Treatment with ursodeoxycholic acid (UDCA) significantly increases liver transplant‐free survival. However, incomplete response to UDCA reduces this beneficial effect. What are the significant and/or new findings of this study? By evaluating prevalence and risk factors for UDCA incomplete response through a large multicentric national registry it was found that 53.7% of patients were incomplete responders, according to Paris II criteria, with cirrhosis, elevated gamma‐glutamyl transferase and alkaline phosphatase at diagnosis as the main risk factors.These findings suggest that patients diagnosed at an advanced stage should be closely monitored and might benefit from novel therapies to improve outcomes if incomplete response is present.

Published
2021

231. Pinpointing miRNA and genes enrichment over trait-relevant tissue network in Genome-Wide Association Studies

Author

Lulu Shang, Xiang Zhou, Yongsheng Bai, Yuqi Fan, Julian Dong, Binze Li, and Jiaqi Yu

Subjects
lcsh:Internal medicine, lcsh:QH426-470, Quantitative Trait Loci, Gene regulatory network, SNP, Genome-wide association study, MiRNA binding, Single-nucleotide polymorphism, Computational biology, 3′UTR, Biology, PBC, Polymorphism, Single Nucleotide, Autoimmune Diseases, Metabolic Diseases, Genetics, Humans, GWAS, Gene Regulatory Networks, Genetic Predisposition to Disease, RNA, Messenger, lcsh:RC31-1245, Gene, Genetics (clinical), miRNA, Regulation of gene expression, Three prime untranslated region, Research, Variants, Computational Biology, MicroRNAs, lcsh:Genetics, Gene Expression Regulation, Organ Specificity, Nervous System Diseases, DNA microarray, Software, Genome-Wide Association Study
Abstract

Background Understanding gene regulation is important but difficult. Elucidating tissue-specific gene regulation mechanism is even more challenging and requires gene co-expression network assembled from protein–protein interaction, transcription factor and gene binding, and post-transcriptional regulation (e.g., miRNA targeting) information. The miRNA binding affinity could therefore be changed by SNP(s) located at the 3′ untranslated regions (3′UTR) of the target messenger RNA (mRNA) which miRNA(s) interacts with. Genome-wide association study (GWAS) has reported significant numbers of loci hosting SNPs associated with many traits. The goal of this study is to pinpoint GWAS functional variants located in 3′UTRs and elucidate if the genes harboring these variants along with their targeting miRNAs are associated with genetic traits relevant to certain tissues. Methods By applying MIGWAS, CoCoNet, ANNOVAR, and DAVID bioinformatics software and utilizing the gene expression database (e.g. GTEx data) to study GWAS summary statistics for 43 traits from 28 GWAS studies, we have identified a list of miRNAs and targeted genes harboring 3′UTR variants, which could contribute to trait-relevant tissue over miRNA-target gene network. Results Our result demonstrated that strong association between traits and tissues exists, and in particular, the Primary Biliary Cirrhosis (PBC) trait has the most significant p-value for all 180 tissues among all 43 traits used for this study. We reported SNPs located in 3′UTR regions of genes (SFMBT2, ZC3HAV1, and UGT3A1) targeted by miRNAs for PBC trait and its tissue association network. After employing Gene Ontology (GO) analysis for PBC trait, we have also identified a very important miRNA targeted gene over miRNA-target gene network, PFKL, which encodes the liver subunit of an enzyme. Conclusions The non-coding variants identified from GWAS studies are casually assumed to be not critical to translated protein product. However, 3′ untranslated regions (3′UTRs) of genes harbor variants can often change the binding affinity of targeting miRNAs playing important roles in protein translation degree. Our study has shown that GWAS variants could play important roles on miRNA-target gene networks by contributing the association between traits and tissues. Our analysis expands our knowledge on trait-relevant tissue network and paves way for future human disease studies.

Published
2020

232. IDA - PBC control of shunt active filters for harmonics compensation.

Author

Serra, Federico M., De Angelo, Cristian H., and Forchetti, Daniel G.

Abstract

The design of a passivity-based non-linear controller for a shunt active filter to be used for the compensation of the harmonic components consumed by non linear loads is presented in this paper. The main objective of this control strategy is to inject the necessary compensation current into the system so that the grid current is sinusoidal and balanced, regardless of whether the grid voltage is unbalanced and/or distorted. The reference values for the compensation currents are obtained from applying the Instantaneous Active-Reactive Power Theory. The system is represented by its port-controlled Hamiltonian model and the controller designed on the basis of interconnection and damping assignment using a method based on Lyapunov techniques. The behavior of the proposed control strategy is validated through simulation using a realistic model. [ABSTRACT FROM PUBLISHER]

Published
2012
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233. Diagnostic and Clinical Value of Specific Autoantibodies against Kelch-like 12 Peptide and Nuclear Envelope Proteins in Patients with Primary Biliary Cholangitis

Author

Alicja Bauer, Andrzej Habior, and Damian Gawel

Subjects
PBC, autoantibodies, glycoprotein gp210, nucleoporin p62, KLHL12 peptide, Medicine (miscellaneous), skin and connective tissue diseases, digestive system, digestive system diseases, General Biochemistry, Genetics and Molecular Biology
Abstract

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by the presence of antimitochondrial and antinuclear antibodies in patients’ serum. Here, we analyzed the reactivity of autoantibodies against a novel autoantigen, kelch-like 12 (KLHL12) protein, in a cohort of 138 PBC and 90 non-PBC patients. Additionally, we compared the reactivity of KLHL12 with antinuclear envelope antibodies: anti-gp210, anti-p62, and anti-LBR. Commercially available kits and an ‘in-house’ ELISA were used in the studies. Antinuclear envelope antibodies were detected in 65% of PBC patients and the presence of these antibodies was observed more frequently in patients diagnosed with later stages (III/IV) of PBC, according to Ludwig’s classification (p < 0.05) and were found to correlate with a higher concentration of bilirubin. Overall, anti-KLHL12 antibodies were found more frequently in PBC patients than in non-PBC controls (p < 0.001). Anti-KLHL12 antibodies were detected in 36% of the tested PBC cohort, including PBC patients negative for antimitochondrial antibodies. Presence of anti-KLHL12 was also associated with a higher concentration of bilirubin and correlated with fibrosis (p < 0.05). Anti-KLHL12 antibodies were detected in 30% of PBC individuals positive for antinuclear envelope antibodies, while anti-KLHL12 and antinuclear envelope antibodies were found in 17% of all PBC cases. Concluding, our data confirm that antibodies against the KLHL12 protein are highly specific for PBC and when used in combination with other markers, may significantly increase the diagnosis of PBC.

Published
2022

234. Investigating Primary Biliary Cholangitis for a Human Betaretrovirus Superantigen signature

Author

Syed, Hussain

Subjects
Hepatology, Primary Biliary Cholangitis, PBC, Liver, HBRV, Superantigen, TCR-VB, Human Betaretrovirus
Abstract

Abstract: Primary Biliary Cholangitis (PBC) is an idiopathic autoimmune disease characterized by destruction of small hepatic bile ducts and presence of antimitochondrial antibodies (AMA). A Human Betaretrovirus (HBRV) sharing 91-99% sequence similarity with the Mouse Mammary Tumor virus has been identified in PBC patients. The autoimmune biliary disease mouse model for PBC produces spontaneous AMA and is infected by the MMTV suggesting a role for MMTV involvement in disease development. The MMTV also has well documented superantigen activity. Viral superantigen bind the MHC class II receptor on antigen presenting cells to induce clonal expansion of specific TCR-Vβ subsets followed by eventual depletion of cognate T-cells. This skewing of specific TCR-Vβ subsets is the hallmark of superantigen activity. To evaluate a similar role of HBRV infection and superantigen activity in PBC patients, we investigated a transcriptional database from the POISE phase III clinical trials to 1) classify CD4+/CD8+ ratios and Neutrophil to Lymphocyte ratios (NLR, an indicator of lymphopenia) 2) characterize the TCR-Vβ repertoire profile in PBC to find evidence of VB skewing and 3) conduct differential gene expression analysis between PBC patient subsets to identify immunological pathways associated with disease development and progression. Analyzing RNA-seq database, we detected an increased range and higher mean CD4+/CD8+ ratio in PBC. A depleted CD8+ T-cell expression was notably observed in the high CD4+/CD8+ ratios. The CD4+/CD8+ ratio was also identified to be positively correlated with increased lymphopenia and negatively correlated with platelet counts indicating hypersplenism and overall worse prognosis. TCR-Vβ repertoire alteration consistent with superantigen activity was observed. Skewing of multiple Vβ subsets as well as the tendency of these skewed Vβ to skew together in clusters suggests the presence of multiple HBRV superantigen with varying binding avidities. Finally, pathway expression analysis identified increased anti-viral activity along with interferon responses and TLR activation in PBC samples with high CD4+/CD8+ ratio and high NLR. This suggests ongoing HBRV activity and may predict worse prognosis. Meanwhile, low NLR and CD4+/CD8 ratio samples demonstrated increased T-cell activation, activated innate immunity, NK cell immunity and negative regulation of viral transcription indicating a resolving disease process. We also identified CD3E-204, a transcript for the CD3E lymphocyte marker, which had a strong negative correlation with TCR-Vβ skewing. Further studies into the mechanistic differences between the CD3E transcripts need to be made to evaluate the significance of this finding. In future studies, we hope to investigate serial samples from PBC patients to identify changes in TCR-Vβ skewing over time and changes in CD4+/CD8+ ratios over time in patients with known clinical outcomes. We will also investigate TCR-Vβ skewing in isolated CD4+ and CD8+ T-cells in order to better understand the source of CD8+ T-cell depletion. Finally, we propose to clone HBRV superantigen from PBC patient lymphnode using conserved viral superantigen sequences. This will help highlight superantigen proteins in PBC and shed light on their contribution to PBC pathogenesis.

Published
2022

236. Impact of Microbes on the Pathogenesis of Primary Biliary Cirrhosis (PBC) and Primary Sclerosing Cholangitis (PSC)

Author

Jochen Mattner

Subjects
PSC, PBC, intestinal microbiota, bile acids, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) represent the major clinical entities of chronic cholestatic liver diseases. Both disorders are characterized by portal inflammation and slowly progress to obliterative fibrosis and eventually liver cirrhosis. Although immune-pathogenic mechanisms have been implicated in the pathogenesis of PBC and PSC, neither disorder is considered to be a classical autoimmune disease, as PSC and PBC patients do not respond to immune-suppressants. Furthermore, the decreased bile flow resulting from the immune-mediated tissue assault and the subsequent accumulation of toxic bile products in PBC and PSC not only perpetuates biliary epithelial damage, but also alters the composition of the intestinal and biliary microbiota and its mutual interactions with the host. Consistent with the close association of PSC and inflammatory bowel disease (IBD), the polyclonal hyper IgM response in PBC and (auto-)antibodies which cross-react to microbial antigens in both diseases, an expansion of individual microbes leads to shifts in the composition of the intestinal or biliary microbiota and a subsequent altered integrity of epithelial layers, promoting microbial translocation. These changes have been implicated in the pathogenesis of both devastating disorders. Thus, we will discuss here these recent findings in the context of novel and alternative therapeutic options.

Published
2016
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238. A HYBRID HIERARCHICAL IDENTITY BASED CRYPTOGRAPHY SCHEME IN A WIRELESS SENSOR NETWORK.

Author

CHIFOR, BOGDAN-COSMIN

Subjects
CRYPTOGRAPHY, WIRELESS sensor networks, INTERNET of things, ENVIRONMENTAL monitoring, STRUCTURAL health monitoring, CERTIFICATE authority, DIGITAL certificates
Abstract

Wireless sensor networks is a topic increasingly important in the context of the growing concept of Internet of things (IOT) and lately the Internet of Everything (IOE). Wireless sensor networks can be found in many aspects of our lives, among which: the environmental monitoring (air, water, soil, etc.), the asset tracking, the industrial machine monitoring, the process monitoring, the structural monitoring for buildings and bridges. Because sensors can be employed in critical areas of our lives, the data transmitted in the WSN must be protected against eavesdroppers and must be authenticated. Achieving this goal is not an easy task due to the computational and energy constraints of the WSN. Because of this, a classic PKI architecture can not be utilized in such a scenario. In this paper is presented an alternative security solution which uses identity based cryptography. This solution in contrast to a classic PKI architecture requires no public key distribution and uses a lightweight format of digital certificates. The wireless sensor network is divided into several areas, each area being subordinate to a certificate authority called the PKG (Private Key Generator), which generates the private keys for the nodes. By using the node's identity and the private keys generated by the PKG, the data is aggregated, encrypted and routed until it reaches the base station (the network gateway). [ABSTRACT FROM AUTHOR]

Published
2014

239. Geoepidemiology and space-time analysis of Primary biliary cirrhosis in Crete, Greece.

Author

Koulentaki, M, Mantaka, A, Sifaki-Pistolla, D, Thalassinos, E, Tzanakis, N, and Kouroumalis, E

Subjects
*CIRRHOSIS of the liver, *DISEASE prevalence, *DISEASE incidence, *GENETIC polymorphisms, *IMMUNOFLUORESCENCE, *T-test (Statistics), *CHRONIC active hepatitis
Abstract

Background & Aims The prevalence of Primary biliary cirrhosis varies in different geographical areas. This might reflect genetic or environmental risk factors. We aimed to define Primary biliary cirrhosis prevalence and incidence, describe patient's spatial distribution, generate prediction maps and detect any possible routing pattern of time-spatial appearance of the disease in Crete, Greece. Methods From 1990-2010, 245 Primary biliary cirrhosis patients diagnosed and followed up at the Gastroenterology Department of the University Hospital and the District Hospitals of the island, were contacted and 222 were included in the time-spatial analysis. To map their spatial distribution per 5-year periods, geospatial models were applied in Gis-ArcMap 9.3 software. Kriging Interpolation methods were used to generate prediction maps for the disease in Crete. Areas of high and low probability of disease occurrence were estimated through multicriteria modelling. The disease route was defined by Gis-ArcMap's toolbox. Results Prevalence was found to be 365 cases per million, with a mean incidence of 20.88 (range 3.79-35.99). Prediction map estimates from 1.22 to 11 patients per 50 km2 all over Crete. Areas of high risk of disease occurrence are located in the Eastern part, while low risk in the Western part of the island. Discussion Prevalence and incidence of Primary biliary cirrhosis in Crete are among the higher published in Europe. Given the homogeneous and stable study population and the geopolitics of the island, the heterogeneity in the time-spatial distribution and the route of disease appearance strongly suggest a role for environmental causative agents. [ABSTRACT FROM AUTHOR]

Published
2014
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240. Rising incidence and prevalence of primary biliary cirrhosis: a large population-based study.

Author

Boonstra, Kirsten, Kunst, Anton E., Stadhouders, Paul H., Tuynman, Hans A., Poen, Alexander C., Nieuwkerk, Karin. M. J., Witteman, Ellen M., Hamann, Dörte, Witteman, Ben J., Beuers, Ulrich, and Ponsioen, Cyriel Y.

Subjects
*INFECTIOUS disease transmission, *EPIDEMIOLOGY, *CIRRHOSIS of the liver, *LIVER diseases, *MEDICAL informatics, *HEALTH facilities
Abstract

Background & Aims Large population-based studies are much needed to accurately establish the epidemiology of primary biliary cirrhosis ( PBC). We aimed to collect all PBC patients in a geographically defined area to evaluate the epidemiology of PBC and examine the possible association of PBC with smoking, age at menarche, age at first pregnancy and number of pregnancies. Methods All PBC patients between 2000 and 2008 were identified in a geographically defined area of the Netherlands, comprising 50% of the Dutch population. Four independent hospital databases were searched in 44 hospitals. Medical records were reviewed on site verifying diagnosis and for collection of clinical data. Age- and gender matched controls were recruited from the outpatient clinics of four participating hospitals. Patients and controls were asked to fill out a questionnaire regarding family history, previous and current smoking behaviour and fertility status. Results Nine hundred and ninety-two PBC patients fulfilled all inclusion criteria, resulting in a mean incidence of 1.1 per 100 000; 0.3 in men and 1.9 in women. On January 1st 2008 the point prevalence was 13.2 per 100 000 inhabitants. Incidence and prevalence rates were increasing over time ( P < 0.001). No geographical differences in disease distribution were observed. Smoking behaviour, age at menarche, age at first pregnancy, gravidity and number of children were not significantly different between cases and controls. Conclusion Incidence and prevalence rates of PBC are increasing over time. PBC was not found to be associated with smoking, age at menarche, age at first pregnancy or number of pregnancies. [ABSTRACT FROM AUTHOR]

Published
2014
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241. Genetic polymorphisms of OCT- 1 confer susceptibility to severe progression of primary biliary cirrhosis in Japanese patients.

Author

Ohishi, Yuki, Nakamuta, Makoto, Ishikawa, Naoko, Saitoh, Ohki, Nakamura, Hitomi, Aiba, Yoshihiro, Komori, Atsumasa, Migita, Kiyoshi, Yatsuhashi, Hiroshi, Fukushima, Nobuyoshi, Kohjima, Motoyuki, Yoshimoto, Tsuyoshi, Fukuizumi, Kunitaka, Ishibashi, Makoto, Nishino, Takashi, Shirabe, Ken, Taketomi, Akinobu, Maehara, Yoshihiko, Ishibashi, Hiromi, and Nakamura, Minoru

Subjects
*GENETIC polymorphisms, *ORGANIC cation transporters, *DISEASE susceptibility, *CIRRHOSIS of the liver, *DISEASE progression, *JAPANESE people, *PATIENTS, *DISEASES
Abstract

Background: To identify the genetic factors involved in the pathogenesis of primary biliary cirrhosis (PBC), we focused on the organic cation transporter 1 (OCT1/SLC22A1), which is closely associated with phosphatidylcholine synthesis in hepatocytes. Methods: We selected four (rs683369, rs2282143, rs622342 and rs1443844) OCT- 1 single nucleotide polymorphisms (SNPs), and genotyped these SNPs using the TaqMan probe method in 275 Japanese PBC patients and 194 gender-matched, healthy volunteers as controls. Results: The Chi-square test revealed that the rs683369 variant allele (G) was associated with insusceptibility to PBC development [ P = 0.009, odds ratio (OR) 0.60, 95 % confidence interval (CI) 0.40-0.88] in an allele model, and that the rs683369 variant allele (G) was associated with jaundice-type progression in a minor allele dominant genotype model ( P = 0.032, OR 3.10, 95 % CI 1.05-9.14). The OCT-1 rs2282143 variant (T) and rs622342 variant (C) were also associated with jaundice-type progression in a minor allele recessive genotype model ( P = 0.0002, OR 10.58, 95 % CI 2.36-47.54, and P = 0.006, OR 7.84, 95 % CI 1.39-44.36, respectively). Furthermore, the association of OCT- 1 rs683369 and rs622342 with susceptibility to jaundice-type progression was confirmed by a replication study with a distinct set of PBC patients who underwent liver transplantation. Conclusions: The present study is the first report on the association of OCT- 1 genetic polymorphisms with the overall development and jaundice-type progression of PBC. [ABSTRACT FROM AUTHOR]

Published
2014
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242. Functional Role of the Secretin/Secretin Receptor Signaling During Cholestatic Liver Injury

Author

Paolo Onori, Nan Wu, Eugenio Gaudio, Vik Meadows, Tianhao Zhou, Heather Francis, Lindsey Kennedy, Gianfranco Alpini, Ludovica Ceci, Chaodong Wu, Lixian Chen, Antonio Franchitto, Fanyin Meng, Konstantina Kyritsi, Debjyoti Kundu, Keisaku Sato, Ilaria Lenci, Leonardo Baiocchi, Domenico Alvaro, Burcin Ekser, and Shannon Glaser

Subjects
dnTGF-βRII, PBC, secretin0, Epithelium, Receptors, G-Protein-Coupled, Secretin, Settore MED/12, fluids and secretions, PSC, Bile, PKA, CFTR, Receptor, Liver injury, NGF, Cholestasis, microRNA, primary biliary cholangitis, multidrug resistance 2 (Abcb4), primary sclerosing cholangitis, Liver, Secretin receptor, Signal transduction, cholangiocarcinoma, Liver pathology, hormones, hormone substitutes, and hormone antagonists, Signal Transduction, dominant-negative transforming growth factor β receptor II, Functional role, CCA, cystic fibrosis transmembrane conductance regulator, Mdr2, miRNA, nerve growth factor, protein kinase A, Sct, Cellular senescence, digestive system, Article, Receptors, Gastrointestinal Hormone, Bile Acids and Salts, medicine, Animals, Humans, Hepatology, business.industry, medicine.disease, digestive system diseases, Disease Models, Animal, Chronic Disease, Cancer research, Bile Ducts, business
Abstract

The gastrointestinal peptide, secretin (Sct) is an important homeostatic regulator of pancreatic and liver secretory function. With regard to the liver, discoveries have been made, in the last decades, indicating a key role for the secretin/secretin receptor axis during normal or cholestatic conditions. Since large cholangiocytes are the only cells to express secretin receptor in the liver, research on secretin also expanded our knowledge on biliary epithelia. In this review we examined in detail the role of the secretin/secretin receptor axis, not only on biliary secretion, but also on cholangiocyte proliferation and senescence, as well as in prompting fibrotic processes involving biliary epithelia. Relevant data on human chronic cholestatic liver diseases, such as primary biliary cholangitis or primary sclerosing cholangitis, and obtained in animal models mimicking the diseases or in correlative studies on human are also reported. The aim of this review is to provide an update on the progress regarding the interactions between secretin and the biliary epithelia in normal and pathological conditions, underlining the aspects that suggests modulation of secretin pathway as a possible therapeutic approach for chronic cholestatic human liver disease.

Published
2020

243. The long-term outcomes of deceased-donor liver transplantation for primary biliary cirrhosis: a two-center study in China

Author

Jinglan Jin, Junqi Niu, Yanjun Cai, Xiaodong Shi, Wanyu Li, Ning Liu, Xiaodong Sun, Guoyue Lv, Chao Sun, and Lin Chen

Subjects
medicine.medical_specialty, Bioinformatics, medicine.medical_treatment, Immunology, Surgery and Surgical Specialties, lcsh:Medicine, Gastroenterology and Hepatology, 030230 surgery, Liver transplantation, PBC, Gastroenterology, Liver function, General Biochemistry, Genetics and Molecular Biology, Organ transplantation, 03 medical and health sciences, 0302 clinical medicine, Primary biliary cirrhosis, Internal medicine, medicine, Survival rate, APRI, medicine.diagnostic_test, Proportional hazards model, business.industry, General Neuroscience, Hazard ratio, lcsh:R, General Medicine, medicine.disease, rPBC, Liver transpantation, 030211 gastroenterology & hepatology, General Agricultural and Biological Sciences, business, Liver function tests
Abstract

Background & Aims Factors that influence the outcomes after deceased-donor liver transplantation (DDLT) for primary biliary cirrhosis (PBC) are not well known. We aimed to clarify these effects on the outcomes after DDLT. Methods We retrospectively analyzed patients with PBC who underwent DDLT from March 2006 to July 2018 at the organ transplantation center of the First Hospital of Jilin University and the First Central Hospital of Tianjin. Changes in liver function were assessed posttransplantation. Recurrence, survival rate, and complications were recorded at follow-up. The effect of liver transplantation on survival and recurrence was evaluated using univariate and/or multivariate Cox regression analyses. Results In total, 69 patients with PBC undergoing DDLT were included in this study. At 4 weeks posttransplant, all liver function tests were normal. During a median follow-up time of 32 months, 5-year overall survival and recurrence rates were estimated as 95.1% and 21.8%, respectively. A recipient aspartate aminotransferase-to-platelet ratio index (APRI) greater than 2 was negatively associated with survival (P = 0.0018). Multivariate regression analysis demonstrated that age younger than 48 years was an independent risk factor for recurrent PBC in recipients undergoing liver transplantation (hazard ratio 0.028, 95% confidence interval 0.01–0.71, P = 0.03). Posttransplant infections (62%) and biliary tract complications (26%) were the most common complications. Conclusion Liver transplantation is an effective treatment for patients with PBC. Liver function normalizes by 4 weeks posttransplant. Although posttransplant survival rate is high, recurrence is possible. To some extent, survival rate and recurrence rate can be predicted by APRI and age, respectively.

Published
2020

244. 3-[(E)-2-(4-fenil-1,3-tiyazol-2-yl)hidrazin-1-yiliden]-indolin-2-on Bileşiğinin tautomer yapısı üzerinde gaz ve katı fazında teorik hesaplamalar

Author

Tuncay Karakurt

Subjects
Espresso, 021105 building & construction, 0211 other engineering and technologies, 02 engineering and technology, General Medicine, 010501 environmental sciences, PBC, 01 natural sciences, Gaussian 09, DFT, Quantum, 0105 earth and related environmental sciences
Abstract

Tiyazol halkası içeren 3-[(E)-2-(4-fenil-1,3-tiyazol-2-yl)hidrazin-1-yiliden]-indolin-2-on bileşiğinin iki tautomer formu üzerinde gaz ve katı fazında hesaplamalar yapılmıştır. İki tautomer yapı için gaz fazında Gaussian 09 programı ile DFT/B3LYP/6-31G(d) metodu, katı fazında ise Quantum-Espresso paket programı ile periyodik sınır şartları (PBC) kullanılarak molekülün geometriksel parametreleri ve frontier moleküler orbital enerjileri (FMO) incelenmiştir. Ayrıca tautomer yapılar, IRC (Intrinsic Reaction Coordinate) analiz yöntemi ile de karşılaştırılmıştır. Teorik tüm çalışmalar iki tautomer yapı üzerinde yapılmış olup bileşiğin hem gaz hem de katı fazında hesaplanan kararlı yapılarının x-ışınları yöntemiyle elde edilen yapıyla uyumlu olduğu görülmüştür. compound 3-[(E)-2-(4-phenyl-1,3-thiazol-2-yl)hydrazin-1-ylidene]-indolin-2-one in gas and solid phase under the periodic boundary conditions. For the two tautomer forms, some geometric parameters of the molecule and the molecular orbital energies of the frontier (FMO) have been investigated using Gaussian 09 program with the DFT/B3LYP/6-31G(d) method in the gas phase and with QuantumEspresso package program using periodic boundary conditions (PBC) in the solid. In addition, the tautomer structures were compared by IRC (Intrinsic Reaction Coordinate) analysis method. All In this study, theoretical calculations were made on two tautomer forms of the thiazole containing theoretical studies were performed for two tautomeric structures. As a consequence, all calculations show that stable structure of the title compound is compatible with the structure obtained by X-raysin both gas and solid phase.

Published
2020

245. Characteristics of patients with primary biliary cholangitis in a tertiary hospital facility

Author

Madir, Anita, Grgurević, Ivica, Filipec Kanižaj, Tajana, and Markeljević, Jasenka

Subjects
therapy, data, characteristics, prevalence, PBC, patients
Abstract

Uvod: Primarni bilijarni kolangitis (PBC) je progresivna, autoimuna bolest jetre, kroničnog tijeka i nedovoljno poznate etiologije. Bolest se aktivira kada osobe s genetskom predispozicijom budu izložene štetnim čimbenicima iz okoliša. U zadnje vrijeme, opisuje se porast prevalencije i incidencije primarnog bilijarnog kolangitisa u cijelom svijetu. Epidemiološki gradijent pokazuje pad prevalencije u smjeru zapad-istok i sjever-jug. Trenutno nema objavljenih podataka o incidenciji, prevalenciji ili demografskim značajkama oboljelih od PBC-a u Hrvatskoj. Glavni cilj ovog istraživanja bio je prikazati epidemiološke, kliničke i demografske karakteristike PBC bolesnika liječenih u Kliničkoj bolnici Dubrava. ----- Metode: Provedeno je retrospektivno istraživanje bolničke baze podataka za period od 2007. do 2017. godine. Identificirano je 46 PBC pacijenata s dostupnom medicinskom dokumentacijom. Analizirani su demografski, klinički i epidemiološki podatci, odgovor na terapiju nakon 12 mjeseci korištenja, te klinički ishod bolesti. Lošim kliničkim ishodom smatrani su: smrt, razvoj raka jetre, potreba za transplantacijom jetre ili jetrena dekompenzacija. Za procjenu incidencije i prevalencije uzeti su u obzir samo bolesnici s prebivalištem na geografskom području odgovornosti KB Dubrava. ----- Rezultati: Uključeni bolesnici bili su pretežito ženskog spola (87%) s medijanom starosti od 57,5 godina, a 68,8% ih je bilo u ranom kliničkom stadiju bolesti. Analizom bolesnika s prebivalištem na području odgovornosti KBD (N=38) izračunata je prevalencija od 11,47 bolesnika na 100,000 stanovnika i godišnja incidencija od 0,54 na 100,000 stanovnika. Svi bolesnici liječeni su ursodeoksikolnom kiselinom (UDCA). Među 32 bolesnika za koje su bili dostupni podatci nakon 12 mjeseci terapije, povoljan biokemijski odgovor zabilježen je u njih 25 (78%). Čimbenici povezani s uspjehom liječenja bili su redovito uzimanje terapije (P = 0,007) i niska inicijalna koncentracija IgM-a (P = 0,009). Loš klinički ishod zabilježen je u 5 bolesnika. U multivarijatnoj analizi osteoporoza je bila jedini čimbenik neovisno povezan s lošim ishodom bolesti (HR = 9,27; P = 0,031). ----- Zaključak: PBC je rijetka bolest, koja u opisanoj kohorti pogađa pretežito žene, srednje dobi, a većina ih ima blagi klinički stadij i dobru prognozu. Iako zemljopisno ograničeno, ovo istraživanje pruža prve epidemiološke podatke o PBC-u u Hrvatskoj i time nadopunjuje PBC kartu Europe., Introduction: Primary biliary cholangitis (PBC) is a chronic and progressive cholestatic liver disease of unknown etiology. Nowadays, PBC is considered an autoimmune disease activated by environmental factors in individuals with a genetic predisposition. Prevalence and incidence rates of PBC appear to increase worldwide. The epidemiological gradient shows a decline in prevalence from West to East and from North to South. There are no published data on incidence, prevalence or demographic characteristics of patients with primary biliary cholangitis (PBC) in Croatia. The aim of this study was to show the epidemiological and demographic characteristics of PBC patients treated at Dubrava Clinical Hospital. ----- Methods: A retrospective search of the hospital´s database was conducted. Data from 2007 to 2017 were reviewed during the study. 46 PBC patients with retrievable medical records were identified. Epidemiologic data were restricted to patients from the hospital´s catchment area. Statistical analysis involving the entire cohort included descriptive data as well as response to therapy after 12 months and a survival analysis. Risk factors for an adverse outcome were identified. An adverse outcome was defined as a composite event (ascites, variceal bleeding, encephalopathy), or HCC, liver transplantation and death. ----- Results: Most patients were female (87%) with a median age of disease onset of 57.5 years. The cohort included 38 patients (83%) from the hospital´s catchment area resulting in the prevalence of 11.47/100.000 and incidence of 0.54/100.000 inhabitants per year. From 32 patients analyzed concerning the response to therapy, 78% responded well. Adherence to therapy (P=0.007) and low IgM concentration at diagnosis (P=0.009) were associated with therapy success. An adverse outcome was reported in five patients. Among factors related to shorter event-free survival, osteoporosis remained relevant in multivariate analysis after adjusting for age (HR=9.27; P=0.031). ----- Conclusion: Despite some drawbacks, this study gives pioneer insights into the epidemiological data of PBC in the southeast corner of Europe, therefore complementing the PBC map of Europe.

Published
2020

246. Aging-Related Molecular Pathways in Chronic Cholestatic Conditions

Author

C. Pinto, Elisabetta Ninfole, Luca Maroni, Marco Marzioni, and Antonio Benedetti

Subjects
0301 basic medicine, Drug, Senescence, senescence, Mini Review, medicine.medical_treatment, media_common.quotation_subject, Inflammation, Disease, Liver transplantation, PBC, Bioinformatics, Primary sclerosing cholangitis, 03 medical and health sciences, 0302 clinical medicine, PSC, Fibrosis, therapeutics, Medicine, Functional decline, media_common, lcsh:R5-920, business.industry, aging, fibrosis, General Medicine, medicine.disease, 030104 developmental biology, inflammation, 030211 gastroenterology & hepatology, medicine.symptom, lcsh:Medicine (General), business
Abstract

Aging is commonly defined as the time-dependent functional decline of organs and tissues. Average life expectancy has increased considerably over the past century and is estimated to increase even further, consequently also the interest in understanding the aging processes. Although aging is not a disease, it is the major risk factor for the development of many chronic diseases. Pathologies, such as Primary Biliary Cholangitis (PBC) and Primary Sclerosing Cholangitis (PSC) are cholestatic liver diseases characterized by chronic inflammation, biliary damage and ultimately liver fibrosis, targeting specifically cholangiocytes. To date, the influence of aging in these biliary diseases is not fully understood. Currently, liver transplantation is the only solution because of lacking in efficiently therapies. Although liver cells have a high regenerative capacity, they undergo extensive molecular changes in response to aging. Following time-dependent damage induced by aging, the cells initially activate protective compensatory processes that, if hyperstimulated, can lead to the decline of regenerative ability and the development of pathologies. Recent studies have introduced novel therapeutic tools for cholangiopathies that have showed to have promising potential as novel therapies for PSC and PBC and for the development of new drugs. The recent advancements in understanding of molecular aging have undoubtedly the potential to unveil new pathways for selective drug treatments, but further studies are needed to deepen their knowledge.

Published
2020

247. The toxicity of the methylimidazolium ionic liquids, with a focus on M8OI and hepatic effects

Author

Stephanie K. Meyer, Tarek M. Abdelghany, Anna Kjerstine Rosenmai, Ibrahim Ibrahim, Jeremy M. Palmer, Lucy Bates, Lynsay I. Blake, Peter G. Blain, Katie Morse, Martin P. Cooke, Philip M. E. Probert, Alistair C. Leitch, Matthew C. Wright, Noha F. Abdelkader, Michael Dunn, Agneta Oskarsson, Colin H Wilson, David Jones, and Rodrigo Figueiredo

Subjects
Ionic Liquids, Autoimmunity, PPARα, peroxisome proliferator activated receptor alpha, Pharmacology and Toxicology, PBC, Toxicology, Article, Cell Line, Xenobiotics, PBC, primary biliary cholangitis, also previously known as primary biliary cirrhosis, 03 medical and health sciences, chemistry.chemical_compound, 0404 agricultural biotechnology, 11. Sustainability, Animals, Humans, Autoimmune liver disease, Volatile solvents, M8OI, 1 octyl 3 methylimidazolium, PDC-E2, pyruvate dehydrogenase complex E2 component, 030304 developmental biology, 0303 health sciences, ALP, alkaline phosphatase, Chemistry, 1-octyl-3-methylimidazolium, Imidazoles, ERα, estrogen receptor α, 04 agricultural and veterinary sciences, General Medicine, Contamination, 040401 food science, C8[mim], Experimental animal, Liver, GGT, γ-glutamyltransferase, 13. Climate action, AhR, aryl hydrocarbon receptor, Environmental chemistry, AMA, anti-mitochondrial antibody, Toxicity, Ionic liquid, AR, androgen receptor, Food Science
Abstract

Ionic liquids are a diverse range of charged chemicals with low volatility and often liquids at ambient temperatures. This characteristic has in part lead to them being considered environmentally-friendly replacements for existing volatile solvents. However, methylimidazolium ionic liquids are slow to break down in the environment and a recent study at Newcastle detected 1 octyl 3 methylimidazolium (M8OI) – an 8 carbon variant methylimidazolium ionic liquid - in soils in close proximity to a landfill site. The current M8OI toxicity database in cultured mammalian cells, in experimental animal studies and in model indicators of environmental impact are reviewed. Selected analytical data from the Newcastle study suggest the soils in close proximity to the landfill site, an urban soil lacking overt contamination, had variable levels of M8OI. The potential for M8OI - or a structurally related ionic liquid – to trigger primary biliary cholangitis (PBC), an autoimmune liver disease thought to be triggered by an unknown agent(s) in the environment, is reviewed., Highlights • “Ionic liquids” defines a diverse range of chemicals proposed as green chemicals. • There are limited data in mammalian systems regarding their potential toxicity. • The ionic liquid M8OI has been found at high levels in the environment. • M8OI inhibits mitochondrial function and induces mammalian cell apoptosis. • M8OI is metabolised to a lipoic acid mimetic and may be a hazard trigger for PBC.

Published
2020

248. A Review of Tools for Project Financial Assessments

Author

Goran Mladenovic, Cesar Queiroz, Ignaccolo, Matteo, and Tiboni, Michela

Subjects
PPP, media_common.quotation_subject, 0211 other engineering and technologies, 02 engineering and technology, PBC, 021105 building & construction, 0502 economics and business, 11. Sustainability, Revenue, availability payments, media_common, Finance, 050210 logistics & transportation, Present value, financial, business.industry, OPBRC, 05 social sciences, Equity (finance), Internal rate of return, Payment, Debt service coverage ratio, tolling, transport infrastructure, Cash flow, Business, Transport infrastructure
Abstract

Governments not always have the funds to build transport and other infrastructure projects that are economically justified and environmentally and socially sound. Under certain circumstances, projects meeting such conditions can be implemented by involving private financing, through public-private partnerships (PPP), which is a means to get projects completed by leveraging scarce public resources. In a PPP project, the sources of revenue to the private partner (or concessionaire) may include (i) the users of the facility (e.g., road tolling), (ii) the government (e.g. through availability payments, capital grants and shadow tolls), and (iii) both users and government, which is usually called a hybrid concession. As a key step in considering attracting private investors for such projects, decision makers and practitioners need to assess their financial viability, an endeavor that can be greatly facilitated by relatively simple tools now available. This paper reviews and provides case studies of two existing tools for assessing the financial viability of: (i) hybrid road PPP projects, which involve both tolls and availability payments; and (ii) output- and performance-based road contracts (OPBRC), which involves payments by the government. The main output generated by both models include the project’s internal rate of return, equity internal rate of return, annual debt service coverage ratio and the present value of the government’s cash flow. Transport Infrastructure and systems in a changing world. Towards a more sustainable, reliable and smarter mobility.TIS Roma 2019 Conference Proceedings

Published
2020

249. Structure of 2-(2-(anthracen-9-ylmethylene)hydrazinyl)-4-(3-methyl-3-phenylcyclobutyl)thiazole by combined X-Ray crystallographic and molecular modelling studies

Author

Alaaddin Cukurovali, Tuncay Karakurt, İbrahim Kani, Mühendislik-Mimarlık Fakültesi, Tuncay Karakurt / 0000-0001-6944-9883, and Anadolu Üniversitesi

Subjects
Anthracene, Materials science, 010304 chemical physics, Hirshfeld surface, Biophysics, X-ray, Quantum-Espresso, 010402 general chemistry, Condensed Matter Physics, PBC, 01 natural sciences, 0104 chemical sciences, Cyclobutane, chemistry.chemical_compound, Crystallography, chemistry, Quantum ESPRESSO, 0103 physical sciences, X-Ray, solid phase, Physical and Theoretical Chemistry, Thiazole, Molecular Biology, Single crystal
Abstract

Karakurt, Tuncay/0000-0001-6944-9883; CUKUROVALI, Alaaddin/0000-0002-8297-2350; Kani, Ibrahim/0000-0002-7654-6013, WOS: 000511590700001, A single crystal of 2-(2-(anthracen-9-ylmethylene)hydrazinyl)-4-(3-methyl-3-phenylcyclobutyl)thiazole (C29H25N3S) containing anthracene, thiazole and cyclobutane rings has been synthesised. the synthesised crystal structure was characterised using IR, H-1-NMR and C-13-NMR spectroscopic and X-Ray analysis techniques. in the crystal, neighbouring molecules formed chains along [110] by interconnecting with N-H center dot center dot center dot N hydrogen bonding and pi-pi interactions. the geometrical parameters of the title compound were optimised by Gaussian 09 software in the gas phase and Quantum-Espresso software under Periodic Boundary Conditions (PBC) in the solid phase. Theoretically, IR, NMR spectra, Mulliken, NPA and AIM atomic charges, Hirshfeld surface and frontier molecular orbitals (FMOs) of the title compound were examined. Using the Hirshfeld surface and two-dimensional (2D) fingerprint graphics, the presence of intermolecular interactions in the crystal packing were analysed. the energies of these interactions and their distribution on the crystal structure were shown graphically. in general, it was seen that theoretical calculations were consistent with X-Ray results.

Published
2020

250. Noninvasive Evaluation of Fibrosis and Portal Hypertension in Primary Biliary Cholangitis.

Author

Corpechot C

Subjects
Humans, Ursodeoxycholic Acid therapeutic use, Liver Cirrhosis complications, Fibrosis, Liver Cirrhosis, Biliary complications, Liver Cirrhosis, Biliary diagnosis, Liver Cirrhosis, Biliary drug therapy, Hypertension, Portal complications
Abstract

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease that, if left untreated or insufficiently treated, inexorably progresses toward cirrhosis and its potentially fatal complications. Alongside with the biochemical response to ursodeoxycholic acid therapy, advanced liver fibrosis and portal hypertension (PH) were shown to be major prognostic determinants in PBC. Therefore, one of the goals of noninvasive PBC evaluation should be to early diagnose compensated advanced disease and/or clinically significant PH. In this article, the main methods of noninvasive assessment of liver fibrosis and PH in PBC, and their clinical relevance, will be reviewed., Competing Interests: Conflict of interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Published
2022
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