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Perianal disease,small bowel disease,smoking,prior steroid or early azathioprine/biological therapy are predictors of disease behavior change in patients with Crohn's disease

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World Journal of Gastroenterology 2009年第28期15卷 3504-3510页

作者： Peter Laszlo Lakatos Zsofia Czegledi Tamas Szamosi janos Banai Gyula David Ferenc Zsigmond Tunde Pandur Zsuzsanna Erdelyi Orsolya Gemela janos papp Laszlo Lakatos 1st Department of Medicine Semmelweis University H-1083 Budapest Hungary Department of Gastroenterology State Health Center H-1062 Budapest Hungary 1st Department of Medicine Csolnoky F. County Hospital HH8201-Veszprem Hungary

AIM:To assess the combined effect of disease phenotype, smoking and medical therapy [steroid, azathioprine(AZA), AZA/biological therapy] on the probability of disease behavior change in a Caucasian cohort of patients with Crohn's disease(CD).METHODS:Three hundred and forty well-characterized, unrelated, consecutive CD patients were analyzed(M/F:155/185, duration:9.4 ± 7.5 years) with a complete clinical follow-up.Medical records including disease phenotype according to the Montreal classification, extraintestinal manifestations, use of medications and surgical events were analyzed retrospectively.Patients were interviewed on their smoking habits at the time of diagnosis and during the regular follow-up visits.RESULTS:A change in disease behavior was observed in 30.8% of patients with an initially non-stricturing, non-penetrating disease behavior after a mean diseaseduration of 9.0 ± 7.2 years.In a logistic regression analysis corrected for disease duration, perianal disease, smoking, steroid use, early AZA or AZA/ biological therapy use were independent predictors of disease behavior change.In a subsequent Kaplan-Meier survival analysis and a proportional Cox regression analysis, disease location(P = 0.001), presence of perianal disease(P < 0.001), prior steroid use(P = 0.006), early AZA(P = 0.005) or AZA/biological therapy(P = 0.002), or smoking(P = 0.032) were independent predictors of disease behavior change.CONCLUSION:Our data suggest that perianal disease, small bowel disease, smoking, prior steroid use, early AZA or AZA/biological therapy are all predictors of disease behavior change in CD patients.

关键词：生物治疗硫唑嘌呤疾病类固醇小肠吸烟预测行为

Germline MLH1 and MSH2 mutational spectrum including frequent large genomic aberrations in Hungarian hereditary non-polyposis colorectal cancer families:Implications for genetic testing

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World Journal of Gastroenterology 2007年第19期13卷 2727-2732页

作者： janos papp Marietta E Kovacs Edith Olah Department of Molecular Genetics National Institute of Oncology Rath Gy. u. 7-9 H-1122 Budapest Hungary

AIM: To analyze the prevalence of germline MLH1 and MSH2 gene mutations and evaluate the clinical characteristics of Hungarian hereditary non-polyposis colorectal cancer (HNPCC) families. METHODS: Thirty-six kindreds were tested for mutations using conformation sensitive gel electrophoreses, direct sequencing and also screening for genomic rearrangements applying multiplex ligation-dependent probe amplifi cation (MLPA). RESULTS: Eighteen germline mutations (50%) were identifi ed, 9 in MLH1 and 9 in MSH2. Sixteen of these sequence alterations were considered pathogenic, the remaining two were non-conservative missense alterations occurring at highly conserved functional motifs. The majority of the defi nite pathogenic mutations (81%, 13/16) were found in families fulfilling the stringent Amsterdam Ⅰ/Ⅱ criteria, including three rearrangements revealed by MLPA (two in MSH2 and one in MLH1). However, in three out of sixteen HNPCC-suspected families (19%), a disease-causing alteration could be revealed. Furthermore, nine mutations described here are novel, and none of the sequence changes were found in more than one family.CONCLUSION: Our study describes for the f irst time the prevalence and spectrum of germline mismatch repair gene mutations in Hungarian HNPCC and suspected-HNPCC families. The results presented here suggest that clinical selection criteria should be relaxed and detection of genomic rearrangements should be included in genetic screening in this population.

关键词：匈牙利人 MLH1 MSH2 种系突变染色体组异常非息肉性结直肠癌家族遗传学检验

NKX2-3 and IRGM variants are associated with diseasesu sceptibility to IBD in Eastern European patients

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World Journal of Gastroenterology 2010年第41期16卷 5233-5240页

作者： Nora Meggyesi Lajos S Kiss Magdalena Koszarska Martin Bortlik Dana Duricova Laszlo Lakatos Tamas Molnar Martin Lenicek Libor Vítek Istvan Altorjay Maria papp Zsolt Tulassay Pal Miheller janos papp Attila Tordai Hajnalka Andrikovics Milan Lukas Peter Laszlo Lakatos Department of Molecular Diagnostics Hun-garian National Blood Transfusion Service H-1113 BudapestHungary 1st Depart-ment of Medicine Semmelweis University H-1083 BudapestHungary IBD Clinicaland Research Centre ISCARE IVF and 1st Medical FacultyCharles University 170 04 Prague Czech Republic 1st Department of Medicine Csolnoky F.County Hospital H8200 Veszprem Hungary 1st Department of Medicine University ofSzeged H6720 Szeged Hungary Department of Biochemistry andLaboratory Diagnostics 1st Medical Faculty Charles Univer-sity 170 04 Prague Czech Republic 2nd Department of Medicine University of Debrecen H4032 Debrecen Hungary 2nd Department of Medicine Semmelweis University H1085 Budapest Hungary

AIM: To investigate variants of immunity-related GT-Pase family M (IRGM) and NKX2-3 genes and genotype-phenotype in Eastern European patients with inflammatory bowel disease (IBD).METHODS: We analyzed 1707 Hungarian and Czech subjects with Crohn’s disease (CD) (n = 810, age: 37.1 ± 12.6 years, duration: 10.7 ± 8.4 years) and ulcerative colitis (UC) (n = 428, age: 43.7 ± 15.0 years, duration: 12.6 ± 9.9 years), as well as 469 healthy controls. IRGM rs13361189, NKX2-3 rs10883365 and ECM1 rs13294 polymorphisms were tested by LightCy-cler allele discrimination. Detailed clinical phenotypes were determined by reviewing the medical charts. RESULTS: NKX2-3 rs10883365 variant allele was as-sociated with increased risk for CD (P = 0.009, OR = 1.24, 95% CI = 1.06-1.48) and UC (P = 0.001, OR = 1.36, 95% CI = 1.13-1.63), whereas variant IRGM allele increased risk for CD (P = 0.029, OR = 1.36, 95% CI = 1.03-1.79). In contrast, ECM1 rs13294 was not associat-ed with either CD or UC. In CD, the variant IRGM allele was associated with a colon-only location (P = 0.02, OR = 1.62, 95% CI = 1.07-2.44), whereas in UC, the ECM1 variant was associated with cutaneous manifestations (P = 0.002, OR = 3.36, 95% CI = 1.48-7.63). Variant alleles did not predict resistance to steroids or azathio-prine, efficacy of infliximab, or need for surgery. CONCLUSION: NKX2-3 and IRGM are susceptibility locifor IBD in Eastern European patients. Further studies are needed to confirm the reported phenotype-genotype associations.

关键词： Crohn’s disease Ulcerative colitis NKX2-3 Immunity-related GTPase family M ECM1 Genotype Phenotype Pharmacogenetics

Current concept on the pathogenesis of inflammatory bowel disease-crosstalk between genetic and microbial factors:Pathogenic bacteria and altered bacterial sensing or changes in mucosal integrity take"toll"?

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World Journal of Gastroenterology 2006年第12期12卷 1829-1841页

作者： Peter Laszlo Lakatos Simon Fischer janos papp Laszlo Lakatos Istvan Gal Department of Medicine Semmelweis UniversityBudapestHungary Department of Medicine Csolnoky F.County HospitalVeszpremHungary Department of Medicine Kenezi Gy.County HospitalDebrecenHungary

煽动性的肠疾病(IBD ) 的致病仅仅部分被理解。各种各样环境并且主人(例如基因 -- ，上皮 -- ，有免疫力、非有免疫力) 因素被包含。它是有可能的基因异质的多因素的复合基因疾病。一些基因自己与 IBD 被联系，当其它增加 ulcerative (U... 详细信息

煽动性的肠疾病(IBD ) 的致病仅仅部分被理解。各种各样环境并且主人(例如基因 -- ，上皮 -- ，有免疫力、非有免疫力) 因素被包含。它是有可能的基因异质的多因素的复合基因疾病。一些基因自己与 IBD 被联系，当其它增加 ulcerative (UC ) 或 Crohn 的疾病(CD ) 的风险或与疾病地点或行为被联系时。这评论在 IBD 的遗传探讨最近的进展。文章在在微生物引起、基因的因素之间的串音上讨论当前的信息(例如 NOD2/CARD15， SLC22A46A5 和 DLG5 ) 。在理解 IBD 和罐头的致病在最近的年帮助获得的基因数据为治疗学的干预识别很多个潜在的目标。以后，遗传可以更精确地帮助在 IBD 诊断并且预言疾病路线。

关键词：电流病理机制炎症遗传因素微生物肠黏膜

Mucocele of the appendix: An unusual cause of lower abdominal pain in a patient with ulcerative colitis-. A case report and review of literature

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World Journal of Gastroenterology 2005年第3期11卷 457-459页

作者： Peter Laszlo Lakatos Gabriella Gyori Judit Halasz Peter Fuszek janos papp Balazs Jaray Peter Lukovich Laszlo Lakatos Department of Medicine Department of Pathology Department of Surgery

The authors report the case of a 60-year-old male patient.In November 2001 he developed intestinal symptoms of bloody diarrhea and abdominal pain. Colononoscopy and biopsy established the diagnosis of ulcerative colitis (proctosigmoiditis). The disease activity was moderate at the beginning.No significant laboratory alterations were found (including CEA, CA19-9),and mesalazine was started orally.He was in remission until November 2003, when he was admitted to our Outpatient Clinic for upper and right lower abdominal pain and bloody diarrhea. Colonoscopy found proctosigmoiditis with a moderate activity, gastroscopy revealed chronic gastritis,laboratory data was normal. Treatment was amended with mesalazine clysma and methylprednisolone (16 mg) orally. Symptoms ameliorated;however, right lower abdominal pain persisted. US and CT examination demonstrated a pericecal cystic mass (11 cmx3.5 cm). At first pericecal abscess was suspected, as the previous US examination (6 mo earlier) had revealed normal findings. Fine needle aspiration was performed. Cytology confirmed the diagnosis of mucocele.The patient underwent partial cecum resection and extirpation of the mucocele. He recovered well and the final histology revealed a cystadenoma of the appendix. Follow up was started. The patient is now free of symptoms.Although primary adenocarcinoma of the appendix is uncommon, the authors emphasize that preoperative diagnosis of an underlying malignancy in a mucocele is important for patient management; however, it is difficult on imaging studies.

关键词：粘液囊肿阑尾下腹部疾病大肠溃疡消化系统

Toll-like receptor 4 and NOD2/CARD15 mutations in Hungarian patients with Crohn's disease: Phenotype-genotype correlations

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World Journal of Gastroenterology 2005年第10期11卷 1489-1495页

作者： Peter Laszlo Lakatos Laszlo Lakatos Ferenc Szalay Claudia Willheim-Polli Christoph (O|¨)sterreicher Zsolt Tulassay Tamas Molnar Walter Reinisch janos papp Gyula Mozsik Hungarian IBD Study Group Peter Ferenci 1st Department of Medicine Laszlo Lakatos Department of Internal Medicine 4 2nd Department of Medicine Semmelweis University 2nd Department of MedicineSemmelweis UniversityBudapest:Laszlo PronaiAnnamaria NemethPal Miheller Erzsebet Hospital 1st Department of MedicineBudapest: Agota KovacsLaszlo Bene Szent janos Hospital 1st Department of Medicine:Gyorgy Szekely University of Pecs 1st Department of MedicinePecs:Beata Gasztonyi University of Szeged 1st Department of MedicineSzeged:Ferenc NagyJanos Lonovics Semmelweis Hospital 1st Department of MedicineMiskolc:Laszlo Ujszaszy University of Debrecen 2nd Department of MedicineDebrecen:Istvan AltorjaiKaroly Palatka Kenezi Gy. County Hospital 2nd Department of MedicineDebrecen: Gyula G. Kiss County Hospital 2nd Department of MedicineZalaegerszeg Ferenc Tarnok Markusovszky Hospital2nd Department of MedicineSzombathely:Zoltan Dobronte Csolnoky F. County Hospital 1st Department of MedicineVeszprem:Zsuzsanna ErdelyiTunde PandurGabor Mester

AIM: To determine common NOD2/CARD15 mutations and TLR4 D299G polymorphism in Hungarian patients with CD.METHODS: A total of 527 unrelated patients with CD (male/female: 265/262, age: 37.1 (SD 7.6) years) and 200 healthy subjects were included. DNA was screened for possible NOD2/CARD15 mutations by denaturing highperformance liquid chromatography (confirmed by direct sequencing). TLR4 D299G was tested by PCR-RFLP.RESULTS: NOD2/CARD15 mutations were found in 185patients (35.1%) and in 33 controls (16.5%, P＜0.0001).SNP8/R702W (10.8% vs 6%, P = 0.02), SNP13/3020insC (19.4% vs 5%, P＜0.0001) and exon4 R703C (2.1% vs 0%, P = 0.02) mutations were more frequent in CD, while the frequency of SNP12/G908R was not increased. The frequency of TLR4 D299G was not different (CD: 9.9% vscontrols: 12.0%). Variant NOD2/CARD15 allele was associated with an increased risk for CD (ORhet = 1.71,95%CI = 1.12-2.6, P= 0.0001, ORtwo-riskalleles = 25.2,95%CI = 4.37- , P＜0.0001), early disease onset (carrier:26.4 years vs non-carrier: 29.8 years, P = 0.0006), ileal disease (81.9% vs 69.5%, OR = 1.99, 95%CI = 1.29-3.08,P = 0.02, presence of NOD2/CARD15 and TLR4: 86.7% vs64.8%), stricturing behavior (OR = 1.69, 95%CI = 1.13-2.55,P = 0.026) and increased need for resection (OR=1.71,95%CI: 1.13-2.62, P= 0.01), but not with duration, extraintestinal manifestations, familial disease or smoking. TLR4exhibited a modifier effect: age of onset in wt/TLR4 D299G carriers: 27.4 years vs NOD2mut/TLR D299G: 23 years (P= 0.06), in NOD2mut/wt: 26.7 years.CONCLUSION: These results confirm that variant NOD2/CARD15 (R702W, R703C and 3020insC) alleles are associated with earlier disease onset, ileal disease,stricturing disease behavior in Hungarian CD patients. In contrast, although the frequency of TLR4 D299G polymorphism was not different from controls, NOD2/TLR4mutation carriers tended to present at earlier age.

关键词：基因型基因多态性 NOD2/CARD15 基因突变克罗恩病肠炎

Location-based prediction model for Crohn’s disease regarding a novel serological marker,anti-chitinase 3-like 1 autoantibodies

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World Journal of Gastroenterology 2023年第42期29卷 5728-5750页

作者： Nora Sipeki Patricia Julianna Kovats Claudia Deutschmann Peter Schierack Dirk Roggenbuck Maria papp Division of Gastroenterology Department of Internal MedicineFaculty of MedicineUniversity of DebrecenDebrecen H-4032Hungary Kálmán Laki Doctoral School Faculty of MedicineUniversity of DebrecenDebrecen H-4032Hungary Institute of Biotechnology Faculty Environment and Natural SciencesBrandenburg University of Technology Cottbus-SenftenbergSenftenberg 01968Germany Faculty of Health Sciences Brandenburg Brandenburg University of Technology Cottbus-SenftenbergSenftenberg 01968Germany Medipan GmbH&GA Generic Assays GmbH Dahlewitz-Berlin 15827Germany

BACKGROUND Defective neutrophil regulation in inflammatory bowel disease(IBD)is thought to play an important role in the onset or manifestation of IBD,as it could lead to damage of the intestinal mucosal barrier by the infiltration of neutrophils in the inflamed mucosa and the accumulation of pathogens.Like neutrophils in the context of innate immune responses,immunoglobulin A(IgA)as an acquired immune response partakes in the defense of the intestinal epithelium.Under normal conditions,IgA contributes to the elimination of microbes,but in connection with the loss of tolerance to chitinase 3-like 1(CHI3L1)in IBD,IgA could participate in CHI3L1-mediated improved adhesion and invasion of potentially pathogenic microorganisms.The tolerance brake to CHI3L1 and the occurrence of IgA autoantibodies to this particular target,the exact role and underlying mechanisms of CHI3L1 in the pathogenesis of IBD are still unclear.AIM To determine the predictive potential of Ig subtypes of a novel serological marker,anti-CHI3L1 autoantibodies(aCHI3L1)in determining the disease phenotype,therapeutic strategy and long-term disease course in a prospective referral cohort of adult IBD patients.METHODS Sera of 257 Crohn’s disease(CD)and 180 ulcerative colitis(UC)patients from a tertiary IBD referral center of Hungary(Division of Gastroenterology,Department of Internal Medicine,Faculty of Medicine,University of Debrecen)were assayed for IgG,IgA,and secretory IgA(sIgA)type aCHI3L1 by enzyme-linked immunosorbent assay using recombinant CHI3L1,along with 86 healthy controls(HCONT).RESULTS The IgA type was more prevalent in CD than in UC(29.2%vs 11.1%)or HCONT(2.83%;P<0.0001 for both).However,sIgA subtype aCHI3L1 positivity was higher in both CD and UC patients than in HCONT(39.3%and 32.8%vs 4.65%,respectively;P<0.0001).The presence of both IgA and sIgA aCHI3L1 antibodies was associated with colonic involvement(P<0.0001 and P=0.038,respectively)in patients with CD.Complicated disease behavior at sample procurement was associated with aCHI3L1

关键词： Chitinase 3-like 1 autoantibodies Crohn’s disease Ulcerative colitis Disease progression Immunoglobulin subtypes Enzyme-linked immunosorbent assay

Immune dysfunction in cirrhosis

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World Journal of Gastroenterology 2014年第10期20卷 2564-2577页

作者： Nora Sipeki Peter Antal-Szalmas Peter L Lakatos Maria papp Institute of Medicine Department of Gastroenterology University of Debrecen H-4032 DebrecenHungary Department of Laboratory Medicine University of Debrecen H-4032 Debrecen Hungary 1st Department of Medicine Semmelweis University H-1083 Budapest Hungary

Innate and adaptive immune dysfunction,also referred to as cirrhosis-associated immune dysfunction syndrome,is a major component of cirrhosis,and plays a pivotal role in the pathogenesis of both the acute and chronic worsening of liver function.During the evolution of the disease,acute decompensation events associated with organ failure(s),so-called acute-on chronic liver failure,and chronic decompensation with progression of liver fibrosis and also development of disease specific complications,comprise distinct clinical entities with different immunopathology mechanisms.Enhanced bacterial translocation associated with systemic endotoxemia and increased occurrence of systemic bacterial infections have substantial impacts on both clinical situations.Acute and chronic exposure to bacteria and/or their products,however,can result in variable clinical consequences.The immune status of patients is not constant during the illness;consequently,alterations of the balance between pro-and anti-in-flammatory processes result in very different dynamic courses.In this review we give a detailed overview of acquired immune dysfunction and its consequences for cirrhosis.We demonstrate the substantial influence of inherited innate immune dysfunction on acute and chronic inflammatory processes in cirrhosis caused by the pre-existing acquired immune dysfunction with limited compensatory mechanisms.Moreover,we highlight the current facts and future perspectives of how the assessment of immune dysfunction can assist clinicians in everyday practical decision-making when establishing treatment and care strategies for the patients with end-stage liver disease.Early and efficient recognition of inappropriate performance of the immune system is essential for overcoming complications,delaying progression and reducing mortality.

关键词： Cirrhosis Immune dysfunction Endotoxemia

Prevalence, significance and predictive value of antiphospholipid antibodies in Crohn's disease

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World Journal of Gastroenterology 2015年第22期21卷 6952-6964页

作者： Nora Sipeki Laszlo Davida Eszter Palyu Istvan Altorjay Jolan Harsfalvi Peter Antal Szalmas Zoltan Szabo Gabor Veres Zakera Shums Gary L Norman Peter L Lakatos Maria papp Division of Gastroenterology Department of Internal Medicine Faculty of Medicine University of Debrecen Clinical Research Center Faculty of MedicineUniversity of Debrecen Department of Laboratory Medicine Faculty of Medicine University of Debrecen Division of Emergency Medicine Department of Internal Medicine Faculty of Medicine University of Debrecen 1~(st) Department of Medicine Semmelweis University Inova Diagnostics Inc. San Diego California

AIM: To assess the prevalence and stability of different antiphospholipid antibodies(APLAs) and their association with disease phenotype and progression in inflammatory bowel diseases(IBD) patients.METHODS: About 458 consecutive patients [Crohn's disease(CD): 271 and ulcerative colitis(UC): 187] were enrolled into a follow-up cohort study in a tertiary IBD referral center in Hungary. Detailed clinical phenotypes were determined at enrollment by reviewing the patients' medical charts. Disease activity, medical treatment and data about evolvement of complications or surgical interventions were determined prospectively during the follow-up. Disease course(development f complicated disease phenotype and need for surgery),occurrence of thrombotic events, actual state of diseaseactivity according to clinical, laboratory and endoscopic scores and accurate treatment regime were recorded during the follow-up,(median, 57.4 and 61.6 mo for CD and UC). Sera of IBD patients and 103 healthy controls(HC) were tested on individual anti-β2-Glycoprotein-I(anti-β2-GPI IgA/M/G), anti-cardiolipin(ACA IgA/M/G)and anti-phosphatidylserine/prothrombin(anti-PS/PT IgA/M/G) antibodies and also anti-Saccharomyces cerevisiae antibodies(ASCA IgA/G) by enzyme-linked immunosorbent assay(ELISA). In a subgroup of CD(n = 198) and UC patients(n = 103), obtaining consecutive samples over various arbitrary timepoints during the disease course, we evaluated the intraindividual stability of the APLA status. Additionally,we provide an overview of studies, performed so far, in which significance of APLAs in IBD were assessed.RESULTS: Patients with CD had significantly higher prevalence of both ACA(23.4%) and anti-PS/PT(20.4%) antibodies than UC(4.8%, p < 0.0001 and10.2%, p = 0.004) and HC(2.9%, p < 0.0001 and15.5%, p = NS). No difference was found for the prevalence of anti-β2-GPI between different groups(7.2%-9.7%). In CD, no association was found between APLA and ASCA status of the patients.Occurrence of anti-β2-GPI, ACA and anti-PS/PT was not different

关键词： Crohn's disease Ulcerative colitis Diseaseprogression Antiphospholipid antibodies Anti-β2-Glycoprotein-I antibodies Anti-phosphatidylserine/prothrombin Anti-cardiolipin antibodies Thrombosis