Pancreatic autoantibodies in Crohn's disease: a feasible diagnostic tool?

Potential implications of antibody markers in Crohn's disease: Diagnostic markers, alone or in conjunction with other antibodies? Delineation of clinical phenotypes? Markers of disease behaviour? Markers of (genetic) susceptibility? Identification of genetically homogenous subgroups? Bridge between basic science and clinic? The exact role of serum antibodies in inflammatory bowel disease remains a matter of ongoing debate. Although a direct implication in the disease pathogenesis is unlikely, their diagnostic potential in cases of an undetermined colitis or in defining clinical phenotypes in Crohn's disease has been shown in several studies. Serum antibodies might also be helpful in predicting the disease behaviour and are thus valuable tools in the choice of medical or surgical therapy.     

UK Biobank: a project in search of a protocol?

Before it has even begun recruiting participants, the UK Biobank project has raised extraordinary passions among scientists. Some scientists are broadly supportive of the project, and feel that it is a scientifically valid, potentially valuable resource, although they still have reservations over the details of the current protocol. Others see it as an ill-conceived, politically motivated project, in which consultations have only been done to give an appearance of legitimacy and in which the scientific case has not been made for its design. There has been resentment over how the protocol has evolved, and the secrecy and legal constraints that surrounded the process for groups bidding to be involved has had the appearance of attempting to stifle debate. For this article even supporters of the project have been unwilling to be quoted on the record. The only point that everyone seems to agree on is that sufficient debate about the project has not taken place.     

Thyroid-related autoantibodies and celiac disease: a role for a gluten-free diet?

An association between celiac disease and other autoimmune disorders--such as insulin-dependent diabetes, Addison's disease, systemic lupus erythematous, rheumatoid arthritis, alopecia areata, and autoimmune endocrine diseases--has been described. The aim of this study was to evaluate the prevalence of celiac disease in 100 patients with autoimmune thyroid disease. Moreover, the monitoring of patients with concomitant celiac and autoimmune thyroid diseases, after a gluten-free diet or a gluten-containing diet, can give important insights into the effect of dietary habits in thyroid autoantibodies modulation. In our study, the prevalence of celiac disease in patients with autoimmune thyroid disease was 2%. In these two celiac patients, the serologic markers became undetectable 6 months after beginning a gluten-free diet. However, thyroid autoantibodies did not positively correlate with dietary habits.     

GAD autoantibodies in a selection-free population of insulin-treated diabetic patients: indicator of a high prevalence of LADA?

Up to the present only few data have been available concerning the prevalence of diabetes-specific autoantibodies (anti-GAD, ICA, IAA, IA-2) in unselected populations, in particular in type 2 diabetic patients. Hence, the aim of the present study was to determine the prevalence of anti-GAD in a selection-free population of insulin-treated diabetic patients. Accordingly, 90% of all the insulin-treated diabetic patients (type 1, n=127, type 2, n=117) aged 16-60 years and living in the city of Jena (100242 inhabitants) were examined. In order to test sera for anti-GAD, serum samples were taken in 75% of type 1 (n=95) and in 80% of insulin-treated type 2 diabetic (n=94) patients. Results: In the group of type 1 diabetic patients 55% of the patients tested were positive for anti-GAD. But, interestingly, in the type 2 group, a total of 21% patients were positive. With respect to this high percentage of anti-GAD positive type 2 diabetic patients it must be suggested that the frequency of patients with latent autoimmune diabetes mellitus in adults (LADA) was underestimated in the past.     

Neutrophil-elastase in chronic inflammatory bowel disease: a marker of disease activity?

BACKGROUND/AIMS: Neutrophil elastase is a proteinase which exists in granulocytes and plays an important role in the pathogenesis of inflammatory disorders. In inflammatory bowel disease there is a leukocyte infiltration of the bowel mucosa. The purpose of this study was to examine whether plasma elastase represents a reliable laboratory marker for establishing the activity of chronic inflammatory bowel disease. METHODOLOGY: We measured plasma elastase concentrations in 61 patients suffering from either Crohn's disease or ulcerative colitis and compared these data with other clinical and laboratory findings and with elastase concentrations in 40 healthy controls. The sensitivity and specificity of the elastase values in chronic IBD were calculated with the use of concomitant measurements of CRP and ESR. RESULTS: Plasma levels were found to be significantly higher in patients (49 micrograms/l) compared with healthy controls (23 micrograms/l). Patients with active disease had higher plasma levels than patients in remission. In general, the sensitivity of elastase to detect active inflammatory bowel disease was about 60%; the specificity was 65%. For patients in remission, the sensitivity was higher than 80%. However, there was a wide range of overlapping values between chronic inactive patients and those with moderately active disease. CONCLUSIONS: We conclude that plasma elastase is a useful independent marker of disease activity in inflammatory bowel disease. Especially for identifying patients in remission, the measurements of elastase seem to be more suitable than other parameters of inflammation, like CRP or ESR.     

Epidemiology and outcome of Crohn's disease in a teaching hospital in Riyadh

AIM:To know the epidemiology and outcome of Crohn'sdisease at King Khalid University Hospital,Riyadh,Saudi Arabiaand to compare the results from other world institutions.METHODS:A retrospective analysis of patients seen for20 years (between 1983 and 2002).Individual case recordswere reviewed with regard to history,clinical,findings fromcolonoscopy,biopsies,small bowel enema,computerizedtomography scan,treatment and outcome.RESULTS:Seventy-seven patients with Crohn's diseasewere revisited,13% presented the disease in the first 10 yearsand 87% over the last 10 years.Thirty-three patients (42.9%)were males and 44 (57.1%) were females.Age rangedfrom 11-70 years (mean of 25.3±11.3 years).Ninety-two(92%) were Saudi.The mean duration of symptoms was26±34.7 mo.The mean annual incidence of the diseaseover the first 10 years was 0.32∶100000 and 1.66∶100000over the last 10 years with a total mean annual incidenceof 0.94∶100 000 over the last 20 years.The chief clinicalfeatures included abdominal pain,diarrhea,weight loss,anorexia,rectal bleeding and palpable mass.Colonoscopicfindings were abnormal in 58 patients (76%) showing mostlyulcerations and inflammation of the colon.Eighty ninepercent of patients showed nonspecific inflammation withchronic inflammatory cells and half of these patientsrevealed the presence of granulomas and granulations onbowel biopsies.Similarly,69 (89%) of small bowel enemaresults revealed ulcerations (49%),narrowing of the bowellumen (42%),mucosal thickening (35%) and cobblestoneappearance (35%).CT scan showed abnormality in 68(88%) of patients with features of thickened loops (66%)and lymphadenopathy (37%).Seventy-eight percent ofpatients had small and large bowel disease,16% had smallbowel involvement and only 6% had colitis alone.Of thetotal 55 (71%) patients treated with steroids at some pointin their disease history,a satisfactory response to therapywas seen in 28 patients (51%) while 27 (49%) showedrecurrences of the condition with mild to moderatesymptoms of abdominal pain and diarrhea most of whichwere due to poor compliance to medication.Seven patients(33%) remained with active Crohn's disease.Nine (12%) patients underwent surgery with resections of some partsof bowel,2 (2.5%) had steroid side effects,6 (8%) withperianal Crohn's disease and five (6.5%) with fistulae.CONCLUSION:The epidemiological characteristics ofCrohn's disease among Saudi patients are comparable tothose reported from other parts of the world.However theincidence of Crohn's disease in our hospital increased overthe last 10 years.The anatomic distribution of the diseaseis different from other world institutions with less isolatedcolonic affection.     

Antineutrophil cytoplasmic antibodies in patients with Graves’ disease: association of antimyeloperoxidase autoantibodies with propylthiouracil therapy

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitic disorders have been reported in patients with Graves disease during propylthiouracil (PTU) therapy. To investigate whether ANCA are found in serum samples from patients with Graves disease, and whether PTU therapy is associated with ANCA positivity, levels of serum ANCA were examined in Graves-disease patients receiving either PTU (n = 49) or 1-methyl-2-mercaptoimidazole (methimazole, MMI) (n = 50), and in untreated Graves-disease patients (n = 32) by enzyme-linked immunosorbent assay (ELISA). Serum samples from patients with Hashimotos thyroiditis (n = 46) were also analyzed. Antimyeloperoxidase (MPO) autoantibodies (MPO-ANCA) were present in 10 (20.4%) of 49 Graves-disease patients receiving PTU therapy, whereas MPO-ANCA were not detected in Graves-disease patients receiving MMI, in untreated Graves-disease patients, or in Hashimotos thyroiditis patients. The MPO-ANCA-positive sera showed a perinuclear staining pattern which was detected by indirect immunofluorescence microscopy using a human polymorphonuclear leukocyte–cytospin preparation. Furthermore, Western blot analysis revealed that MPO-ANCA in the Graves-disease patients, as well as MPO-ANCA in patients with idiopathic pauci-immune necrotizing and crescentic glomerulonephritis, recognize the 105-kD protein of native MPO. These results indicate that MPO-ANCA in Graves-disease patients are strongly associated with PTU therapy, and not simply related to the autoimmune thyroid disease. This study also suggests that the presence of MPO-ANCA alone may not be sufficient for the development of vasculitic disorders.     

Colorectal cancer surveillance in inflammatory bowel disease： The search continues

Patients with inflammatory bowel disease （IBD） are at increased risk for colorectal cancer （CRC）. Risk factors for the development of CRC in the setting of IBD include disease duration, anatomic extent of disease, age at time of diagnosis, severity of inflammation, family history of colon cancer, and concomitant primary sclerosing cholangitis. The current surveillance strategy of surveillance colonoscopy with multiple random biopsies most likely reduces morbidity and mortality associated with IBD-related CRC. Unfortunately, surveillance colonoscopy also has severe limitations including high cost, sampling error at time of biopsy, and interobserver disagreement in histologically grading dysplasia. Furthermore, once dysplasia is detected there is disagreement about its management. Advances in endoscopic imaging techniques are already underway, and may potentially aid in dysplasia detection and improve overall surveillance outcomes. Management of dysplasia depends predominantly on the degree and focality of dysplasia, with the mainstay of management involving either proctocolectomy or continued colonoscopic surveillance. Lastly, continued research into additional chemopreventive agents may increase our arsenal in attempting to reduce the incidence of IBD-associated CRC.     

Evolution of disease phenotype in adult and pediatric onset Crohn’s disease in a population-based cohort

AIM:To investigate the evolution of disease phenotypein adult and pediatric onset Crohn’s disease(CD) populations,diagnosed between 1977 and 2008.METHODS:Data of 506 incident CD patients were analyzed(age at diagnosis:28.5 years,interquartile range:22-38 years).Both in-and outpatient records were collected prospectively with a complete clinical follow-up and comprehensively reviewed in the population-based Veszprem province database,which included incident patients diagnosed between January 1,1977 and December 31,2008 in adult and pediatric onset CD populations.Disease phenotype according to the Montreal classification and long-term disease course was analysed according to the age at onset in time-dependent univariate and multivariate analysis.RESULTS:Among this population-based cohort,seventy-four(12.8%) pediatric-onset CD patients were identified(diagnosed ≤ 17 years of age).There was no significant difference in the distribution of disease behavior between pediatric(B1:62%,B2:15%,B3:23%) and adult-onset CD patients(B1:56%,B2:21%,B3:23%) at diagnosis,or during follow-up.Overall,the probability of developing complicated disease behaviour was 49.7% and 61.3% in the pediatric and 55.1% and 62.4% in the adult onset patients after 5-and 10-years of follow-up.Similarly,time to change in disease behaviour from non stricturing,non penetrating(B1) to complicated,stricturing or penetrating(B2/B3) disease was not significantly different between pediatric and adult onset CD in a Kaplan-Meier analysis.Calendar year of diagnosis(P = 0.04),ileal location(P < 0.001),perianal disease(P < 0.001),smoking(P = 0.038) and need for steroids(P < 0.001) were associated with presence of,or progression to,complicated disease behavior at diagnosis and during follow-up.A change in disease location was observed in 8.9% of patients and it was associated with smoking status(P = 0.01),but not with age at diagnosis.CONCLUSION:Long-term evolution of disease behavior was not different in pediatric-and adult-onset CD patients in this     

LKM1 autoantibodies in chronic hepatitis C infection: a case of molecular mimicry?

Anti-liver-kidney microsome type 1 (LKM1) autoantibodies directed against the cytochrome P450 2D6 (CYP2D6) are considered specific markers of type 2 autoimmune hepatitis, but are also found in 5% of sera from patients chronically infected by hepatitis C virus (HCV). Molecular mimicry between HCV proteins and CYP2D6 has been proposed to explain the emergence of these autoantibodies. Anti-LKM1 autoantibodies from hepatitis C-infected patients were affinity-purified against immobilized CYP2D6 protein and used to screen a phage display library. CYP2D6 conformational epitopes were identified using phage display analysis and the identification of statistically significant pairs (SSPs). Cross-reactivity between CYP2D6 and HCV protein candidates was tested by immunoprecipitation. Nineteen different clones were isolated, and their sequencing resulted in the mapping of a conformational epitope to the region of amino acids 254-288 of CYP2D6. Candidate HCV proteins for molecular mimicry included: core, E2, NS3 and NS5a. Affinity-purified autoantibodies from HCV+/LKM1+ patients immunoprecipitated either NS3, NS5a, or both, and these reactivities were specifically inhibited by immobilized CYP2D6. In conclusion, HCV+/LKM1+ sera recognize a specific conformational epitope on CYP2D6 between amino acids 254 to 288, the region that contains the major linear epitope in type 2 autoimmune hepatitis patients. Cross-reactivity due to molecular mimicry at the B-cell level was shown between the CYP2D6 and the HCV NS3 and NS5a proteins and could explain the presence of anti-LKM1 in patients chronically infected with HCV. Further investigation of the role played by this molecular mimicry in HCV-infected patients may lead to more specific strategies for diagnosis and treatment.     

Peptic ulcer disease in dyspeptic patients with ischemic heart disease: search and treat?

OBJECTIVE: The aim of this study was to determine the prevalence and risk factors for peptic ulcer disease (PUD) in dyspeptic patients with ischemic heart disease (IHD), and to assess whether the healing of PUD before coronary artery bypass grafting (CABG) could reduce the need for urgent postoperative endoscopy. PATIENTS AND METHODS: A series of 894 patients referred to Dubrava University Hospital in Zagreb for elective CABG during the period from May 1998 until April 2001 was prospectively analysed. Dyspepsia was assessed by a questionnaire, PUD by upper gastrointestinal endoscopy, and H. pylori status by histology/Giemsa staining and the rapid urease test. The need for urgent postoperative endoscopy (hematemesis and/or melena, sudden onset of anemia or unexplained epigastric pain) was compared between the prospective study group of 894 patients and a series of 463 patients referred for CABG to Dubrava University Hospital during the period from January 1997 until April 1998. RESULTS: Gastroduodenal dyspepsia predominated in 184 (20.6 %) patients, 142 (77.2 %) of them with Helicobacter (H.) pylori infection and 69 (37.5 %) with verified PUD. Univariate analysis indicated the increased risk of multiple PUD to be related to a previous diagnosis of PUD (OR 3.61, 95 % CI 1.32 - 9.82), H. pylori infection (OR 18.86, 95 % CI 2.31 - 153.98), use of aspirin (OR 5.70; 95 % CI 1.80 - 18.03) and left coronary artery occlusions (3.10, 95 % CI 1.00 - 9.59). Multivariate analysis pointed to H. pylori infection (OR 16.30, 95 % CI 1.57 - 168.53) and left coronary artery occlusions (OR 4.84, 95 % CI 1.05 - 22.30) as independent risk factors for multiple PUD. The OR for urgent postoperative endoscopy due to a major gastrointestinal event was 9.9 (95 % CI 2.2 - 45.1) and the OR for active peptic ulcer with stigmata of recent bleeding was 6.9 (95 % CI 1.4 - 33.1) in the group of patients with IHD who were not submitted to evaluation for dyspepsia prior to elective heart surgery. CONCLUSIONS: In areas with a high prevalence of H. pylori infection, endoscopy and a "search and treat" strategy for IHD patients with dyspepsia before elective cardiac surgery should significantly reduce the need for urgent postoperative endoscopy due to major gastrointestinal events.     

Association of extraintestinal manifestations of inflammatory bowel disease in a province of western Hungary with disease phenotype： Results of a 25-year follow-up study

AIM: IBD is a systemic disease associated with a large number of extraintestinal manifestations (EIMs). Our aim was to determine the prevalence of EIMs in a large IBD cohort in Veszprem Province in a 25-year follow-up study. METHODS: Eight hundred and seventy-three IBD patients were enrolled (ulcerative colitis/UC/: 619, m/f: 317/302,mean age at presentation: 38.3 years, average disease duration: 11.2 years; Crohn‘s disease/CD/: 254, m/f: 125/129,mean age at presentation: 32.5 years, average disease duration: 9.2 years). Intestinal, extraintestinal signs and laboratory tests were monitored regularly. Any alteration suggesting an EIMs was investigated by a specialist. RESULTS: A total of 21.3 % of patients with IBD had EIM(UC: 15.0 %, CD: 36.6 %). Age at presentation did not affect the likelihood of EIM. Prevalence of EIMs was higher in women and in CD, ocular complications and primary sclerosing cholangitis (PSC) were more frequent in UC. In UC there was an increased tendency of EIM in patients with a more extensive disease. Joint complications were more frequent in CD(22.4 % vsUC 10.2 %, P&lt;0.01). In UC positive family history increased the risk of joint complications (OR:3.63). In CD the frequency of type-1 peripheral arthritis was increased in patients with penetrating disease (P=-0.028). PSC was present in 1.6 % in UC and 0.8 % in CD. Dermatological complications were present in 3.8 % in UC and 10.2 % in CD, the rate of ocular complications was around 3 % in both diseases. Rare complications were glomerulonephritis, autoimmune hemolytic anaemia and celiac disease. CONCLUSION: Prevalence of EIM in Hungarian IBD patients is in concordance with data from Western countries. The high number of EIM supports a role for complex followup in these patients.