Molecular Reclassification of Crohn's Disease by Cluster Analysis of Genetic Variants

Background Crohn's Disease (CD) has a heterogeneous presentation, and is typically classified according to extent and location of disease. The genetic susceptibility to CD is well known and genome-wide association scans (GWAS) and meta-analysis thereof have identified over 30 susceptibility loci. Except for the association between ileal CD and NOD2 mutations, efforts in trying to link CD genetics to clinical subphenotypes have not been very successful. We hypothesized that the large number of confirmed genetic variants enables (better) classification of CD patients. Methodology/Principal Findings To look for genetic-based subgroups, genotyping results of 46 SNPs identified from CD GWAS were analyzed by Latent Class Analysis (LCA) in CD patients and in healthy controls. Six genetic-based subgroups were identified in CD patients, which were significantly different from the five subgroups found in healthy controls. The identified CD-specific clusters are therefore likely to contribute to disease behavior. We then looked at whether we could relate the genetic-based subgroups to the currently used clinical parameters. Although modest differences in prevalence of disease location and behavior could be observed among the CD clusters, Random Forest analysis showed that patients could not be allocated to one of the 6 genetic-based subgroups based on the typically used clinical parameters alone. This points to a poor relationship between the genetic-based subgroups and the used clinical subphenotypes. Conclusions/Significance This approach serves as a first step to reclassify Crohn's disease. The used technique can be applied to other common complex diseases as well, and will help to complete patient characterization, in order to evolve towards personalized medicine. </sec

Primary syphilitic proctitis

A 36-year-old man was seen at the outpatient clinic after referral by his general practitioner to exclude underlying perianal abscess since the patient was complaining about mushy stools mixed with blood and mucus during the last four days. At the same time, he mainly suffered from a perianal discomfort, abdominal pain and a fever (38.9 degrees Celsius). He had no prior important medical history. Familial history revealed a sister with severe Crohn’s disease. Further systemic history didn’t reveal any important issues. A physical examination showed a mild abdominal tenderness in the right lower quadrant of the abdomen. Anal inspection showed no signs of an abscess or fistula. Adenopathies could not be clinically discovered. Laboratory analyses demonstrated a normal white blood cell count (8.69 x10*9/l) with a normal differentiation, but an elevated C-reactive protein level (40 mg/l [0.0 – 5.0]) was seen. The remainder of the blood analysis was satisfying. We performed a stool analysis that could not identify any pathogens. Analysis of fecal calprotectin turned out to be highly positive (814 microgram / g feces, whereas a normal range is below 50). The patient was admitted the same day in the hospital for a semi-urgent diagnostic work-up. We performed a magnetic resonance imaging of the lower abdomen and pelvis for the purpose of excluding hidden abscesses and fistulae, also because this was the reason of patient referral by the general practitioner since the patient had a sister with severe Crohn’s disease with perianal manifestations. The images showed an edematous rectal abdominal wall with inflammatory infiltration of the mesorectal adipose tissue and the presence of enlarged lymphatic nodules. An ileocolonoscopy was performed the day after. There was a normal appearing mucosa of the terminal ileum and colon, except for the inspection of the rectal mucosa, which showed multiple atypical mucosal ulcerations with adjacent edematous mucosa. Multiple biopsies were taken as well of the ileum, the colon as the rectum. The anatomopathological findings of the terminal ileum and colon were normal. Those of the rectum showed a mild chronic inflammatory reaction suggestive of an infectious colitis with also an excess of plasma cells in the inflammatory infiltrate. There was no evidence for underlying inflammatory bowel disease. Taking into account that the rectal ulcers had atypical characteristics, we asked for sexual behavior. Because the patient admitted having unprotected anal intercourse, we performed testing for sexually transmitted disease (STD). The analyses of Chlamydia trachomatis and Neisseria gonorrhoeae on a rectal swab and on an urine sample (to exclude urethritis as a co-infection) were negative. We also performed a more general diagnostic work-up for other STD by screening for hepatitis B, hepatitis C and HIV by serologic tests. These results turned out to be negative. Laboratory analyses demonstrated a positive Treponema pallidum hemagglutination assay (TPHA) (index 15.8, positive when > 1.1) and a positive Venereal Disease Research Laboratory test (VDRL). We established the diagnosis of an early primary syphilis infection of the anorectum, also described as a syphilitic proctitis, and treated the patient and his sexual partner with one intramuscular injection of 2.4 million units of benzathine penicillin G. An endoscopic reassessment was performed six weeks after initiation of the treatment. This showed a proper endoscopic healing with remaining small stellate scars. Control of serologic tests after treatment showed a negativation of the VDRL test while the TPHA test remained positive. Rectal ulcerations are an uncommon presentation of a primary syphilis infection or primary syphilitic proctitis. It is difficult to diagnose because of its often asymptomatic or atypical clinical presentation. It is important to consider sexually transmitted diseases in all patients presenting with rectal symptoms. A history of anal sexual intercourse should be made, especially in men having sex with men (MSM). Moreover, the possibility of a primary syphilis infection of the rectum should be considered. Endoscopic findings might be diverse, whereas a typical chancre can present as an anorectal ulcer associated with regional lymphadenopathy. It is important to consider other causes of anorectal ulcers, like other STD, IBD or even malignant causes. The diagnosis of anorectal syphilis is based on the combination of the clinical presentation, serology tests, endoscopic findings and biopsies. The cornerstone of the treatment is based on an intramuscularly administration of a long-acting preparation of penicillin (benzathine penicillin G).status: publishe

Een op het eerste gezicht banaal thoraxtrauma ..

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Een gezwollen hoofd ... allergie?

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"Coin lesion" in de long. Overzicht van de diagnostische aanpak

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Standardized approach to idiopathic retroperitoneal fibrosis: a comprehensive review of the literature

BACKGROUND: Idiopathic retroperitoneal fibrosis (iRPF) is a rare fibro-inflammatory disease, characterized by inflammation of the abdominal aorta and its surrounding structures. The exact pathophysiology remains unclear. Diagnosis is often troublesome due to the non-specific and highly variable clinical presentation. Standardized treatment protocols are lacking. OBJECTIVE: This article presents a review on iRPF, addressing clinical and diagnostic modalities as well as its pathophysiology and the possible inclusion within the IgG4-related disease (IgG4-RD) spectrum. Finally, a diagnostic-therapeutic algorithm for a standardized approach to iRPF is proposed. METHODS: The PubMed Internet database was searched. Articles were selected based on the relevance of abstract, article type and impact of the journal. RESULTS: iRPF and IgG4-RD share a common autoimmune aetiology. Diagnostics are multimodal and based on imaging. Ruling out malignancy should be of primary concern. Complications are mostly of renal or vascular origin due to compression of retroperitoneal structures. Corticosteroids remain the first-line treatment regimen and are mostly successful, but evidence supporting alternative immunosuppressive and anti-inflammatory treatments is growing. Long-term therapy, as well as follow-up, is paramount in this chronic and often relapsing disease.status: publishe

Een patiënte met abdominale last en anorexie

A 72-year-old woman was referred to the Department of Gastroenterology because of complaints of abdominal pain, anorexia and constipation. An endoscopical evaluation of the gastro-intestinal tract revealed diffuse submucosal lesions, from which biopsies were taken. Further investigations confirmed a metastasized lobular breast carcinoma. According to the literature gastrointestinal tract metastases are only rarely the first manifestation of a breast cancer. In our case it was important to differentiate with a primary gastrointestinal malignancy. The reason why the primary tumor is almost always a breast carcinoma of the lobular type, remains unknown.status: publishe

Eosinofiele gastro-enteritis in de differentiaaldiagnostiek bij persisterende gastro-intestinale symptomen. Casuïstiek en literatuuroverzicht

Eosinophilic gastroenteritis is uncommon. The eosinophilic granulocyte is the central actor. Activation results in degranulation of eosinophilic granules and tissue damage. An association with food allergies and atopy is presumed. The clinical presentation is variable. Persisting gastrointestinal complaints necessitate taking biopsies which ultimately reveal tissue eosinophilia as the most prominent and diagnostic characteristic. Therapy with corticoids can lead to an overt response in most cases. The importance to confirm or rule out an underlying EGE in cases of persisting gastrointestinal symptomatology is emphasized.status: publishe

A Case of IgG4-Related Sclerosing Disease With Retroperitoneal Fibrosis, Autoimmune Pancreatitis and Bilateral Focal Nephritis

A 74-year-old male patient presented with progressive anorexia, cholestatic liver function tests, and a diffuse enlarged pancreas suggestive of a pancreatic carcinoma. There was a marked elevation of total immunoglobulin G4 (IgG4) in serum. Further investigation led to the diagnosis of IgG4-related sclerosing disease with involvement of the pancreas, retroperitoneal fibrosis, and bilateral focal nephritis. To our knowledge, this is the first report on these 3 clinical entities occurring in the same patient.A short review of the literature concerning autoimmune pancreatitis and retroperitoneal fibrosis is made, with special interest to the concept of IgG4-related pathology. This systemic disease can have several clinical manifestations: IgG4-positivity not only can be found in the pancreas, but also at the level of extrahepatic biliary ducts, gallbladder, salivary glands, retroperitoneal tissue, kidneys, ureters, and lymph nodes. Although further investigation is required to determine its exact pathophysiologic role, IgG4 seems to be an important key player.status: publishe

Cytomegalovirus-associated superior mesenteric vein thrombosis treated with systemic and in-situ thrombolysis

A 56-year-old patient, first diagnosed with an acute cytomegalovirus infection, presented with progressive abdominal pain because of a superior mesenteric vein thrombosis for which he was treated with systemic thrombolysis and heparin in continuous infusion. As this therapy did not have the intended success after 5 days, an interventional radiological procedure was performed with local thrombolysis in the superior mesenteric artery resulting in recanalisation of the vein. Oral anticoagulation was initiated and continued for a period of 6 months. Mesenteric venous thrombosis is a relatively uncommon cause of mesenteric ischemia that can be associated with severe morbidity and significant mortality. With noninvasive techniques, it is possible to establish a diagnosis in the majority of the cases. The importance of an early diagnosis and therapy - not only with anticoagulation, but also thrombolysis in selected cases - is shown with this case and review of the literature.status: publishe