Hepatic portal venous gas: Physiopathology, etiology, prognosis and treatment

Hepatic portal venous gas (HPVG), an ominous radiologic sign, is associated in some cases with a severe underlying abdominal disease requiring urgent operative intervention. HPVG has been reported with increasing frequency in medical literature and usually accompanies severe or lethal conditions. The diagnosis of HPVG is usually made by plain abdominal radiography, sonography, color Doppler flow imaging or computed tomography (CT) scan. Currently, the increased use of CT scan and ultrasound in the inpatient setting allows early and highly sensitive detection of such severe illnesses and also the recognition of an increasing number of benign and non-life threatening causes of HPVG. HPVG is not by itself a surgical indication and the treatment depends mainly on the underlying disease. The prognosis is related to the pathology itself and is not influenced by the presence of HPVG. Based on a review of the literature, we discuss in this paper the pathophysiology, risk factors, radiographic findings, management, and prognosis of pathologies associated with HPVG.

Current view of the immunopathogenesis in inflammatory bowel disease and its implications for therapy

Although the aetiology of inflammatory bowel disease (IBD) remains unknown, the pathogenesis is gradually being unravelled, seeming to be the result of a combination of environmental, genetic, and immunological factors in which an uncontrolled immune response within the intestinal lumen leads to inflammation in genetically predisposed individuals. Multifactorial evidence suggests that a defect of innate immune response to microbial agents is involved in IBD. This editorial outlines the immunopathogenesis of IBD and their current and future therapy. We present IBD as a result of dysregulated mucosal response in the intestinal wall facilitated by defects in epithelial barrier function and the mucosal immune system with excessive production of cytokines growth factors, adhesion molecules, and reactive oxygen metabolites, resulting in tissue injury. Established and evolving therapies are discussed in the second part of this editorial and at the end of this section we review new therapies to modulate the immune system in patients with IBD.

Role of the intestinal barrier in inflammatory bowel disease

A critical function of the intestinal mucosa is to form a barrier that separates luminal contents from the interstitium. The single layer of intestinal epithelial cells (IECs) serves as a dynamic interface between the host and its environment. Cell polarity and structural properties of the epithelium is complex and is important in the development of epithelial barrier function. Epithelial cells associate with each other via a series of intercellular junctions. The apical most intercellular junctional complex referred to as the Apical Junction Complex (AJC) is important in not only cell-cell recognition, but also in the regulation of paracellular movement of fluid and solutes. Defects in the intestinal epithelial barrier function have been observed in a number of intestinal disorders such as inflammatory bowel disease (IBD). It is now becoming evident that an aberrant epithelial barrier function plays a central role in the pathophysiology of IBD. Thus, a better understanding of the intestinal epithelial barrier structure and function in healthy and disease states such as IBD will foster new ideas for the development of therapies for such chronic disorders.

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"?

The pathogenesis of inflammatory bowel disease （IBD） is only partially understood. Various environmental and host （e.g. genetic-, epithelial-, immune and nonimmune） factors are involved. It is a multifactorial polygenic disease with probable genetic heterogeneity. Some genes are associated with IBD itself, while others increase the risk of ulcerative colitis （UC） or Crohn＇ s disease （CD） or are associated with disease location and/or behaviour. This review addresses recent advances in the genetics of IBD. The article discusses the current information on the crosstalk between microbial and genetic factors （e.g. NOD2/CARD15, SLC22A46A5 and DLG5）. The genetic data acquired in recent years help in understanding the pathogenesis of IBD and can identify a number of potential targets for therapeutic intervention. In the future, genetics may help more accurately diagnose and predict disease course in IBD.

Associations of sense of coherence with psychological distress and quality of life in inflammatory bowel disease

AIM:To investigate the relationship between sense of coherence,psychological distress and health related quality of life in inflammatory bowel disease(IBD).METHODS:This cross-sectional study enrolled a consecutive sample of 147 IBD(aged 45.1 ± 14.1 years; 57.1% female) patients recruited from a tertiary gastroenterology service.Sixty-four participants met diagnostic criteria for Crohn's disease,while eightythree patients had ulcerative colitis.Socio-demographic data(education,age,race,gender,gross monthly income and marital status),disease-related variables(illness activity,relapse rate in past 2 years,history of surgery and time since diagnosis),sense of coherence(Antonovsky's SOC scale),psychological distress symptoms(Hospital Anxiety and Depression Scale) and health-related quality of life(HRQo L; WHOQOLBref) were assessed.Hierarchical multiple regression analyses were performed to identify factors that are independently associated with psychological distress and HRQo L in patients with IBD and to provide indications for possible moderating or mediating effects.In addition,formal moderation and mediation analyses(Sobel tests) were performed to confirm potential moderators/mediators of the relationship between SOC,psychological distress symptoms and HRQoL.RESULTS:Lower SOC scores(std beta=-0.504; P < 0.001),female gender(std beta = 0.176; P = 0.021) and White race(std beta = 0.164; P = 0.033) were independently associated with higher levels of depressive symptoms,while lower levels of SOC(std beta =-0.438; P < 0.001) and higher relapse rate(std beta = 0.161; P = 0.033) were independently associated with more severe anxiety symptoms.A significant interaction between time since diagnosis and SOC was found with regard to the severity of depressive or anxiety symptoms,as the interaction term(time since diagnosis X SOC) had beta coefficients of-0.191(P = 0.009) and-0.172(P = 0.026),respectively.Lower levels of anxiety symptoms(std beta =-0.369; P < 0.001),higher levels of SOC(std beta = 0.231; P = 0.016) and non-White race(std beta =-0.229; P = 0.006),i.e.,mixed-race,which represented the reference category,were independently associated with higher levels of overall HRQoL.Anxiety symptoms were the most potent independent correlate of most aspects of HRQoL.In addition,anxiety mediated the association between SOC and satisfaction with health,as well as its relationship with physical,mental,and social relations HRQo L.Depressive symptoms also mediated the association between SOC and mental HRQoL.CONCLUSION:Our data indicated that SOC is an important construct,as it influences psychological distress and has significant albeit indirect effects on several HRQoL domains in IBD.

Fecal calprotectin correlated with endoscopic remission for Asian inflammatory bowel disease patients

AIM: To evaluate the correlation between fecal calprotectin(f C), C-reactive protein(CRP), and endoscopic disease score in Asian inflammatory bowel disease(IBD) patients.METHODS: Stool samples were collected and assessed for calprotectin levels by Quantum Blue Calprotectin High Range Rapid test. Crohn's disease endoscopic index of severity(CDEIS) and ulcerative colitis endoscopic index of severity(UCEIS) were used for endoscopic lesion scoring. RESULTS: A total of 88 IBD patients [36 patients with Crohn's disease(CD) and 52 with ulcerative colitis(UC)] were enrolled. For CD patients, f C correlated with CDEIS(r = 0.465, P = 0.005) and CRP(r = 0.528, P = 0.001). f C levels in UC patients correlated with UCEIS(r = 0.696, P < 0.0001) and CRP(r = 0.529, P = 0.0005). Calprotectin could predict endoscopic remission(CDEIS < 6) with 50% sensitivity and 100% specificity(AUC: 0.74) in CD patients when using 918 μg/g as the cutoff. When using 191 μg/g as the cut-off in UC patients, calprotectin could be used for predicting endoscopic remission(UCEIS < 3) with 88% sensitivity and 75% specificity(AUC: 0.87). CONCLUSION: f C correlated with both CDEIS and UCEIS. f C could be used as a predictor of endoscopic remission for Asian IBD patients.

Is infliximab safe to use while breastfeeding?

Inflammatory bowel disease (IBD) often affects women around the age of conception and pregnancy. Most drugs used to treat IBD are safe in pregnancy, but physicians must consider the clinical implications of certain treatment regimens in young, fertile females. We report an informative case of a pregnant patient with IBD who underwent treatment with infliximab during her pregnancy and while nursing her infant. Serum and breast milk infliximab levels were monitored throughout this time period. This case report suggests that targeted monoclonal antibodies and other biologic agents can be used with caution in pregnant and breastfeeding patients.

Meta-analysis of the effectiveness and safety of vedolizumab for ulcerative colitis

AIM: To conduct a meta-analysis examining the effectiveness and safety of vedolizumab for the treatment of ulcerative colitis(UC).METHODS: A search was conducted of MEDLINE, Cochrane, EMBASE, and Google Scholar on July 31, 2013. Inclusion criteria were:(1) Randomized controlled trial(RCT);(2) Patients treated for UC; and(3) Intervention was vedolizumab. The following information/data were extracted from studies that met the inclusion criteria: the name of the first author, year of publication, study design, patient demographic information, response rate, remission rate, and adverse events. The primary outcome was clinical response rate, and the secondary outcomes were clinical remission rate and serious adverse events. Odds ratio(OR) with 95%CI were calculated for each outcome. RESULTS: Of 224 studies initially identified, three RCTs examining the use of vedolizumab meeting the inclusion criteria were included in the meta-analysis. All studies examined the use of vedolizumab at dosages ranging from 0.5 to 10 mg/kg body weight(one study used a standard dose of 300 mg). The follow-up periods were approximately 6 wk. The total number of patients in the intervention groups was 901, and in the control groups was 221. The mean age of the patients was approximately 41 years, and approximately half were males. The follow-up periods ranged from 43 d to 6 wk. The clinical response and remission rates were significantly higher for patients who received vedolizumab as compared to control patients(clinical response: OR = 2.69; 95%CI: 1.94-3.74, P < 0.001 and remission rate: OR = 2.72; 95%CI: 1.76-4.19, P < 0.001). Serious adverse events were not higher in patients that received vedolizumab.CONCLUSION: This analysis supports the use of vedolizumab for the treatment of UC.

Use of infliximab in the prevention and delay of colectomy in severe steroid dependant and refractory ulcerative colitis

AIM: To determine if infliximab can prevent or delay surgery in refractory ulcerative colitis (UC). METHODS: UC patients who failed to have their disease controlled with conventional therapies and were to undergo colectomy if infliximab failed to induce a clinical improvement were reviewed. Patients were primarily treated with a single 5 mg/kg infliximab dose. The Colitis Activity Index (CAI) was used to determine response and remission. Data of 8 wk response and colectomy rates at 6 mo and 12 mo were collected. RESULTS: Fifteen patients were included, 7 with UC unresponsive or intolerant to Ⅳ hydrocortisone, and 8 with active disease despite oral steroids (all but one with therapeutic dosage and duration of immunomodulation). All the Ⅳ hydrocortisone-resistant/intolerant patients had been on azathioprine/6-MP < 8 wk. At 8 wk, infliximab induced a response in 86.7% (13/15) with 40% in remission (6/15). Within 6 mo of treatment 26.7% (4/15) had undergone colectomy and surgery was avoided in 46.6% (7/15) at 12 mo. The colectomy rate at 12 mo in those on immunomodulatory therapy < 8 wk at time of infliximab was 12.5% (1/8) compared with 100% (7/7) in patients who were on long-term maintenance immunomodulators (P < 0.02). CONCLUSION: Infliximab prevented colectomy due to active disease in immunomodulatory-na?ve, refractory UC patients comparable to the use of Cyclosporine. In patients, however, on effective dosage and duration of immunomodulation at time of infliximab therapy colectomy was not avoided.

Evaluation of a multiplex PCR assay for detection of cytomegalovirus in stool samples from patients with ulcerative colitis

AIM: To evaluate a multiplex PCR assay for the detection of bacterial and viral enteropathogens in stool samples from patients with ulcerative colitis(UC). METHODS: We prospectively analyzed 300 individuals, including immunocompetent patients, immunocompromised patients, and patients with UC. Stool samples were collected from the recto-sigmoid region of the colon by endoscopy. The samples were qualitatively analyzed for bacterial and viral enteropathogens with a multiplex PCR assay using a Seeplex&#174; Kit. Additional clinical and laboratory data were collected from the medical records. RESULTS: A multiplex PCR assay detected 397 pathogens(191 bacteria and 206 viruses) in 215 samples(71.7%). The most frequently detected bacteria were Escherichia coli H7, 85(28.3%); followed by Aeromonas spp., 43(14.3%); and Clostridium perfringens, 36(12.0%) samples. The most prevalent viruses were Epstein-Barr virus(EBV), 90(30.0%); followed by human herpes virus-6(HHV-6), 53(17.7%); and cytomegalovirus(CMV), 37(12.3%) samples. The prevalence rate of CMV infection was significantly higher in the immunocompromised group than in the immunocompetent group(P < 0.01). CMV infection was more common in patients with UC(26/71; 36.6%)than in the immunocompetent patients excluding UC(6/188; 3.2%)(P < 0.01). CMV infection was more prevalent in UC active patients(25/58; 43.1%) than in UC inactive patients(1/13; 7.7%)(P < 0.05). Among 4 groups which defined by the UC activity and immunosuppressive drugs, the prevalence rate of CMV infection was highest in the UC active patients with immunosuppressive drugs(19/34; 55.8%). EpsteinBarr virus(EBV) infection was more common in the immunocompromised patients excluding UC(18/41; 43.9%) than in the immunocompetent patients excluding UC(47/188; 25.0%)(P < 0.05). The simultaneous presence of CMV and EBV and/or HHV6 in UC active patients(14/58; 24.1%) was greater than in immunocompromised patients excluding UC(5/41; 12.2%)(P < 0.05). CONCLUSION: The multiplex PCR assay that was used to analyze the stool samples in this study may serve as a non-invasive approach that can be used to exclude the possibility of CMV infection in patients with active UC who are treated with immunosuppressive therapy.

Anal transition zone in the surgical management of ulcerative colitis

Preservation of the anal transition zone has long been a significant source of controversy in the surgical management of ulcerative colitis.The two techniques for restorative proctocolectomy and ileal pouch anal anastomosis(RPC IPAA) in common practice are a stapled anastomosis and a handsewn anastomosis;these techniques differ in the amount of remaining rectal mucosa and therefore the presence of the anal transition zone following surgery.Each technique has advantages and disadvantages in long-term functional outcomes,operative and postoperative complications,and risk of neoplasia.Therefore,we propose a selective approach to performing a stapled RPC IPAA based on the presence of dysplasia in the preoperative endoscopic evaluation.

Mucosal healing in inflammatory bowel disease： Maintain orde-escalate therapy

In the past decade, thanks to the introduction of biologic therapies, a new therapeutic goal, mucosal healing(MH), has been introduced. MH is the expression of an arrest of disease progression, resulting in minor hospitalizations, surgeries, and prolonged clinical remission. MH may be achieved with several therapeutic strategies reaching success rates up to 80% for both, ulcerative colitis(UC) and Crohn's disease(CD). Various scoring systems for UC and for the transmural CD, have been proposed to standardize the definition of MH. Several attempts have been undertaken to de-escalate therapy once MH is achieved, thus, reducing the risk of adverse events. In this review, we analysed the available studies regarding the achievement of MH and the subsequent treatment de-escalation according to disease type and administered therapy, together with non-invasive markers proposed as predictors for relapse. The available data are not encouraging since de-escalation after the achievement of MH is followed by a high number of clinical relapses reaching up to 50% within one year. Unclear is also another question, in case of combination therapies, which drug is more appropriate to stop, in order to guarantee a durable remission. Predictors of unfavourable outcome such as disease extension, perianal disease, or early onset disease appear to be inadequate to foresee behaviour of disease. Further studies are warranted to investigate the role of histologic healing for the further course of disease.

Promoter polymorphism of transforming growth factor-β1 gene and ulcerative colitis

AIM: To elucidate the possible difference in two promoter polymorphisms of the transforming growth factor-β1 (TGF-β1) gene (-800G > A, -509C > T) between ulcerative colitis (UC) patients and normal subjects.METHODS: A total of 155 patients with established ulcerative colitis and 139 normal subjects were selected as controls. Two single nucleotide polymorphisms within the promoter region of TGF-β1 gene (-509C > T and -800G > A) were genotyped using PCR-RFLP. RESULTS: There was a statistically significant difference in genotype and allele frequency distributions between UC patients and controls for the -800G > A polymorphism of the TGF-β1 gene (P < 0.05). The frequency of the TGF-β1 gene polymorphism at position -800 showed that the AA genotype and the allele A frequencies significantly differed between the patients and healthy controls (P < 0.05). At position -509, there was no statically significant difference in genotype and allele frequency between the patients and control subjects.CONCLUSION: The results of our study indicate that there is a significant difference in both allele and genotype frequency at position -800G > A of TGF-β1 gene promoter between Iranian patients with UC and normal subjects.

-449 C>G polymorphism of NFKB1 gene,coding nuclear factor-kappa-B,is associated with the susceptibility to ulcerative colitis

AIM:To clarify the association between a polymorphism-449 C>G(rs72696119) in 5'-UTR of NFKB1 with ulcerative colitis(UC).METHODS:The studied population comprised 639 subjects,including patients with UC(UC cases,n = 174) and subjects without UC(controls,n = 465).We employed polymerase chain reaction-single strand conformation polymorphism to detect the gene polymorphism.RESULTS:The rs72696119 G allele frequencies in controls and UC cases were 33.4% and 38.5%,respectively(P = 0.10).Genotype frequency of the GG homozygote in UC cases was significantly higher than that in controls(P = 0.017),and the GG homozygote was significantly associated with susceptibility to UC [odds ratio(OR),1.88;95%CI,1.13-3.14].In male subjects,the GG homozygote was associated with an increased risk for UC(OR,3.10;95%CI,1.47-6.54;P = 0.0053),whereas this association was not found in female subjects.In addition,the GG homozygote was significantly associated with the risk of non-continuous disease(OR,2.06;95%CI,1.12-3.79;P = 0.029),not having total colitis(OR,2.40;95%CI,1.09-3.80,P = 0.040),disease which developed before 20 years of age(OR,2.80;95%CI,1.07-7.32,P = 0.041),no hospitalization(OR,2.28;95%CI,1.29-4.05;P = 0.0090) and with a maximum of 8 or less on the UCDAI score(OR,2.45;95%CI,1.23-4.93;P = 0.022).CONCLUSION:Our results provide evidence that NFKB1 polymorphism rs72696119 was significantly associated with the development of UC.This polymorphism influences the susceptibility to and pathophysiological features of UC.

Management of hepatitis C infection before and after livertransplantation

Healthcare systems throughout the world continueto face emerging challenges associated with chronicdisease management. Due to the likely increase inchronic conditions in the future it is now vital thatcooperation and support between specialists, generalistsand primary health care physicians is conducted.Inflammatory bowel disease （IBD） is one such chronicdisease. Despite specialist care being essential, muchIBD care could and probably should be delivered inprimary care with continued collaboration betweenall stakeholders. Whilst most primary care physiciansonly have few patients currently affected by IBD intheir caseload, the proportion of patients with IBDrelatedhealthcare issues cared for in the primarycare setting appears to be widespread. Data suggestshowever, that primary care physician＇s IBD knowledgeand comfort in management is suboptimal. Currenttreatment guidelines for IBD are helpful but they arenot designed for the primary care setting. Few nonexpertIBD management tools or guidelines existcompared with those used for other chronic diseasessuch as asthma and scant data have been publishedregarding the usefulness of such tools including IBDaction plans and associated supportive literature. Thepurpose of this review is to investigate what nonspecialisttools, action plans or guidelines for IBD arepublished in readily searchable medical literature andcompare these to those which exist for other chronicconditions.

Surgical strategies in paediatric inflammatory bowel disease

Inflammatory bowel disease(IBD) comprises two distinct but related chronic relapsing inflammatory conditions affecting different parts of the gastrointestinal tract. Crohn's disease is characterised by a patchy transmural inflammation affecting both small and large bowel segments with several distinct phenotypic presentations. Ulcerative colitis classically presents as mucosal inflammation of the rectosigmoid(distal colitis), variably extending in a contiguous manner more proximally through the colon but not beyond the caecum(pancolitis). This article highlights aspects of the presentation, diagnosis, and management of IBD that have relevance for paediatric practice with particular emphasis on surgical considerations. Since 25% of IBD cases present in childhood or teenage years, the unique considerations and challenges of paediatric management should be widely appreciated. Conversely, we argue that the organizational separation of the paediatric and adult healthcare worlds has often resulted in late adoption of new approaches particularly in paediatric surgical practice.

Changes of plasma fasting carnitine ester profile in patients with ulcerative colitis

AIM： To determine the plasma carnitine ester profile in adult patients with ulcerative culitis （UC） and compared with healthy control subjects. METHOD： Using ESI triple quadrupole tandem mass spectrometry, the carnitine ester profile was measured in 44 patients with UC and 44 age- and sex-matched healthy controls. RESULTS： There was no significant difference in the fasting free carnitine level between the patients with UC and the healthy controls. The fasting propionyl- （0.331 ± 0.019 vs 0.392 ± 0.017 μmol/L）, butyryl- （0.219 ± 0.014 vs 0.265 ± 0.012）, and isovalerylcarniUne （0.111 ± 0.008 vs 0.134 ± 0.008） levels were decreased in the UC patients. By contrast, the level of octanoyl- （0.147 ± 0.009 vs 0.114 ± 0.008）, decanoyl- （0.180 ± 0.012 vs 0.137 ± 0.008）, myristoyl- （0.048 ± 0.003 vs 0.039 ± 0.003）, palmitoyl- （0.128 ± 0.006 vs 0.109 ± 0.004）, palmitoleyl- （0.042±0.003 vs 0.031 ± 0.002） and oleylcarnitine （0.183 ± 0.007 vs 0.163 ± 0.007; P 〈 0.05 in all comparisons） were increased in the patients with UC. CONCLUSION： Our data suggest selective involvement of the carnitine esters in UC patients, probably due to their altered metabolism.

Design, Synthesis and Biological Evaluation of Potent and Selective S1PR1 Agonists for the Treatment of Ulcerative Colitis

The binding of Sphingosine-1-phosphate(S1P)with the S1PR1-5 plays a fundamental physiological role in a number of processes including vascular development and stabilization,lymphocyte migration and distribution.S1P-S1PR1 signal axis established roles in immune cell trafficking thus playing a therapeutic role in multiple sclerosis and inflammatory bowel disease.In this study,a series of oxadiazole derivatives were designed and synthesized as S1PR1 agonists based on rational drug design.Among them,compound 9i was identified as a potent and selective S1PR1 agonist with activities onβ-arrestin recruitment(EC50=0.36 nmol/L)and receptor internalization(EC50=8.09 nmol/L).Meanwhile,compound 9i displayed an oral bioavailability up to 93.6%.Based on its excellent activity to S1PR1 and pharmacokinetic properties,compound 9i effectively alleviated dextran sulfate sodium(DSS)-induced ulcerative colitis in mice at a dose of 0.1 mg/kg.