Cholangiocytes: Cell transplantation

Background:Due to significant limitations to the access to orthotropic liver transplantation, cell therapies forliver diseases have gained large interest worldwide.Scope of review:To revise current literature dealing with cell therapy for liver diseases. We discussed the ad-vantages and pitfalls of the different cell sources tested so far in clinical trials and the rationale underlying thepotential benefits of transplantation of human biliary tree stem cells (hBTSCs).Major conclusions:Transplantation of adult hepatocytes showed transient benefits but requires immune-sup-pression that is a major pitfall in patients with advanced liver diseases. Mesenchymal stem cells and hemato-poietic stem cells transplanted into patients with liver diseases are not able to replace resident hepatocytes butrather they target autoimmune or inflammatory processes into the liver. Stem cells isolated from fetal or adultliver have been recently proposed as alternative cell sources for advanced liver cirrhosis and metabolic liverdisease. We demonstrated the presence of multipotent cells expressing a variety of endodermal stem cell markersin (peri)-biliary glands of bile ducts in fetal or adult human tissues, and in crypts of gallbladder epithelium. Inthefirst cirrhotic patients treated in our center with biliary tree stem cell therapy, we registered no adverse eventbut significant benefits.General significance:The biliary tree stem cell could represent the ideal cell source for the cell therapy of liverdiseases. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by JesusBanales, Marco Marzioni, Nicholas LaRusso and Peter Jansen

Endoscopic findings and psychometric abnormalities: what is the relationship in upper endoscopic outpatients?

Background. Psychological disorders are often associated with diseases of the upper digestive tract. Although emotions can influence gastrointestinal function in healthy individuals, psychological setting in upper gastrointestinal patients are unclear. We evaluate the psychological alterations prevalence in outpatients submitted to upper endoscopy. Materials and Methods. A total of 130 patients (50 males and 80 females; mean age 54±17 years) submitted to upper gastrointestinal endoscopy, were enrolled over the period May 2009 - September 2010. Subjects were asked to complete questionnaires before endoscopic examination. Alexithymia, anxiety, depression and coping style were assessed using the Toronto Alexithymia Scale, Spielberger Trait Anxiety Inventory, Beck Depression Inventory and Coping Inventory for Stressful Situations, respectively. Results. Coping impairment, Alexithymia, Anxiety and Depression were found respectively in 80.3%, 25.4%, 24.6% and 17.2%, often in association. Task-oriented, emotion-oriented and avoidance-oriented alterations were found in 41.8%, 40% and 30.6%, respectively. No correlations were demonstrated between diagnosis of upper gastrointestinal disease and psychometric results. Conclusions. In our study, a high prevalence of psychometric alterations in gastrointestinal outpatients was unconnected with endoscopic findings, especially considering coping style alterations. This aspect should be taken into account in patients management and a long-term follow-up should clarify a possible role of these factors in patients prognosis and compliance

Higher risk of tuberculosis reactivation when anti-TNF is combined with immunosuppressive agents. A systematic review of randomized controlled trials

Objective. Treatment with tumour necrosis factor antagonists (anti-TNF) has been recognized as a risk factor for tuberculosis (TB) reactivation. Our aim was to evaluate risk of TB reactivation in rheumatologic and non-rheumatologic diseases treated with the same anti-TNF agents with and without concomitant therapies. Methods. We searched for randomized controlled trials (RCTs) evaluating infliximab, adalimumab, and certolizumab in both rheumatologic and non-rheumatologic diseases until 2012. Results were calculated as pooled rates and/or pooled odd ratios (OR). Results. Overall, 40 RCTs with a total of 14,683 patients (anti-TNF: 10,010; placebo: 4673) were included. TB reactivation was 0.26% (26/10,010) in the anti-TNF group and 0% (0/4673) in the control group, corresponding to an OR of 24.8 (95% CI 2.4-133). TB risk was higher when anti-TNF agents were combined with methotrexate or azathioprine as compared with either controls (24/4241 versus 0/4673; OR 54; 95% CI 5.3-88) or anti-TNF monotherapy (24/4241 versus 2/5769; OR 13.3; 95% CI 3.7-100). When anti-TNF was used as monotherapy, TB risk tended to be higher than placebo (2/5769 versus 0/4673; OR 4; 95% CI 0.2-15.7). Conclusions. TB risk with anti-TNF agents appeared to be increased when these agents were used in combination with methotrexate or azathioprine as compared with monotherapy regimen. TB risk seemed to be higher than placebo, even when monotherapy is prescribed

The staging of gastritis with the olga system in the italian setting. histological features and gastric cancer risk

BACKGROUND: Recently OLGA (Operative Link on Gastritis Assessment) classification has been proposed to identify high-risk forms of gastritis that can evolve in gastric cancer (stages III and IV). Helicobacter pylori infection and age older than 40 have been considered as independent risk factor for high-risk OLGA stages

Bismuth-based quadruple therapy following H. Pylori eradication failures: A multicenter study in clinical practice

Background & Aims: Helicobacter pylori (H. pylori) eradication in patients who failed one or more therapeutic attempts remains challenging. This study aimed to assess the efficacy of three-in-one capsules bismuth-based quadruple therapy (Pylera®) in these patients managed in clinical practice. Methods: This was a prospective, open-label, multicenter study enrolling consecutive, adult patients with persistent H. pylori infection following at least one standard therapy. All patients received a rescue quadruple therapy with Pylera (3 capsules four times daily) and esomeprazole 20 mg (1 tablet twice daily) for 10 days. H. pylori eradication was assessed by using Urea Breath Test 4-6 weeks following therapy ending. H. pylori eradication rates, compliance, and side-effects were calculated. Results: A total of 208 patients in the 9 participating centres were enrolled. Overall, 180 patients were successfully cured from the infection, accounting for 86.5% (95% CI 81.9-91.2) and 92.3% (95% CI 88.6-96.1) eradication rates at intention-to-treat analysis and at per protocol analysis, respectively. Cure rates were similar across patients who failed one to three previous therapy attempts, but the success rate fell to 67% after 4 or more therapy failures. Compliance to therapy was good in 198 (95.2%) patients, whilst in 7 (5.3%) cases the therapy was interrupted within 5 days due to side effects. A total of 97 (46.6%) patients complained of at least one side effect; nausea, diarrhea and vomiting were the most frequently reported. Conclusions: Our study found that this bismuth-based quadruple therapy is highly effective as second-line and rescue therapy for H. pylori eradication in clinical practic

Bismuth-based quadruple therapy following H. Pylori eradication failures: A multicenter study in clinical practice

Background & Aims: Helicobacter pylori (H. pylori) eradication in patients who failed one or more therapeutic attempts remains challenging. This study aimed to assess the efficacy of three-in-one capsules bismuth-based quadruple therapy (Pylera®) in these patients managed in clinical practice. Methods: This was a prospective, open-label, multicenter study enrolling consecutive, adult patients with persistent H. pylori infection following at least one standard therapy. All patients received a rescue quadruple therapy with Pylera (3 capsules four times daily) and esomeprazole 20 mg (1 tablet twice daily) for 10 days. H. pylori eradication was assessed by using Urea Breath Test 4-6 weeks following therapy ending. H. pylori eradication rates, compliance, and side-effects were calculated. Results: A total of 208 patients in the 9 participating centres were enrolled. Overall, 180 patients were successfully cured from the infection, accounting for 86.5% (95% CI 81.9-91.2) and 92.3% (95% CI 88.6-96.1) eradication rates at intention-to-treat analysis and at per protocol analysis, respectively. Cure rates were similar across patients who failed one to three previous therapy attempts, but the success rate fell to 67% after 4 or more therapy failures. Compliance to therapy was good in 198 (95.2%) patients, whilst in 7 (5.3%) cases the therapy was interrupted within 5 days due to side effects. A total of 97 (46.6%) patients complained of at least one side effect; nausea, diarrhea and vomiting were the most frequently reported. Conclusions: Our study found that this bismuth-based quadruple therapy is highly effective as second-line and rescue therapy for H. pylori eradication in clinical practic

Transplantation of human fetal biliary tree stem/progenitor cells into two patients with advanced liver cirrhosis.

Efforts to identify cell sources and approaches for cell therapy of liver diseases are ongoing, taking into consideration the limits recognized for adult liver tissue and for other forms of stem cells. In the present study, we described the first procedure of via hepatic artery transplantation of human fetal biliary tree stem cells in patients with advanced cirrhosis.MethodsThe cells were immune-sorted from human fetal biliary tree by protocols in accordance with current good manufacturing practice (cGMP) and extensively characterized. Two patients with advanced cirrhosis (Child-Pugh C) have been submitted to the procedure and observed through a 12 months follow-up.ResultsThe resulting procedure was found absolutely safe. Immuno-suppressants were not required, and the patients did not display any adverse effects correlated with cell transplantation or suggestive of immunological complications. From a clinical point of view, both patients showed biochemical and clinical improvement during the 6 month follow-up (Table1), and the second patient maintained a stable improvement for 12 months.ConclusionThis report represents proof of the concept that the human fetal biliary tree stem cells are a suitable and large source for cell therapy of liver cirrhosis. The isolation procedure can be carried out under cGMP conditions and, finally, the infusion procedure is easy and safe for the patients. This represents the basis for forthcoming controlled clinical trials

Use of albumin infusion for cirrhosis-related complications: An international position statement

BACKGROUND & AIMS: Numerous studies have evaluated the role of human albumin (HA) in managing various liver cirrhosis-related complications. However, their conclusions remain partially controversial, probably because HA was evaluated in different settings, including indications, patient characteristics, and dosage and duration of therapy. METHODS: Thirty-three investigators from 19 countries with expertise in the management of liver cirrhosis-related complications were invited to organise an International Special Interest Group. A three-round Delphi consensus process was conducted to complete the international position statement on the use of HA for treatment of liver cirrhosis-related complications. RESULTS: Twelve clinically significant position statements were proposed. Short-term infusion of HA should be recommended for the management of hepatorenal syndrome, large volume paracentesis, and spontaneous bacterial peritonitis in liver cirrhosis. Its effects on the prevention or treatment of other liver cirrhosis-related complications should be further elucidated. Long-term HA administration can be considered in specific settings. Pulmonary oedema should be closely monitored as a potential adverse effect in cirrhotic patients receiving HA infusion. CONCLUSIONS: Based on the currently available evidence, the international position statement suggests the potential benefits of HA for the management of multiple liver cirrhosis-related complications and summarises its safety profile. However, its optimal timing and infusion strategy remain to be further elucidated. IMPACT AND IMPLICATIONS: Thirty-three investigators from 19 countries proposed 12 position statements on the use of human albumin (HA) infusion in liver cirrhosis-related complications. Based on current evidence, short-term HA infusion should be recommended for the management of HRS, LVP, and SBP; whereas, long-term HA administration can be considered in the setting where budget and logistical issues can be resolved. However, pulmonary oedema should be closely monitored in cirrhotic patients who receive HA infusion

Performance of the model for end-stage liver disease score for mortality prediction and the potential role of etiology

Bakground & aims Although discrimination of the model for end stage liver disease (MELD) is generally considered acceptable, its calibration is still unclear. In a validation study, we assessed the discrimination and calibration performance of 3 versions of the model: original MELD-TIPS, used to predict survival after transjugular intra-hepatic portosystemic shunt (TIPS); classic MELD-Mayo; MELD-UNOS, used by United Network for Organ Sharing (UNOS). Recalibration and model updating were also explored. Methods 776 patients submitted to elective TIPS (TIPS cohort), and 445 unselected patients (non-TIPS cohort) were included. Three, 6 and 12-month mortality predictions were calculated by the 3 MELD versions: discrimination was assessed by c-statistics and calibration by comparing deciles of predicted and observed risks. Cox and Fine and Grey models were used for recalibration and prognostic analyses. Results Major patient characteristics in TIPS/non-TIPS cohorts were: viral etiology 402/188, alcoholic 185/130, NASH 65/33; mean follow-up± SD 25±9/19±21months; 3-6-12 month mortality were respectively, 57-102-142/31-47-99. C-statistics ranged from 0.66 to 0.72 in TIPS and 0.66 to 0.76 in non-TIPS cohorts across prediction times and scores. A post-hoc analysis revealed worse c-statistics in non-viral cirrhosis with more pronounced and significant worsening in non-TIPS cohort. Calibration was acceptable with MELD-TIPS but largely unsatisfactory with MELD-Mayo and -UNOS whose performance improved much after recalibration. A prognostic analysis showed that age, albumin, and TIPS indication might be used for a MELD updating. Conclusions In this validation study the MELD performance was largely unsatisfactory, particularly in non-viral cirrhosis. MELD recalibration and candidate variables for a MELD updating are proposed. Lay summary While discrimination performance of the Model for End Stage Liver Disease (MELD) is credited to be fair to good, its calibration, the correspondence of observed to predicted mortality, is still unsettled. We found that application of 3 different versions of the MELD in two independent cirrhosis cohorts yielded largely imprecise mortality predictions particularly in non-viral cirrhosis and propose a validated model recalibration. Candidate variables for a MELD updating are proposed