Pathophysiology of ascites: The importance of the intestine. A surgical contribution to the understanding of a medical problem.

The understanding of the mechanisms for the development of ascites has evolved over the years, involving the liver, peritoneum, heart, and kidneys as key responsible for its formation. In this article, we review the pathophysiology of ascites formation, introducing the role of the intestine as a major responsible for ascites production through "a game changer" case.

A Decreased Response to Resistin in Mononuclear Leukocytes Contributes to Oxidative Stress in Nonalcoholic Fatty Liver Disease.

BACKGROUND: Deregulation of immune response and oxidative stress contribute to nonalcoholic fatty liver disease (NAFLD) pathogenesis. Resistin is a physiological modulator of inflammation and redox homeostasis of different cell types. Increased resistin serum concentration and the direct association between resistin hepatic expression and NAFLD severity suggest that resistin participates in NAFLD pathogenesis. AIMS: To evaluate resistin-induced regulation of redox homeostasis in mononuclear leukocytes from NAFLD patients and controls. METHODS: We evaluated basal and resistin-mediated modulation of reactive oxygen species (ROS) and glutathione content by flow cytometry, and antioxidant enzyme activities by spectrophotometry. RESULTS: Peripheral blood mononuclear cells (PBMC) from NAFLD patients showed higher ROS content and glutathione peroxidase activity and lower glutathione content, superoxide dismutase and glutathione reductase activities than control PBMC. Resistin decreased ROS levels and superoxide dismutase activity and increased glutathione reductase and catalase activities in PBMC from controls but not from patients. Resistin decreased glutathione content in PBMC from control and NAFLD patients, with greater effect on patient cells. Basal and resistin-modulated ROS levels were directly associated with obesity-related risk factors for NAFLD. Hepatic myeloid cells and T-lymphocytes from NAFLD patients showed higher basal ROS content than cells from controls. Resistin decreased ROS levels in hepatic T-lymphocytes from controls but not from patients. CONCLUSIONS: Resistin regulates redox homeostasis in mononuclear leukocytes. A decreased response to resistin in leukocytes from NAFLD patients is associated with an impaired redox homeostasis.

Autologous gastrointestinal reconstruction surgery for short bowel syndrome: the cornerstone for intestinal rehabilitation.

PURPOSE OF REVIEW: Intestinal failure (IF) evolved from being the last recognized organ failure, to become one of the most progressive fields in terms of therapeutic alternatives and results. Short bowel syndrome (SBS) is the main cause of IF in adults and children. The use of surgery allowed patients with unfavorable anatomy type and length to be wean off parenteral nutrition. We aim to evaluate its current impact on intestinal rehabilitation. RECENT FINDINGS: Autologous gastro-intestinal reconstructive surgery (AGIRS), including bowel lengthening contributes by converting patient's anatomy to a more favorable one, improving quality of life, and modifying the natural history of the disease, allowing to recover intestinal autonomy in approximately 70% of the adults and 50% of the children's with SBS-IF. The current use of postsurgical medical rehabilitation strategies including the use of enterohormones complement the path to sufficiency, increasing the chances of success in both age group of patients. SUMMARY: The development of AGIRS has changed the outcome of SBS-IF patients, becoming the main surgical procedure prescribed in multidisciplinary units, allowing to enhance the number of patients achieving intestinal autonomy throughout rehabilitation, leaving transplantation as the last surgical alternative.

Quality of life after intestinal transplantation.

PURPOSE OF REVIEW: Intestinal transplantation (ITx) is the last therapeutic option in chronic intestinal failure (CIF) patients who develop life-threatening complication related to home parenteral nutrition (HPN). Improvement of quality of life (QoL) has been proposed as one of the nonconventional indications for ITx in these patients. This review aims to summarize the current evidence about QoL assessment in ITx recipients. RECENT FINDINGS: Several studies were conducted to determine QoL in ITx patients, with differences in the samples and instruments used to assess it. Patients evaluated for ITx had lower QoL than those on HPN without complications. QoL seems to improve in most psychological, emotional and social areas after a successful ITx, a trend that seems to increase over time. These results would support the rehabilitative role of ITx for patients with irreversible CIF and impossibility to continue receiving HPN. SUMMARY: Although QoL after ITx patients improved over time compared with life on HPN, the heterogeneity in the samples included in several studies, and the lack of validated assessment tools, hinder the possibility to draw conclusions about improvement of QoL after ITx.

A detailed analysis of the current status of intestinal transplantation in Latin America.

PURPOSE OF REVIEW: Latin America and the Caribbean represent a vast territory, with very different economic and healthcare realities, which result in significant disparities in the management of intestinal failure patients throughout the region. Since 1968, multiple attempts have been done to accomplish a successful intestinal transplant; but it was not until 2004, with the establishment of multidisciplinary programs, that large series with long-term results could be obtained. Currently, three countries (Colombia, Argentina, and Brazil) in the region are actively performing these procedures. RECENT FINDINGS: A total number of 135 intestinal transplants have been performed; 11 attempts before 2004, and 124 after that period, 66 transplants were done in Argentina (42 in children), 40 in Colombia, 15 in Brazil (1 child), 2 in Costa Rica and 1 in México; 76% have been isolated, whereas 2 were done with living donors. SUMMARY: Publications are still scarce, and compliance to existing registries remains limited. The challenge for the next years is to develop more 'comprehensive units' and extend home parenteral nutrition availability in the rest of the region. Regional cooperation and networking need to be set, in order to achieve regional self-sufficiency and improve long-term results.

The Novel N,N-bis-2-Hydroxyethyl-2-Aminoethanesulfonic Acid-Gluconate-Polyethylene Glycol-Hypothermic Machine Perfusion Solution Improves Static Cold Storage and Reduces Ischemia/Reperfusion Injury in Rat Liver Transplant.

Organ transplantation is the treatment of choice against terminal and irreversible organ failure. Optimal preservation of the graft is crucial to counteract cold ischemia effects. As we developed an N,N-bis-2-hydroxyethyl-2-aminoethanesulfonic acid-gluconate-polyethylene glycol (BGP)-based solution (hypothermic machine perfusion [HMP]), we aimed to analyze the use of this solution on static cold storage (SCS) of rat livers for transplantation as compared with the histidine tryptophan ketoglutarate (HTK) preservation solution. Livers procured from adult male Sprague Dawley rats were preserved with BGP-HMP or HTK solutions. Liver total water content and metabolites were measured during the SCS at 0°C for 24 hours. The function and viability of the preserved rat livers were first assessed ex vivo after rewarming (90 minutes at 37°C) and in vivo using the experimental model of reduced-size heterotopic liver transplantation. After SCS, the water and glycogen content in both groups remained unchanged as well as the tissue glutathione concentration. In the ex vivo studies, livers preserved with the BGP-HMP solution were hemodynamically more efficient and the O2 consumption rate was higher than in livers from the HTK group. Bile production and glycogen content after 90 minutes of normothermic reperfusion was diminished in both groups compared with the control group. Cellular integrity of the BGP-HMP group was better, and the histological damage was reversible. In the in vivo model, HTK-preserved livers showed a greater degree of histological injury and higher apoptosis compared with the BGP-HMP group. In conclusion, our results suggest a better role of the BGP-HMP solution compared with HTK in preventing ischemia/reperfusion injury in the rat liver model.

Pediatric living donor liver transplant in a recipient with biliary atresia and portal vein duplication-How did we manage it?

Portal vein malformations might occur during the embryonic period, as a consequence of abnormal remodeling of vitelline veins during embryonic life. Patients suffering from biliary atresia are particularly prone to have vascular malformations; although being the most frequent indication for liver transplantation in the pediatric age, portal vein duplication has not been so far associated with biliary atresia, and to the best of our knowledge, there is no-written evidence describing how to manage it when it is first diagnosed while performing a pediatric liver transplant. Therefore, we present a recent case from our group, describing the intraoperative diagnosis of a double portal system in a patient with biliary atresia and failed Kasai. We aim to describe its surgical management, understanding that it is a real challenge to find them unexpectedly during the surgical procedure in the setting of cirrhosis and portal hypertension, particularly in small patients; therefore, by reporting this case, we aim to make readers aware about the chance of finding it, and how to managed it, to include this approach as part of the surgical armamentarium.

Group 2 innate lymphoid cells exhibit progressively higher levels of activation during worsening of liver fibrosis.

INTRODUCTION: The interleukin-33/interleukin-13 pathway is involved in the immunopathology of liver fibrosis and recently characterized group 2 innate lymphoid cells (ILC2) were identified as profibrotic immune cells in the liver of mouse models. Our aim was to elucidate whether ILC2 might be present in human liver tissue and whether ILC2 contribute to liver fibrosis. MATERIALS AND METHODS: To identify ILC2 in liver tissue and blood, we purified mononuclear immune cells from needle biopsies, cirrhotic explant specimen, and paired peripheral blood samples. Cell suspensions were incubated with specific markers for ILC2 and analyzed by flow cytometry. The CD69 marker was included to assess the activation level of ILC2. In addition, we determined the IL-33 plasma level. RESULTS: Results were correlated with the METAVIR fibrotic score of patients enrolled in this study. We detected ILC2 in a higher percentage of CD45+ cells in liver tissue than in paired peripheral blood. The number of ILC2 was significantly increased in fibrotic tissue, but only slightly increased in paired peripheral blood. A higher percentage of CD69+ ILC2 was observed in fibrotic tissue, and this increase correlates positively with aggravation of liver fibrosis measured by fibrotic METAVIR score. A higher level of plasma IL-33 was only detected in samples obtained from cirrhotic patients. CONCLUSION: Our study indicates that ILC2 are present in the human liver and are activated in tissue contributing to the immunopathology of human liver fibrosis, independently of the etiology; which might be a potential new therapeutic target.

Unusual spontaneous porto-systemic shunt: The importance of diagnosing non-anatomical porto-systemic shunts to improve portal flow in pediatric living-related liver transplantation. Case report.

Collateral circulation secondary to liver cirrhosis may cause the development of large PSSs that may steal flow from the main portal circulation. It is important to identify these shunts prior to, or during the transplant surgery because they might cause an insufficient portal flow to the implanted graft. There are few reports of "steal flow syndrome" cases in pediatrics, even in biliary atresia patients that may have portal hypoplasia as an associated malformation. We present a 12-month-old female who received an uneventful LDLT from her mother, and the GRWR was 4.8. During the early post-operative period, she became hemodynamically unstable, developed ascites, and altered LFT. The post-operative ultrasound identified reversed portal flow, finding a non-anatomical PSS. A 3D CT scan confirmed the presence of a mesocaval shunt through the territory of the right gonadal vein, draining into the right iliac vein, with no portal inflow into the liver. The patient was re-operated, and the shunt was ligated. An intraoperative Doppler ultrasound showed adequate portal inflow after the procedure; the patient evolved satisfactorily and was discharged home on day number 49. The aim was to report a case of post-operative steal syndrome in a pediatric recipient due to a mesocaval shunt not diagnosed during the pretransplant evaluation.

Management of intestinal failure in middle-income countries, for children and adults.

PURPOSE OF REVIEW: Intestinal failure is a life-threatening medical condition that remains as a rare or orphan disease in most countries. The prevalence of intestinal failure and the therapeutic options available in middle-income countries (MIC) remain unclear. We aim to provide an overview on the current differences in management of intestinal failure patients in MIC from Latin America and Asia. RECENT FINDINGS: In order to fulfil the challenge, and after facing the difficulties of going over a topic with scarce available data, from countries with an extreme variety of social and economic problems, which are closely related to the treatment of intestinal failure patients, we have used both the existing publications and personal surveys to draft this document. Our results have shown that there is still significant disparity among MIC over the last years, concepts such as the need for establishing multidisciplinary dedicated teams as well as the need to evolve first home parenteral nutrition (HPN), then rehabilitation, and finally transplantation, have become important signals of an adequate understanding of this evolving field. SUMMARY: The manuscript presents, for the first time, an overview of the different developments and needs to manage intestinal failure patients in MIC from Latin America and Asia. Future discussions will emerge from this manuscript, aiming to pursue the development of registries, guidelines and health policies to continue improving the long-term care of intestinal failure patients in all MIC.

Techniques for abdominal wall reconstruction in intestinal transplantation.

PURPOSE OF REVIEW: One of the most important challenges in the intestinal (ITx) and multivisceral transplant (MVTx) is to achieve a successful abdominal wall closure. RECENT FINDINGS: A tension-free primary closure should be our aim. In most of the cases, we need to perform a component separation technique, alone or combined, to the use of a synthetic mesh. If those options are not feasible, the abdominal wall composite vascularized allograft transplant (AW-CVA) utilizing direct orthotopic vascularization can be considered. The nonvascularized abdominal rectus fascia has also become an alternative method used worldwide, proving to be simple and well tolerated procedure. Furthermore, the use of the AW has been recently proposed as a new tool for a sentinel monitoring of the intestinal or pancreas allograft. SUMMARY: There are different validated options for abdominal wall closure following intestinal transplantation. The long-term benefits of transplanting the abdominal wall, full or partial thickness and vascularized or nonvascularised, were shown. New developments might help to expand their applications in different areas such as reconstructive surgery and immunology.

Avances en Gastroenterología Trasplante intestinal desde la clínica a la investigación traslacional: contribuciones de una unidad integral de insuficiencia intestinal, rehabilitación y trasplante. Seguimiento biomédico del proceso de trasplante intestinal y su correlación con los distintos eventos fisiopatológicos que atraviesa el paciente.

One of the greatest achievements in gastroenterology and surgery of the last 50 years has been the capability to transplant different abdominal organs of the digestive system separately or as a whole. The complexity of the intestinal transplantation demands a multidisciplinary team engaged in the management of patients with intestinal failure responsible for defining the need for nutritional support, rehabilitation, or intestinal transplantation. This team should include a basic research area to provide answers to unresolved clinical problems. The aim of this work is to update the current status of intestinal transplantation, and to show the progress and results of our center; emphasizing our achievements in the clinical area, and the contributions of the translational research and mucosal immunology studies as part of the integral unit of intestinal failure, rehabilitation and transplantation. The data reported here demonstrate that the intestinal transplantation has been established as a therapeutic option in our country and Latin America, with long term results that have ranked our service at the level of the best centers in the world positioning us as referent in the specialty.

Immunosuppressive therapies after intestinal transplant modulate the expression of Th1 signature genes during acute cellular rejection. Implications in the search for rejection biomarkers.

BACKGROUND AND AIMS: Acute cellular rejection (ACR) and infections are leading causes of graft loss and death in intestinal transplant patients. Our aim was to evaluate the impact of maintenance immunosuppressive therapies on the expression of pro-inflammatory mediators in small bowel at ACR diagnosis. MATERIALS AND METHODS: We analyzed expression levels of Th1-associated genes, IFNG, CXCL10, and CXCL11 by qPCR in 46 selected graft biopsies unequivocally assigned to mild ACR (n = 14) or normal histopathology and clinical condition (n = 32) from 15 patients receiving two different immunosuppressive (IS) schemes. Double treatment: corticosteroids and tacrolimus (n = 17) and triple treatment: sirolimus or mycophenolate mofetil in addition to the basal therapy (n = 29). RESULTS: IFNG, CXCL10, and CXCL11 were induced during rejection (p < 0.05; p < 0.005, and p < 0.05, respectively). However, when rejection and control groups were classified according to immunosuppressive treatment, in the rejection group, significant differences of IFNG, CXCL10, and CXCL11 expression (p < 0.001; p < 0.005, and 0.01, respectively) were detected, whereas no differences were observed in the control group. CONCLUSION: Gene expression of Th1 response mediators is higher during ACR. Triple IS group showed significantly lower expression of pro-inflammatory Th1 mediators during mild ACR indicating that use of these markers to monitor rejection can be affected by the IS treatment used.

Development of an experimental model of portal vein ligation associated with parenchymal transection (ALPPS) in rats.

BACKGROUND: Liver failure might be a cause of death after major hepatectomies. The ALPPS technique appears to be a promising strategy to avoid it, however no experimental studies supporting this procedure have been previously described. The aim was to develop an experimental model of ALPPS in rats. METHOD: Experimental. A total of 30 Sprague Dawley rats were used. To develop the ALPPS procedure, ligation of the left portal branch of the middle lobe (LM) was performed. This demarcates the left side (SILM) from the right side (SDLM); parenchyma transection was performed following the demarcated line. The animal's weight, volume and weight of both LM were analyzed. Sacrifice at 3, 7 and 14 days after the procedure (10 per group) was performed. RESULTS: No bleeding or ascites were observed during the postoperative period. The LM increased by 24.1, 86.9 and 120.4% at 3, 7 and 14 days. The SDLM increased by 34.4, 78.8 and 102.0% at 3, 7 and 14 days. The SILM decreased 42.6, 64.8, and 79.3% at day 3, 7 and 14 days respectively. CONCLUSION: The ALPPS procedure can be performed in rats, achieving the expected results. Comparison studies to 2 staged hepatectomy will be necessary.

History of clinical intestinal transplantation.

The intestines have been considered the "forbidden organ" for years, and intestinal failure became the last organ failure recognized as such in the medical field. The impossibility of providing adequate nutritional support, turned these patients into recipients of just palliative comfort. In the 1960's, parenteral nutrition appeared as the most reasonable replacement therapy, but the initial success obtained with clinical kidney, heart, liver, lung and pancreas transplantation served as background to explore intestinal transplantation. The first clinical report of an isolated intestinal transplant was done by Richard Lillihei in 1967; in 1983, Thomas Starzl, performed the first multi visceral transplant, and in 1990, David Grant performed the first combined liver-intestinal transplant in an adult recipient in Canada. Since then, advances in immunosuppressive therapies and surgical innovations have allowed not only a continuous increase in indications, but also a worldwide application of all procedures, bringing clinical intestinal transplantation to reality. In this historical account, the most important contributions have been summarized, thus describing the steady progress, expansion and novelties developed over the last 56 years, since the first attempt. Clinical intestinal transplantation remains a complex and evolving field; ongoing research and technological advancements will continue shaping its future.

Endoscopic Surveillance of the Intestinal Allograft: Recommendations From the Intestinal Rehabilitation and Transplant Association Working Group.

Intestinal transplant (ITx) rejection lacks a reliable noninvasive biomarker and rejection surveillance relies on serial endoscopies and mucosal biopsies followed by histologic assessment. Endoscopic biopsies are also essential for identifying other ITx-related complications such as infectious, allergic, and inflammatory graft enteritis as well as post-transplant lymphoproliferative disease or graft versus host disease. In spite of its central role in ITx, published guidelines on endoscopy and biopsy are lacking and significant variability between centers in terms of timing and technical performance exists. Therefore, an international expert group convened and discussed several aspects related to the surveillance endoscopy after ITx with the aim to summarize and standardize its practice. This article summarizes these considerations on endoscopic ITx monitoring and highlights practices of surveillance and for-cause endoscopy, biopsy techniques, pathologic evaluation, potential risks and complications, outsourcing, and less-invasive monitoring techniques.

[Hepatocellular carcinoma within Milan criteria and beyond: outcomes of liver transplantation in a single Argentinian institution]. / Hepatocarcinoma dentro y fuera de los criterios de Milán: resultados de un centro de trasplante hepático en la Argentina.

Hepatocellular carcinoma (HCC) recurrence following liver transplantation is associated to bad prognosis. We retrospectively analyzed the data of 95 patients who underwent liver transplantation for HCC. Recurrence rate and variables associated with recurrence were reviewed. According to the findings on the explanted livers they were divided in two groups: Milan (M) 67% and non-Milan (NM) 33%. Global recurrence rate, and M-group and NM-group recurrence rates were 19%; 12% and 32%, respectively (P = 0.001). Although in the univariate analysis we found some factors associated to recurrence (hemocromathosis, year of transplant, bilobar distribution, vascular invasion and previous chemoembolization), they were not independent predictors of recurrence in the multivariate analysis. Actuarial survival in cirrhotic patients with and without HCC at 1, 3 and 5 years was 86% and 91% (NS), 77% and 88% (NS), and 67% and 86% (P = 0.002), respectively; whereas actuarial survival of the M and NM groups was 86% and 71%; 82% and 61%, and 78% and 58%, respectively (P = 0.02). We had a satisfactory five-year global survival in our series even though one third of our patients grafted for HCC were outside Milan criteria.

IL-22BP controls the progression of liver metastasis in colorectal cancer.

Background: The immune system plays a pivotal role in cancer progression. Interleukin 22 binding protein (IL-22BP), a natural antagonist of the cytokine interleukin 22 (IL-22) has been shown to control the progression of colorectal cancer (CRC). However, the role of IL-22BP in the process of metastasis formation remains unknown. Methods: We used two different murine in vivo metastasis models using the MC38 and LLC cancer cell lines and studied lung and liver metastasis formation after intracaecal or intrasplenic injection of cancer cells. Furthermore, IL22BP expression was measured in a clinical cohort of CRC patients and correlated with metastatic tumor stages. Results: Our data indicate that low levels of IL-22BP are associated with advanced (metastatic) tumor stages in colorectal cancer. Using two different murine in vivo models we show that IL-22BP indeed controls the progression of liver but not lung metastasis in mice. Conclusions: We here demonstrate a crucial role of IL-22BP in controlling metastasis progression. Thus, IL-22 might represent a future therapeutic target against the progression of metastatic CRC.

CD4+ T cell-derived IL-22 enhances liver metastasis by promoting angiogenesis.

Metastasis is a cancer-related systemic disease and is responsible for the greatest mortality rate among cancer patients. Interestingly, the interaction between the immune system and cancer cells seems to play a key role in metastasis formation in the target organ. However, this complex network is only partially understood. We previously found that IL-22 produced by tissue resident iNKT17 cells promotes cancer cell extravasation, the early step of metastasis. Based on these data, we aimed here to decipher the role of IL-22 in the last step of metastasis formation. We found that IL-22 levels were increased in established metastatic sites in both human and mouse. We also found that Th22 cells were the key source of IL-22 in established metastasis sites, and that deletion of IL-22 in CD4+ T cells was protective in liver metastasis formation. Accordingly, the administration of a murine IL-22 neutralizing antibody in the establishment of metastasis formation significantly reduced the metastatic burden in a mouse model. Mechanistically, IL-22-producing Th22 cells promoted angiogenesis in established metastasis sites. In conclusion, our findings highlight that IL-22 is equally as important in contributing to metastasis formation at late metastatic stages, and thus, identify it as a novel therapeutic target in established metastasis.