Treatment For End-stage Liver Disease Research Articles

A Review on the Management of Biliary Complications after Orthotopic Liver Transplantation.

Orthotopic liver transplantation is the definitive treatment for end-stage liver disease and hepatocellular carcinomas. Biliary complications are the most common complications seen after transplantation, with an incidence of 10–25%. These complications are seen both in deceased donor liver transplant and living donor liver transplant. Endoscopic treatment of biliary complications with endoscopic retrograde cholangiopancreatography (commonly known as ERCP) has become a mainstay in the management post-transplantation. The success rate has reached 80% in an experienced endoscopist’s hands. If unsuccessful with ERCP, percutaneous transhepatic cholangiography can be an alternative therapy. Early recognition and treatment has been shown to improve morbidity and mortality in post-liver transplant patients. The focus of this review will be a learned discussion on the types, diagnosis, and treatment of biliary complications post-orthotopic liver transplantation.

Comparison of effects of melatonin, pentoxifylline and dimethyl sulfoxide in experimental liver ischemia-reperfusion injury by three different methods

Objectives: Liver transplantation is increasingly being used in the treatment of end-stage liver disease. Ischemia-reperfusion injury is one of the major problems encountered in transplantation. In this study, we aimed to compare the effects of melatonin, pentoxifylline, and dimethyl sulfoxide (DMSO), in hepatic ischemia-reperfusion injury with different methods such as biochemical/ultrastructural changes and hepatobiliary scintigraphy. Methods: Thirty rabbits were used in the Laboratory of Experimental Animals of Trakya University under appropriate conditions. Sham laparotomy and only ischemia reperfusion group were planned. They were used melatonin, pentoxifylline, and DMSO after ischemia-reperfusion in the other three groups. 6 rabbits were randomly selected for each group. Rabbits in all groups were subjected to liver scintigraphy. Following scintigraphy, 2 cm2 of liver tissue was removed to examining for liver antioxidant enzyme levels (superoxide dismutase [SOD] and glutathione peroxidase [GPx]) and for liver electron microscopy. Results: Pentoxifylline and melatonin protected significantly uptake and excretion functions in liver scintigraphy. When the effects of all three substances were examined by electron microscopy, it was found that the three substances protected the liver from the effects of ischemia-reperfusion damage at varying rates. All three agents were found to protect SOD and GPx from falling in various amounts. Conclusions: Studies to prevent ischemia-reperfusion injury, which may develop as a result of the Pringle maneuver applied to liver transplantations as well as to liver resections or liver injuries, still maintain their popularity. In our study, the effects of agents were identified in three different ways. Ischemia-reperfusion injury-reducing effect of pentoxifylline gave parallel results with three methods.

Epidemiological characteristics and access to end-stage liver disease care for HIV-positive patients with HCV and/or HBV coinfections in Central/Eastern European and neighboring countries – data from the ECEE network

There is currently an urgent need to harmonize hepatitis standards of care for HIV-positive patients across Europe. The HIV epidemic in Central and Eastern Europe has often been driven by injecting drug use, therefore a higher rate of co-infection with HCV and HBV is expected in this region. We have investigated the epidemiological prevalence and treatment availability for end-stage liver disease in HIV/HCV/HBV coinfections in countries represented in the ECEE Network Group. The Euroguidelines in Central and Eastern Europe (ECEE) Network Group was initiated in February 2016 to compare standards of care regarding HIV infection in the region. Information about HIV/HCV/HBV co-infections and the availability for end-stage liver disease treatment for HIV-positive patients were collected through on-line surveys. The respondents were ECEE members from 16 countries of the region. The information on co-infection prevalence was sourced from WHO, national HIV programmes, articles published in international journals, single clinic reports, and personal information in ten of the participating countries (62.5%). The HIV/HCV co-infection rate was from 3% to 99%. The range of reported of HIV/HBV coinfection percentages was 2.3% to 40%. HIV/HCV/HBV co-infection ranged from 0% to 9%. Regarding treatment for end-stage liver disease, liver transplantation was an available option for HIV-positive patients in only three countries (19%). Our findings revealed only a limited number of treatment options for the end-stage liver disease in HIV-positive patients for the vast majority of Central and Eastern European countries. There are gaps in epidemiological surveillance in this region. It appears there are many differences in the number of co-infected patients among Central and Eastern European and neighboring countries, but there is no unification of information sources.

Patients with hepatorenal syndrome may have better renal outcome after living donor liver transplantation comparing with patients with chronic kidney disease

Introduction: Hepatorenal syndrome (HRS) is one of the most severe complications of liver cirrhosis. Liver transplantation (LT), the ultimate curative treatment for end-stage liver disease, is needed to completely reverse HRS. However, risk of renal function deterioration after LT has been associated with pre-LT renal dysfunction. Several studies have reported outcome comparisons between patients with or without HRS. Here we compare the outcomes between LT patients with HRS or with chronic kidney disease (CKD). Method: Medical records of adult patients receiving living donor liver transplantation (LDLT) at Kaohsiung Chang Gung Memorial Hospital from July 2008 to September 2017 were reviewed. Patients with renal function impairment were enrolled. According to the diagnostic criteria of HRS, 12 patients were type 1, 19 patients were type 2, and 44 patients were CKD, respectively. And 67 patients with normal renal function were chosen for comparison. Result: The serum creatinine levels of the 3 groups with renal dysfunction at initial presentation had no significant differences. At the time of liver transplantation, the serum creatinine level of HRS type 2 group was better than CKD group (1.46mg/dL vs 2.32mg/dL, p = 0.002). There were no significant differences in creatinine level between HRS type 1 and 2, neither between HRS type 1 and CKD group. However, model for end-stage liver disease (MELD) score in HRS type 1 group was significantly higher than in CKD group. Two years later after LDLT, patients in CKD group had the highest serum creatinine level than in HRS type 1 and type 2 group (2.30mg/dL vs. 1.95mg/dL and 1.49mg/dL, p = 0.152 and 0.084, respectively). Conclusion: Despite higher pre-LT disease severity, patients with HRS still had slightly better renal outcome at two years after LDLT than patients with CKD.

The addition of simvastatin administration to cold storage solution of explanted whole liver grafts for facing ischemia/reperfusion injury in an area with a low rate of deceased donation: a monocentric randomized controlled double-blinded phase 2 study

BackgroundLiver transplantation is the best treatment for end-stage liver disease. The interruption of the blood supply to the donor liver during cold storage damages the liver, affecting how well the liver will function after transplant. The drug Simvastatin may help to protect donor livers against this damage and improve outcomes for transplant recipients. The aim of this study is to evaluate the benefits of treating the donor liver with Simvastatin compared with the standard transplant procedure.Patient and methodsWe propose a prospective, double-blinded, randomized phase 2 study of 2 parallel groups of eligible adult patients. We will compare 3-month, 6-month, and 12-month graft survival after LT, in order to identify a significant relation between the two homogenous groups of LT patients. The two groups only differ by the Simvastatin or placebo administration regimen while following the same procedure, with identical surgical instruments, and medical and nursing skilled staff. To reach these goals, we determined that we needed to recruit 106 patients. This sample size achieves 90% power to detect a difference of 14.6% between the two groups survival using a one-sided binomial test.DiscussionThis trial is designed to confirm the effectiveness of Simvastatin to protect healthy and steatotic livers undergoing cold storage and warm reperfusion before transplantation and to evaluate if the addition of Simvastatin translates into improved graft outcomes.Trial registrationISRCTN27083228.

Innate Immune Cells in Immune Tolerance After Liver Transplantation.

Currently, liver transplantation is the most effective treatment for end-stage liver disease. Immunosuppressive agents are required to be taken after the operations, which have significantly reduced rejection rates and improved the short-term (<1 year) survival rates. However, post-transplant complications related to the immunosuppressive therapy have led to the development of new protocols aimed at protecting renal function and preventing de novo cancer and dysmetabolic syndrome. Donor specific immune tolerance, which means the mature immune systems of recipients will not attack the grafts under the conditions without any immunosuppression therapies, is considered the optimal state after liver transplantation. There have been studies that have shown that some patients can reach this immune tolerance state after liver transplantation. The intrahepatic immune system is quite different from that in other solid organs, especially the innate immune system. It contains a variety of liver specific cells, such as liver-derived dendritic cells, Kupffer cells, liver sinusoidal endothelial cells, liver-derived natural killer (NK) cells, natural killer T (NKT) cells, and so on. Depending on their specific structures and functions, these intrahepatic innate immune cells play important roles in the development of intrahepatic immune tolerance. In this article, in order to have a deeper understanding of the tolerogenic functions of liver, we summarized the molecular mechanisms of immune tolerance induced by intrahepatic innate immune cells after liver transplantation.

Clinical use of an immune monitoring panel in liver transplant recipients: A prospective, observational study

Immunosuppressive therapy greatly contributed to making liver transplantation the standard treatment for end-stage liver diseases. However, it remains difficult to predict and measure the efficacy of pharmacological immunosuppression. Therefore, we used a panel of standardized, commonly available, biomarkers with the aim to describe their changes in the first 3 weeks after the transplant procedure and assess if they may help therapeutic drug monitoring in better tailoring the dose of the immunosuppressive drugs.We prospectively studied 72 consecutive patients from the day of liver transplant (post-operative day #0) until the post-operative day #21. Leukocytes, neutrophils, lymphocytes (CD4+, CD8+), natural killer cells, monocytes, immunoglobulins and tacrolimus serum levels were measured on peripheral blood (at day 0, 3, 7, 14, 21 after surgery). Patients who developed infections showed significantly higher CD64+ monocytes on post operative day #7. IgG levels were lower on post operative day #3 among patients who later developed infections. We also found that a sharp decrease in IgA from post operative day #0 to 3 (−226 mg/dL in the ROC curve analysis) strongly correlates with the onset of infections among HCV− patients. No specific markers of rejection emerged from the tested panel of markers. Our results show that some early changes in peripheral blood white cells and immunoglobulins may predict the onset of infections and may be useful in modulating the immunosuppressive therapy. However, a panel of commonly available, standardized biomarkers do not support in improving therapeutic drug monitoring ability to individualize immunosuppressive drugs dosing.

Factors influencing health self-management in adherence to care and treatment among the recipients of liver transplantation.

IntroductionLiver transplantation is the global treatment of end-stage liver diseases. Since the patients’ survival rate has been improved, the patient may experience reductions in physical, cognitive, and psychosocial functions after liver transplantation influencing their adherence to care and treatment. The transplant survival is complex and patients’ adherence to care and treatment should be considered when health care providers make decisions regarding treatment. This qualitative study aimed to explore factors influencing health self-management in adherence to care and treatment among the recipients of care and treatment.MethodsIn this study, 23 interview sessions were carried out with a total 18 patients, 2 family members and 3 transplantation team members from May to November 2017. The patients were selected using the purposive method from both genders, with a various age range and initial diseases leading to liver transplantation, and time passed from liver transplantation. A semi-structured interview guide was developed based on literature review and pilot interviews. The participants were asked to describe their experiences of self-management behaviors in adherence to treatment and care. The data were analyzed using a conventional content analysis method and managing via the MAXQDA-10 software.ResultsTwo themes were developed during data analysis as “self-regulation” and “self-care”. “Self-regulation” consisted of “intentionally changing”, “positively thinking”, “information seeking”, “problem-solving”, “past knowledge transferring”, and “self-controlling”. “Self-care” had three sub-themes “shift to independence”, “vigilance”, and “self-care support”.ConclusionThe participants perceived the health self-management in adherence to care as a set of factors related to “self-regulation” and “self-care” behaviors. “Self-regulation” is required to create a balance in life. Also, “self-care” efforts can help with maintaining and improving patients’ health.

Effects, status and problems of liver transplantation in the treatment of portal hypertension

Liver transplantation is the only effective treatment for portal hypertension (PHT) and end-stage liver disease. However, great therapeutic needs are far from satisfaction due to extreme shortage of donated livers. Good timing and indicator selection for PHT liver transplantation, and appropriate management of complications before or during on the waiting list, can avoid unnecessary liver transplantation and decrease the mortality rate of patients on waiting list. There are some particularities and issues worthy of attention. Understanding these particularities and handling these issues properly are extremely important to increase the success rate of PHT liver transplantation, enhance the recovery after surgery, and decrease the operative mortality. Key words: Portal hypertension; Indication; Liver transplantation; Waiting list

Impact of a Transplantation Critical Care Model on Short-Term Outcomes Following Liver Transplantation in High Acuity Patients: A Single-Center Experience

BackgroundOrthotopic liver transplantation (OLT) is the definitive treatment for end-stage liver disease (ESLD). Patients with high acuity ESLD are frequently denied life-saving OLT by transplant centers due to reported inferior outcomes. We sought to analyze the impact of a specialized transplant critical care model (TCCM) on patient access to OLT and survival outcomes in high acuity patients. MethodsFrom January 2009 to December 2016, 122 adults were wait-listed at our transplant center with laboratory Model for ESLD ≥35 or Status I. Outcomes in Era I (prior to TCCM) were compared to Era II (TCCM established October 1, 2012). ResultsEra II (TCCM) led to a significant increase in patients' access to OLT. Frequency and need to seek OLT at another center dropped 4-fold in Era II. Compared to Era I, the majority of patients in Era II required intensive care unit management (22% vs 83%, P < .01) and renal replacement therapy (11% vs 70%, P < .01) prior to OLT. Despite a higher acuity of illness in Era II, 1-year patient survival was comparable (89% Era I, 80% Era II, P = .35). ConclusionImplementation of a specialized TCCM expanded OLT access to high acuity patients, reduced the need to seek higher level of care elsewhere, and achieved excellent short-term post-transplant survival outcomes.

Expert consensus on diagnosis and treatment of end-stage liver disease complicated with infections

End-stage liver disease (ESLD) is a life threaten clinical syndrome with significantly increasing mortality when patients complicated with infections. For patients with ESLD, infections can induce or aggravate the occurrence of liver decompensation. In turn, infections are among the most common complications under, disease progression. There is lacking of working procedures for early diagnosis and appropriate management for patients of ESLD complicated with infections, neither guidelines nor consensus at home and abroad. This consensus assembled up-to-date knowledge and experience across Chinese colleagues, providing principles as well as working procedures for clinicians to diagnose and treat an ESLD patient complicated with infections.

Technical Aspects of Orthotopic Liver Transplantation—a Survey-Based Study Within the Eurotransplant, Swisstransplant, Scandiatransplant, and British Transplantation Society Networks

BackgroundOrthotopic liver transplantation (OLT) has emerged as the mainstay of treatment for end-stage liver disease. However, technical aspects of OLT are still subject of ongoing debate and are widely based on personal experience and local institutional protocols. MethodsAn international online survey was sent out to all liver transplant centers (n = 52) within the Eurotransplant, Swisstransplant, Scandiatransplant, and British Transplant Society networks. The survey sought information on center-specific OLT caseload, vascular and biliary reconstruction, graft reperfusion, intraoperative control of hemodynamics, and drain policies. ResultsForty-two centers gave a valid response (81%). Out of these, 50% reported piggy-back and 40.5% total caval replacement as their standard technique. While 48% of all centers generally do not apply veno-venous bypass (vvBP) or temporary portocaval shunt (PCS) during OLT, vvBP/PCS are routinely used in six centers (14%). Portal vein first reperfusion is used in 64%, followed by simultaneous (17%), and retrograde reperfusion (12%). End-to-end duct-to-duct anastomosis without biliary drain (67%) is the most frequently performed method of biliary reconstruction. No significant associations were found between the center caseload and the surgical approach used. The predominant part of the centers (88%) stated that techniques of OLT are not evidence-based and 98% would participate in multicenter clinical trials on these topics. ConclusionTechnical aspects of OLT vary widely among European centers. The extent to which center-specific variation of techniques affect transplant outcomes in Europe should be elucidated further in prospective multicenter trials.

Complete portal vein occlusion after cyanoacrylate sclerotherapy in biliary atresia treated by living donor liver transplantation with intraoperative portal vein stenting via segment 4 portal vein stump.

Living donor liver transplantation (LDLT) is a durable treatment for end-stage liver disease due to biliary atresia (BA) with excellent graft and patient survivals as shown in our previous study (1). Vascular complications are a major cause of graft failure in LDLT, particularly in children, where size disparity between donor and recipient vessels is often unavoidable.

The fate of hepatocyte cell line derived from a liver injury model with long-term in vitro passage

Orthotopic Liver Transplantation (OLT) is the therapy of choice for the treatment of end-stage liver disease, but the severe shortage of organ donors, complex and expensive surgical procedure and increased mortality of prospective organ recipient limit the use of OLT. To overcome this problem the technique of hepatocyte transplantation has been considered as an alternative to OLT. Hepatocyte transplantation is less invasive, cost effective cryo-preservable and can be distributed from single donor to multiple recipients. In this study we have established and characterize the hepatocyte cell line possessing the morphological and functional characteristics of hepatocytes from chemically injured liver. Hence we hypothesized that the hepatocyte cell line derived from liver injury can be used for hepatocyte transplantation. To induce the priming of hepatocyte, mice were fed with 3,5-diethoxycarbonyl-1,4-dihydro-collidine (DDC) diet for 3 weeks and hepatocytes were obtained by two step collagenase perfusion method, hepatocytes hence obtained was expended by >300 passages and tested for various hepatocyte specific functions. The cell line derived from liver injury model retains morphological and functional characteristics of hepatocytes in long-term in vitro culture. These cells transplanted to mice showed significant survival rate. The Hepatocyte cell line derived from liver injury model were used for hepatocyte transplantation and showed the significantly higher survival rate.

Feasibility of using marginal liver grafts in living donor liver transplantation.

Liver transplantation (LT) is one of the most effective treatments for end-stage liver disease caused by related risk factors when liver resection is contraindicated. Additionally, despite the decrease in the prevalence of hepatitis B virus (HBV) over the past two decades, the absolute number of HBsAg-positive people has increased, leading to an increase in HBV-related liver cirrhosis and hepatocellular carcinoma. Consequently, a large demand exists for LT. While the wait time for patients on the donor list is, to some degree, shorter due to the development of living donor liver transplantation (LDLT), there is still a shortage of liver grafts. Furthermore, recipients often suffer from emergent conditions, such as liver dysfunction or even hepatic encephalopathy, which can lead to a limited choice in grafts. To expand the pool of available liver grafts, one option is the use of organs that were previously considered “unusable” by many, which are often labeled “marginal” organs. Many previous studies have reported on the possibilities of using marginal grafts in orthotopic LT; however, there is still a lack of discussion on this topic, especially regarding the feasibility of using marginal grafts in LDLT. Therefore, the present review aimed to summarize the feasibility of using marginal liver grafts for LDLT and discuss the possibility of expanding the application of these grafts.

Assessment of the hepatocytic differentiation ability of human skin-derived ABCB5+ stem cells

The continuously decreasing willingness for liver donation aggravates treatment of end-stage liver diseases requiring organ transplantation as the only curative strategy. Cell therapy approaches using human hepatocytes or stem cell-derived hepatocyte-like cells may be a therapeutic option out of this dilemma. ABCB5-positive mesenchymal stromal cells from human skin featured promising potential to treat immune-mediated diseases. Since most of chronic liver diseases involve exaggerating immune mechanisms, it was the aim to demonstrate in this study, whether ABCB5+ stem cells may serve as a resource to generate hepatocytic cells for application in liver cell transplantation. Using an established single-step protocol, which had been successfully applied to differentiate mesenchymal stromal cells into the hepatocytic lineage, ABCB5+ skin-derived stem cells did not gain significant characteristics of hepatocytes. Yet, upon culture in hepatocytic differentiation medium, ABCB5+ stem cells secreted immunomodulatory and anti-fibrotic factors as well as proteins, which may prompt hepatic morphogenesis besides others. Hepatic transplantation of ABCB5+ stem cells, which had been prior cultured in hepatocytic differentiation medium, did not cause any obvious deterioration of liver architecture suggesting their safe application. Thus, human ABCB5+ skin-derived stem cells secreted putative hepatotropic factors after culture in hepatocytic differentiation medium.

Research progress on machine perfusion to reduce the incidence of non-anastomotic biliary stricture after liver transplantation

Liver transplantation has become the most effective treatment for end-stage liver diseases. Due to the shor-tage of organ, more and more extended criteria donors (ECD) grafts had been used, which expand the liver pool. However, a series of complications post transplantation were caused by ischemia, hypoxia, steatosis and so on. The non-anastomotic biliary strictures after liver transplantation is one of the major complications when the ECD donors was be used in clinic. The study on the protective effect of machine perfusion on liver donors is too numerous to list, and existing studies have found that MP can reduce the incidence of NAS after liver transplantation. This review provides an overview of the pathogenesis of NAS and the reduction incidence of NAS by MP. Key words: Live transplantation; Donor; Machine perfusion; Non-anastomotic biliary strictures; Complication

The dawn of liver perfusion machines.

Despite high demand, a severe shortage of suitable allografts limits the use of liver transplantation for the treatment of end-stage liver disease. The transplant community is turning to the utilization of high-risk grafts to fill the void. This review summarizes the reemergence of ex-vivo machine perfusion for liver graft preservation, including results of recent clinical trials and its specific role for reconditioning DCD, steatotic and elderly grafts. Several phase-1 clinical trials demonstrate the safety and feasibility of machine perfusion for liver graft preservation. Machine perfusion has several advantages compared with static cold storage and may provide superior transplantation outcomes, particularly for marginal grafts. Ongoing multicenter trials aim to confirm the results of preclinical and pilot studies and establish the clinical utility of ex-vivo liver machine perfusion. Mounting evidence supports the benefits of machine perfusion for preservation of liver grafts. Thus, machine perfusion is a promising strategy to expand the donor pool by reconditioning and assessing viability of DCD, elderly and steatotic grafts during the preservation period. Additionally, machine perfusion will serve as a platform to facilitate graft intervention and modification to further optimize marginal grafts.

Heterogenic transplantation of bone marrow-derived rhesus macaque mesenchymal stem cells ameliorates liver fibrosis induced by carbon tetrachloride in mouse.

Liver fibrosis is a disease that causes high morbidity and has become a major health problem. Liver fibrosis can lead to the end stage of liver diseases (livercirrhosisand hepatocellularcarcinoma). Currently, liver transplantation is the only effective treatment for end-stage liver disease. However, the shortage of organ donors, high cost of medical surgery, immunological rejection and transplantation complications severely hamper liver transplantation therapy. Mesenchymal stem cells (MSCs) have been regarded as promising cells for clinical applications in stem cell therapy in the treatment of liver diseases due to their unique multipotent differentiation capacity, immunoregulation and paracrine effects. Although liver fibrosis improvements by MSC transplantation in preclinical experiments as well as clinical trials have been reported, the in vivo fate of MSCs after transportation and their therapeutic mechanisms remain unclear. In this present study, we isolated MSCs from the bone marrow of rhesus macaques. The cells exhibited typical MSC markers and could differentiate into chondrocytes, osteocytes, and adipocytes, which were not affected by labeling with enhanced green fluorescent protein (EGFP). The harvested MSCs respond to interferon-γ stimulation and have the ability to inhibit lymphocyte proliferation in vitro. EGFP-labeled MSCs (1 × 106 cells) were transplanted into mice with carbon tetrachloride-induced liver fibrosis via tail vein injection. The ability of the heterogenic MSC infusion to ameliorate liver fibrosis in mice was evaluated by a blood plasma chemistry index, pathological examination and liver fibrosis-associated gene expression. Additionally, a small number of MSCs that homed and engrafted in the mouse liver tissues were evaluated by immunofluorescence analysis. Our results showed that the transplantation of heterogenic MSCs derived from monkey bone marrow can be used to treat liver fibrosis in the mouse model and that the paracrine effects of MSCs may play an important role in the improvement of liver fibrosis.

A predictive model for acute allograft rejection of liver transplantation

Orthotopic liver transplantation (OLT) has become an increasingly used treatment for end-stage liver disease. However, acute allograft rejection is still a problem in postoperative care of liver transplantation with immunosuppressive therapy and it can lead to allograft damage and harm the survival of liver transplantation patient. This work proposes to use data-driven approach to build a predictive model for acute rejection. We consider not only prediction accuracy, but also interpretability of the prediction outcome in building the predictive model, so that the medical staffs can identify how the prediction is induced from data. The experiments use the real data provided by liver transplantation intensive care unit (ICU) of Chang Gung Memorial Hospital, Taiwan. In this work, the data is from a medical center, in which the patient data ranges from 2004 to 2013, and the number of data records is approximately 2 million. To the best of our knowledge, this is the first work using a large-scale database to focus on liver transplantation and generate interpretable rules that could be used by medical staffs. We compare with several methods, including SVM, ANN and random forest, and the experimental results indicate that the proposed method is comparative, and provides interpretable results. Central to the proposed method is to consider interpretability, and the goal is to provide interpretable results for the medical staffs to make decisions. The proposed transformation algorithms belong to data-driven approaches, so they could be applied to other intelligent or expert systems. Moreover, the outcomes are presented in rule format, which could be used by medical staffs and other expert systems.