Post Living Donor Liver Transplantation Small-for-size Syndrome: Definitions, Timelines, Biochemical, and Clinical Factors for Diagnosis: Guidelines From the ILTS-iLDLT-LTSI Consensus Conference.

BACKGROUND: When a partial liver graft is unable to meet the demands of the recipient, a clinical phenomenon, small-for-size syndrome (SFSS), may ensue. Clear definition, diagnosis, and management are needed to optimize transplant outcomes. METHODS: A Consensus Scientific committee (106 members from 21 countries) performed an extensive literature review on specific aspects of SFSS, recommendations underwent blinded review by an independent panel, and discussion/voting on the recommendations occurred at the Consensus Conference. RESULTS: The ideal graft-to-recipient weight ratio of ≥0.8% (or graft volume standard liver volume ratio of ≥40%) is recommended. It is also recommended to measure portal pressure or portal blood flow during living donor liver transplantation and maintain a postreperfusion portal pressure of <15 mm Hg and/or portal blood flow of <250 mL/min/100 g graft weight to optimize outcomes. The typical time point to diagnose SFSS is the postoperative day 7 to facilitate treatment and intervention. An objective 3-grade stratification of severity for protocolized management of SFSS is proposed. CONCLUSIONS: The proposed grading system based on clinical and biochemical factors will help clinicians in the early identification of patients at risk of developing SFSS and institute timely therapeutic measures. The validity of this newly created grading system should be evaluated in future prospective studies.

Detection of DNA methylated microRNAs in hepatocellular carcinoma.

Irregular methylation, including DNA hypomethylation and/or promoter gene CpG hypermethylation, is involved in the pathogenesis of several solid tumors, including liver cancer. miRNAs are small, endogenous, noncoding RNAs that serve as posttranscriptional regulators of gene expression. Previous research has focused on identifying the factors that regulate the expression of miRNAs in hepatic carcinogenesis. The factors that regulate miRNA expression are not clear; in particular, the role of DNA methylation, an epigenetic regulatory factor that controls miRNA transcription, has not been clarified. The goal of this study is to explore our understanding of the mechanism by which HCC may develop and progress through identification of the role of epigenetically regulated miRNAs influences in the liver carcinogenesis. The current study included 60 patients who were well diagnosed as HCC patients. 60 patients who suffer from liver cirrhosis were also enrolled in the current study and 30 healthy control subjects who serve as control group. All patients will be subjected to: full clinical assessment, abdominal ultrasound, Blood sample will be withdrawn from every patients for both biochemical and serum detection of microRNAs (191-203 -335) by real time PCR. We found that all studied microRNAs were down regulated among HCC patients when compared to cirrhotic patients and controls (p value: 0.005, 0.005 and 0.001 for microRNAs 191, 203 and 335 respectively). Moreover, these microRNAs can discriminate cases of HCC from risky cirrhotic patients. We can conclude that downregulated microRNAs among HCC cases proposed a pattern to explain the role of DNA methylation on miRNA and gene expression in HCC.

Management of Patients Who Receive an Organ Transplant Abroad and Return Home for Follow-up Care: Recommendations From the Declaration of Istanbul Custodian Group.

Eradicating transplant tourism depends on complex solutions that include efforts to progress towards self-sufficiency in transplantation. Meanwhile, professionals and authorities are faced with medical, legal, and ethical problems raised by patients who return home after receiving an organ transplant abroad, particularly when the organ has been obtained through illegitimate means. In 2016, the Declaration of Istanbul Custodian Group convened an international, multidisciplinary workshop in Madrid, Spain, to address these challenges and provide recommendations for the management of these patients, which are presented in this paper. The core recommendations are grounded in the belief that principles of transparency, traceability, and continuity of care applied to patients who receive an organ domestically should also apply to patients who receive an organ abroad. Governments and professionals are urged to ensure that, upon return, patients are promptly referred to a transplant center for evaluation and care, not cover the costs of transplants resulting from organ or human trafficking, register standardized information at official registries on patients who travel for transplantation, promote international exchange of data for traceability, and develop a framework for the notification of identified or suspected cases of transnational transplant-related crimes by health professionals to law enforcement agencies.

Outcome of Living-Donor Liver Transplant for Hepatocellular Carcinoma: 15-Year Single-Center Experience in Egypt.

OBJECTIVES: Liver transplant performed for hepatocellular carcinoma must adhere to criteria for the size and number of focal hepatic lesions to lower the incidence of recurrence and achieve survival rates comparable to patients transplanted for other indications. Since the Milan criteria were established in 1996, there have been many less restrictive criteria yielding similar results. Our aim was to identify the prognostic factors for patient survival and for recurrence of hepatocellular carcinoma for patients within and beyond the Milan criteria. MATERIALS AND METHODS: This retrospective and prospective analysis was conducted in 60 adult patients who underwent right lobe living-donor liver transplant for cirrhosis complicated by hepatocellular carcinoma at Dar Al Fouad Hospital, 6th of October City, Egypt, between August 2001 and June 2012. The median follow-up was 39.5 months. RESULTS: Overall 1-, 3-, and 5-year survival rates were 98.3%, 93.5%, and 71.4%. Overall disease-free survival rates at 1, 3, and 5 years were 96.6%, 93.5%, and 64.2%. There was no statistically significant difference in overall survival time between patients within and beyond the Milan criteria. Factors affecting recurrence were the tumor grade, lobar distribution, size of the largest nodule, and the total tumor burden in the explanted liver. Recurrence adversely affected survival. CONCLUSIONS: Using our criteria of a single tumor ≤ 6 cm, or 2 to 3 tumors with the largest ≤ 4.5 cm, or 4 to 5 tumors with the largest ≤ 3 cm and total tumor size ≤ 8 cm resulted in overall survival comparable to patients within the Milan criteria.

Relationship Between Serum microRNA155 and Telomerase Expression in Hepatocellular Carcinoma.

BACKGROUND AND AIMS: Activation of telomerase reverse transcriptase (hTERT) has a role in liver carcinogenesis where telomerase is normally suppressed in most human somatic tissues after birth. In the current study we aimed to detect the significance of hTERT mRNA in early detection of hepatocellular carcinoma (HCC) and to determine the relationship between serum microRNA155 and telomerase expression. METHODS: Serum and liver tissue samples were collected from 40 patients (17 samples from patients with liver cirrhosis and 23 samples from patients with HCC) and 12 blood samples from healthy subjects were collected. Serum miRNA155 levels and blood and tissue hTERT mRNA were detected by real-time quantitative reverse-transcriptase PCR (RT-qPCR) among liver cirrhosis and HCC patients. Moreover, miR-155, blood and tissue hTERT levels were analyzed in relation to clinical and pathological features. RESULTS: Calculated expression of miRNA155 revealed that relative quantity (RQ) miR 155 was overexpressed in sera of HCC patients when compared to patients with liver cirrhosis and controls (p <0.0001). The median values of serum telomerase were significantly increased among HCC patients than in patients with liver cirrhosis and controls (p = 0.04). Moreover, tissue expression of telomerase was significantly higher in malignant tissue more than adjacent nonmalignant tissue among HCC patients (p = 0.02). It was also found that tissue expression of telomerase was significantly decreased in tissue of liver cirrhosis patients (p = 0.03). Interestingly, we found that blood telomerase was directly correlated with serum miRNA155 (p = 0.003). CONCLUSIONS: Both mir 155 and telomerase may have a role in development of HCC and mir 155 could regulate telomerase expression during liver carcinogenesis.

The potential role of miRNAs 21 and 199-a in early diagnosis of hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is regarded as one of the most common malignancies and among the leading causes of cancer death among the whole world. The most urgent needs are to find sensitive markers for early diagnosis for HCC. MicroRNAs (miRNAs) are reported as a group of small non-coding RNAs that can function as endogenous RNA interference to regulate expression of the targeted genes. This study was conducted to detect the serum and tissue expression of miR 21 and miR 199-a to be applied as early detectors for HCC. METHODS: A total of 40 serum and tissue samples (17 samples from chronic hepatitis and 23 samples from HCC patients) were collected. The levels of the two mature miRNAs (miR-21 and miR-199-a) were detected by real time quantitative reverse-transcriptase PCR (RT-qPCR) in sera and tissues of chronic hepatitis and HCC patients. Besides, miR-21 and miR-199-a levels in relation to clinical and pathological factors were explored. RESULTS: We found that the expression of serum miR-21 was distinctly increased in HCC compared with chronic hepatitis (P<0.001). miR 199-a was distinctly decreased in HCC compared with chronic hepatitis (P<0.001). In addition, median of miR 21 was increased in malignant when compared to adjacent non-malignant tissues without significant differences (P=0.191) while miR 199-a was significantly decreased in malignant when compared to adjacent nonmalignant tissues (P<0.001). ROC analysis showed that miR-21 and miR-199-a might be potential biomarkers for HCC. CONCLUSIONS: In conclusion, the expression of miR-21 was significantly up-regulated and miR-199-a was significantly down regulated in serum of patients with HCC. Due to their reasonable sensitivity and specificity for disease progression, miR-21 and miR-199-a could be used as potential circulating biomarkers for HCC.

Relation between microRNAs and Apoptosis in Hepatocellular Carcinoma.

AIM: To determine the relation between serum microRNAs and apoptotic markers as regards development of HCC to understand the underlying mechanism of HCV related hepatocarcinogenesis. PATIENTS AND METHODS: A total of 65 serum samples (25 samples from controls, 20 samples from hepatitis and 20 samples from HCC patients) were collected for miRNAs (mir 21, mir 199-a, and mir 155) detection. Human Programmed cell death protein-4 (PDCD-4) and Human Cytochrome-C (CYT-C) were determined. RESULTS: miRNAs 21 and 155 were over expressed in sera of patients with HCC compared to patients with chronic hepatitis (p < 0.0001). While serum means values of miR 199a was significantly decreased among HCC group patients when compared to patients with chronic hepatitis (p < 0.0001). The serum levels of PCDC4 and CYTC were increased in patients with HCC when compared to chronic hepatitis patients. They were also increased in patients with chronic hepatitis when compared to controls (p < 0.05, significant). There was direct correlations between apoptotic markers and oncomirs miRNAs 21 and 155 while apoptotic markers were inversely correlated with miRNA 199-a. CONCLUSION: Both microRNAs and apoptotic markers have roles in HCC pathogenesis. It seems that oncogenic microRNAs induce liver carcinogenesis in HCV patients irrespective of suppression of apoptosis.

Major vascular complications in living-donor liver transplant recipients: single center team experience.

OBJECTIVES: Vascular problems such as thrombosis and stenosis of the hepatic artery, portal vein, and hepatic vein are serious complications after living-donor liver transplant and can cause increased morbidity, graft loss, and patient death. The aim of this study was to assess the incidence, treatment, and outcome of recipient vascular complications after living-donor liver transplant in a single Egyptian center. MATERIALS AND METHODS: Between November 2006 and March 2014, we performed 226 living-donor liver transplants for 225 patients at Dar Al Fouad Hospital in 6th of October City in Egypt. Review of all patients with vascular complications was performed. RESULTS: In 20 of 225 recipients (8.9%), there were vascular complications that occurred from day 0 to 14 (mean, 5.6 ± 3.4 d). Complications included isolated hepatic artery thrombosis in 7 patients (35%), isolated portal vein thrombosis in 6 patients (30%), isolated hepatic vein stenosis in 3 patients (15%), and isolated hepatic artery stenosis in 1 patient (5%). Combined portal vein thrombosis and hepatic artery thrombosis occurred in 2 patients (10%), and combined portal vein thrombosis and hepatic vein stenosis occurred in 1 patient (5%). Complications were identified with duplex ultrasonography and confirmed with computed tomographic angiography and direct angiography when needed. Multidisciplinary treatment included percutaneous transarterial or transvenous thrombolysis with or without balloon dilation and stenting, open surgical exploration with thrombectomy, vascular revision, or retransplant. There were no intraoperative deaths, but mortality occurred in 15 of 20 patients (75%). Survival ranged from 6 days to 70 months. Preoperative portal vein thrombosis was observed in 3 of 7 patients (43%) who had postoperative portal vein thrombosis. CONCLUSIONS: Major vascular complications in living-donor liver transplant recipients have poor outcome despite early detection and prompt multidisciplinary intervention. Preoperative recipient portal vein thrombosis is a risk factor for postoperative portal vein thrombosis.

Synthetic graft for reconstruction of middle hepatic vein tributaries in living-donor liver transplant.

OBJECTIVES: In middle hepatic vein dominant livers, the anterior segment of the right lobe of the liver (segments V and VIII) drains mainly into the middle hepatic vein. In these donors, when right lobe grafts are procured without the middle hepatic vein, the graft may harbor large segment V and/or VIII veins that need reconstruction to avoid graft congestion and subsequent graft dysfunction. Draining these middle hepatic vein tributaries using autologous or cryopreserved vessels is a solution, despite the possible difficulties of their preparation. However, these vessels are not always available. Our objective was to evaluate the effectiveness and safety of using a synthetic vascular graft. MATERIALS AND METHODS: Between January 2012 and October 2013, eighteen adult recipients underwent living-donor liver transplant using right lobe grafts without the middle hepatic vein at Dar Al Fouad Hospital, 6th of October City, Egypt. All grafts had a large tributary of the middle hepatic vein. Eight-mm ringed expanded polytetrafluoroethylene vascular grafts were used to drain 15 segment V vein tributaries and 3 segment VIII vein tributaries directly to the inferior vena cava. Follow-up was done using duplex ultrasound to evaluate the patency of the vascular graft and the liver congestion and the liver function tests including liver enzymes. RESULTS: Intraoperative Duplex ultrasound confirmed patency and absent segmental congestion in all 18 recipients. The vascular graft patency was 17/18 at 1 week (94.4%) and 15/18 at 1 month (83.3%). No recipients developed graft infection at 1 month. CONCLUSIONS: Synthetic vascular expanded polytetrafluoroethylene grafts could be used effectively and safely in middle hepatic vein tributary reconstruction to overcome the unavailability of autologous or cryopreserved vessel grafts or just to avoid the additional burden of recovering autologous grafts thus simplifying the procedure.

The possible role of Cytochrome c and programmed cell death protein 4 (PDCD4) on pathogenesis of hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is regarded as one of the most common malignancies and among the leading causes of cancer death in the whole world. Apoptosis is a fundamental process controlling cell death and plays a critical role in normal development of multicellular organisms. When abnormalities occur in apoptosis, a variety of diseases are caused, including cancer. The aim of the current study was to determine the serum expression of Cytochrome c and PDCD4 among patients with hepatocellular carcinoma and chronic hepatitis. PATIENTS AND METHODS: A total of 40 serum and tissue samples (17 samples from chronic hepatitis and 23 samples from HCC patients) were collected. Apoptotic markers in serum were carried out using the quantitative sandwich enzyme immunoassay technique. RESULTS: We found that serum levels of PCDC4 and Cytochrome c were increased in patients with HCC when compared to chronic hepatitis patients. They were also increased in patients with chronic hepatitis when compared to controls (p < 0.05, significant). Analyzing the impact of HCC characters on serum values of PDCD4 and Cytochrome c revealed that the mean values of both PDCD4 and Cytochrome c are significantly higher in cases with single lesion of HCC (p < 0.05, significant). Right lobe location of HCC lesions has the highest mean values of PDCD4 (p < 0.05, significant). As regards grade of differentiation, grade П has higher mean values of Cytochrome c (p < 0.05, significant). CONCLUSION: Serum levels of Cytochrome c and PDCD4 are increased in patients with cirrhosis and hepatocellular carcinoma and could be used as diagnostic aid for HCC.

Modification and implementation of NCCN guidelines on hepatobiliary cancers in the Middle East and North Africa region.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) on Hepatobiliary Cancers address hepatocellular cancer, cancer of the gallbladder, extrahepatic cholangiocarcinoma, and intrahepatic cholangiocarcinoma. Hepatocellular cancer incidence is higher in the Middle East and North Africa (MENA) region than in the West, and hepatitis B and C infections are particularly important; the incidence of gallbladder cancer is among the highest in the world. Regional problems include delay in diagnosis, shortage of trained staff, and insufficient liver transplant facilities. Furthermore, costs associated with molecular and targeted therapies are an increasing concern. A committee was formed, consisting of leading specialists and decision-makers from the region, with each member being tasked to suggest modifications to the existing guidelines based on review of the literature and consultations with local colleagues. This committee met as a group, and then continued to discuss and debate the suggested modifications electronically. Several recommendations were finalized after vigorous debate. The final approved recommendations were then presented in April 2009 to the chair of the NCCN Hepatobiliary Cancers Panel for onward transmission and approval. This project represents an effort to modify and implement the NCCN Guidelines on Hepatobiliary Cancers in the MENA region, while taking into consideration local differences in patient and disease characteristics. The hope is that this will form the basis of future local, regional, and international cooperation in guideline development and research.

Crucial issues of hepatic artery reconstruction in living donor liver transplantation: our experience with 133 cases at Dar El-Fouad Hospital, Egypt.

Hepatic artery (HA) reconstruction is a crucial step in living donor liver transplantation (LDLT). However, many important aspects specific to this challenging step are still inadequately documented. From August 2001 through March 2007, we performed a total of 133 cases of LDLT at Dar El-Fouad Hospital. The magnifying loupe was used for performing microanastomoses in the first 31 cases, and the operating microscope was used for 98 cases. There were 128 adult and five pediatric patients. One hundred twenty-five patients received right lobe grafts, and seven patients received left lobe grafts. One patient died intraoperatively and was excluded from analysis. Arterial complications occurred in four patients of the first group (4/30, 13%) in the form of early thrombosis. One patient underwent successful interventional thromboembolectomy, two patients underwent surgical reexploration with revision of anastomoses; these three patients survived. The fourth patient died from fulminant liver failure. Regarding the second group, all arterial anastomoses were patent after reconstruction. Signal problems occurred in the form of intraoperative intermittent flow and postoperative no diastole phenomenon. Our overall arterial complication rate was 4.5%; however, we lost only one patient due to HA thrombosis (0.8%). Microsurgical reconstruction of the HA carries its own challenges. The use of operating microscope reduces the risk of complications, and aggressive interference including salvage surgery maximizes the success of HA reconstruction.

Quality of life of Egyptian donors after living-related liver transplantation.

BACKGROUND AND STUDY AIM: Quality of life after liver donation must remain a primary outcome measure when we consider the utility of living donor liver transplants. In making clinical decisions on the use of transplantation for chronic liver diseases, consideration should be given to the key factors likely to affect subsequent health related quality of life. It would be beneficial for donors, if factors predicting good quality of life are identified. The aim of this study was to assess the health related quality of life changes experienced by donors following living related liver transplantation using the Short Form 36 (SF-36) questionnaire. PATIENTS AND METHODS: Between August 2001 and December 2006, 125 adults received liver grafts from living donors at Dar Al-Fouad Hospital, Cairo, Egypt. The SF-36v2 questionnaire was applied to 30 donors after at least 6 months following donation and maximally 4 years after donation (mean±STD:3.28±1.56 years). Furthermore, 30 healthy volunteers were taken as a control group. RESULTS: None of the donors required re-surgery and no deaths were reported. Only 4 (13.3%) donors experienced minor complications, which did not affect their quality of life and had no long term effects. No significant difference was found between donors and control group when means of the Physical and Mental Component Summary were compared. The physical functioning domain was the only domain of health which showed a statistically significant difference between both groups. CONCLUSION: Health related quality of life of donors was not compromised after full recovery. All donors had good recovery and returned to regular activities within 2-4 months post donation.

Recurrence of hepatitis C virus (genotype 4) infection after living-donor liver transplant in Egyptian patients.

OBJECTIVES: The recurrence of hepatitis C virus infection after liver transplant is common and may endanger both graft and patient survival. We investigated the frequency and outcome of and risk factors for the recurrence of that virus after living-donor liver transplant in hepatitis C virus positive recipients. MATERIALS AND METHODS: Seventy-four adult hepatitis C virus positive subjects were monitored for 36 months after living-donor liver transplant and demographic and laboratory data for the recipients and donors were evaluated. Recurrent hepatitis C virus infection was diagnosed on the basis of viral replication revealed by polymerase chain reaction after transplant, elevated levels of transaminases, and the results of liver biopsy. RESULTS: Hepatitis C virus recurrence was identified in 31.1% of the patients studied. Histopathologic recurrence was mild, and 91% of the subjects had a fibrosis score of < or = F2. No recipient exhibited cirrhosis or clinical decompensation during followup. Recurrent hepatitis C virus infection was associated with pretransplant and posttransplant viral load and antibody positive to hepatitis B core antigen. No other risk factors (sex, donor or recipient age, pretransplant Child-Pugh or Model for End-Stage Liver Disease scores, immunosuppressive drug therapy, and treatment with pulse steroids) were significantly correlated with the frequency of hepatitis C virus recurrence, the grade of the histologic activity index, or the stage of fibrosis. CONCLUSIONS: In living-donor liver transplant recipients, patient and graft survival rates associated with hepatitis C virus (genotype 4) related cirrhosis were comparable to those in deceased-donor liver transplant recipients reported in the literature. Recurrent infection with hepatitic C virus after living-donor liver transplant was mild. After transplant, a higher viral load and the presence of antibody to hepatitis B core antigen could be risk factors for hepatitis C virus recurrence. Long-term follow-up in a large number of patients is required.

Peginterferon alfa-2b therapy in acute hepatitis C: impact of onset of therapy on sustained virologic response.

BACKGROUND & AIMS: Pegylated interferon therapy has not been adequately evaluated in acute hepatitis C virus (HCV) infection. This randomized trial assessed the efficacy, safety, and timing of pegylated interferon alfa-2b for treatment of acute hepatitis C. METHODS: One hundred seventy-five patients acutely infected with HCV were screened. Patients whose infection did not spontaneously resolve by week 8 were randomized to once weekly peginterferon alfa-2b monotherapy (1.5 microg/kg per week) started at weeks 8, 12, or 20 for a duration of 12 weeks. The primary endpoint was undetectable HCV RNA 24 weeks after the end of treatment (sustained virologic response [SVR]). All patients were followed for 48 weeks after cessation of therapy. RESULTS: One hundred twenty-nine subjects started treatment at week 8 (group A, n = 43), week 12 (group B, n = 43), or week 20 (group C, n = 43). By using an intent-to-treat analysis, the overall SVR rate was 87%. The SVR rates were 95%, 92%, and 76% with treatment onset at 8, 12, and 20 weeks, respectively. Overall, SVR rates were better for patients infected with genotypes 2, 3, and 4 than those infected with genotype 1. Earlier initiation of therapy improved SVR rates for patients infected with genotype 1 with high viral load. Peginterferon alfa-2b was well tolerated. Subjects with SVR maintained undetectable HCV RNA 48 weeks after therapy. CONCLUSIONS: Peginterferon alfa-2b monotherapy in acute hepatitis C induces high sustained virologic response rates, prevents chronic evolution, and is well tolerated. Initiation of treatment at week 8 or 12 results in higher sustained virologic rates than initiation at week 20.