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Abdominal closure is a complex surgical problem in intestinal transplant recipients with loss of abdominal domain, as graft exposure results in profound morbidity. Although intraoperative coverage techniques have been described, this is the first report of preoperative abdominal wall augmentation using tissue expanders in patients awaiting intestinal transplantation. We report on five patients who received a total of twelve tissue expanders as a means to increase abdominal surface area. Each patient had a compromised abdominal wall (multiple prior operations, enterocutaneous fistulae, subcutaneous abscesses, stomas) with loss of domain and was identified as high risk for an open abdomen post-transplant. Cross-sectional imaging and dimensional analysis were performed to quantify the effect of the expanders on total abdominal and intraperitoneal cavity volumes. The overall mean increase in total abdominal volume was 958 cm(3) with a mean expander volume of 896.5 cc. Two expanders were removed in the first patient due to infection, but after protocol modification, there were no further infections. Three patients eventually underwent small bowel transplantation with complete graft coverage. In our preliminary experience, abdominal tissue expander placement is a safe, feasible, and well-tolerated method to increase subcutaneous domain and facilitate graft coverage in patients undergoing intestinal transplantation.

Background Locoregional therapies (LRTs) are treatments to achieve local control of hepatocellular carcinoma (HCC). Correlation between radiologic response to LRT and degree of induced tumor necrosis is not well understood. The aim of this study was to evaluate different levels of radiologic response after pre-liver transplant (LT) LRT and its correlation with percentage of tumor necrosis on explanted histopathology. Methods Institutional Review Board approved LT database was queried for treated HCC in patients undergoing LT. Radiologic response was evaluated to predict tumor necrosis in the explanted liver. Tumor response was evaluated 1 to 3 months after LRT with computed tomography or MRI via Response Evaluation Criteria in Solid Tumors (RECIST), and European Association for the Study of the Liver (EASL) guidelines. LRT was repeated as needed until time of LT. Histological tumor necrosis was graded as complete (100%), partial (50%–99%), or poor ( Results Between 2002 and 2011, 128 patients (97 men and 31 women) received pre-LT LRT including transarterial therapy (93), radiofrequency ablation (20), or combination of both (15). The mean age of the patients was 58±9 years. Their mean follow-up was 35±27 months. The median waitlist time was 55 days. One hundred (78%) patients had HCC within the Milan criteria at the initial radiologic diagnosis. Nineteen (15%) of the patients had complete tumor necrosis on histopathology analysis. Fifty (39%) of the patients exhibited partial necrosis, 52 (41%) showed poor or no necrosis and 7 (5%) showed progressive disease. The overall pre-LT radiologic staging was correlated with explant pathology in 73 (57%) of the patients. Underestimated tumor stage was noted in 49 (38%) patients, and overestimated tumor stage in 6 (5%) patients. The post-LT 3-year overall survival and disease free survival were 82% and 80%, and the rates for complete and partial tumor necrosis were 100% vs 78% ( P =0.02) and 100% vs 75% ( P =0.03), respectively. Conclusions In the current era, interpretation of radiologic response after LRT for HCC does not correlate accurately with histologic tumor necrosis. Total tumor necrosis is the goal of LRT; therefore, evolution in its performance is needed. Similarly, ways to predict therapy induced tumor necrosis via radiological investigation need to be improved.

Background and Aim Liver transplantation is a potential cure for liver damage from Wilson’s disease but the course of neuropsychiatric manifestations after transplantation remains undetermined. Material and methods In this study, data on all patients who’d received a liver transplant for Wilson’s disease at the Shiraz Organ Transplantation Center between December 2000 and March 2014 were reviewed and compared to data on a control group who’d received a liver transplant over the same period but due to other causes. Results Out of 2198 patients who’d received a liver transplant in the period; 107 patients were diagnosed with Wilson’s disease (21 with fulminant hepatic failure); age of patient ranged from 5 to 59 years; 56.07% of patients in this series had some type of neuropsychiatric manifestation before transplantation, of which 66.67% showed improvement after the procedure. 18 patients had aggravation of neuropsychiatric symptoms after transplantation. These neuropsychiatric symptoms were mostly for anxiety, tremor and depression but there were four cases of new onset dysarthria, rigidity and ataxia in various combinations. Survival rates of 1-month, 1-year, and 5-years for patients with Wilson’s disease were 88%, 86%, 82%, respectively, evaluations were not statistically different from that of the control group. Conclusions Liver transplantation showed good long-term results in patients with Wilson’s disease, even in those presenting fulminant hepatic failure. Neuropsychiatric manifestations normally show improvement after transplantation but in some cases new onset of manifestations occurred after successful liver transplantation.

Introduction: Hepatitis C is the leading cause of liver disease in individuals with hemophilia (H). HIV co-infection in 80% accelerates HCV disease progression. Although antiretroviral therapy improves HIV survival and slows HCV progression, some ultimately require transplantation. In contrast to non-hemophilic (NH) risk groups, H have 1) longer duration HCV infection with HCV acquisition via clotting factor in the first year of life; and 2) greater bleeding risk due to factor VIII (IX) deficiency in the setting of thrombocytopenia in end-stage liver disease. These risks are important as 1) duration of HCV infection is a significant predictor of liver disease progression; and 2) increased bleeding risk, including gastrointestinal bleeding, increases post-transplant mortality. Several studies have shown that, while post-transplant survival is similar, pre-transplant survival is shorter in HIV/HCV+ H than NH candidates. These studies were small, limiting analysis for predictors of pre-transplant survival. Methods: We conducted a retrospective observational study utilizing United Network for Organ Sharing (UNOS) national transplant registry data, comparing HCV+ H and HCV+ NH candidates. A 7-item case report form was completed on each subject by eight respective transplant centers including 1) hemophilia status (hemophilia A, ICD 286.0; hemophilia B, ICD 286.1); 2) hepatocellular carcinoma status; 3) HIV status; 4) CD4+ count; 5) HIV RNA PCR; 6) HCV RNA PCR; and 7) platelet count, the latter four variables at listing and at transplantation. We performed univariate proportional hazards models for pre-transplant mortality within 90 days of listing, including group and baseline factors. Variables with p Results: We identified 2,502 HCV+ liver transplant candidates, including 144 (5.8%) with HIV infection, 36 (1.4%) with hemophilia, and 1,213 (48.5%) undergoing liver transplantation from eight U.S. university-based transplant centers for the period January 1, 2004 to December 31, 2010. Other than male predominance, 100% vs. 78.0%, and younger age, 41 vs. 48 years, both p Conclusion: This observational study confirms MELD is a significant predictor not only of post-transplant survival, but also pre-transplant survival. Despite longer duration HCV infection and greater bleeding risk, there was no significant difference in pre-transplant survival between HIV+ H and NH, likely due to small numbers of hemophilia candidataes missed by retrospective ICD classification. We suggest implementing ICD classification for H in the UNOS system, to enable robust data collection to determine the impact of HCV antiviral therapies on pre- and post-transplant outcomes, and the potential utility of a combination MELD classification that incorporates age at HCV acquisition and platelet count. Disclosures Ragni: Alnylam Pharmaceuticals: Consultancy, Research Funding; SPARK: Research Funding; Biogen: Consultancy, Research Funding; Baxalta: Research Funding; Biomarin: Consultancy; CSL Behring: Research Funding; Genentech: Research Funding; Novo Nordisk: Research Funding; Shire: Consultancy; Tacere Benitec: Consultancy; Vascular Medicine Institute: Research Funding; OPKO: Research Funding. Sherman:BMS: Research Funding; Gilead: Research Funding; AbbVie: Research Funding; Merck: Consultancy, Research Funding.

e15594Background: Clinical outcomes of biliary tract cancer (BTC) remain suboptimal, even when surgical resection is performed. A better understanding of predictive factors can lead to improved man...

AIM To evaluate risk of recidivism on a case-by-case basis. METHODS From our center’s liver transplant program, we selected patients with alcoholic liver disease who were listed for transplant based on Ohio Solid Organ Transplantation Consortium (OSOTC) exception criteria. They were considered to have either a low or medium risk of recidivism, and had at least one or three or more months of abstinence, respectively. They were matched based on gender, age, and Model for End-Stage Liver Disease (MELD) score to controls with alcohol-induced cirrhosis from Organ Procurement and Transplant Network data. RESULTS Thirty six patients with alcoholic liver disease were approved for listing based on OSOTC exception criteria and were matched to 72 controls. Nineteen patients (53%) with a median [Inter-quartile range (IQR)] MELD score of 24 (13) received transplant and were followed for a median of 3.4 years. They were matched to 38 controls with a median (IQR) MELD score of 25 (9). At one and five years, cumulative survival rates (± standard error) were 90% ± 7% and 92% ± 5% and 73% ± 12% and 77% ± 8% in patients and controls, respectively (Log-rank test, P = 0.837). Four (21%) patients resumed drinking by last follow-up visit. CONCLUSION Compared to traditional criteria for assessment of risk of recidivism, a careful selection process with more flexibility to evaluate eligibility on a case-by-case basis can lead to similar survival rates after transplantation.

Refractory vitamin E deficiency is thought to have irreversible effects on neurologic function. We report an adolescent boy with severe refractory vitamin E deficiency due to progressive familial intrahepatic cholestasis (PFIC) type 2. His consequent neurologic dysfunction included severe ataxia, dysmetria, dysarthria, and cranial nerve VI palsy. He underwent liver transplantation at age 13 due to his neurologic dysfunction; and afterward, he had marked improvement in neurologic function. We demonstrate that in a patient with PFIC 2 and severe refractory vitamin E deficiency, liver transplant can improve vitamin E absorption, prevent further neurological sequelae, and reverse prior neurologic dysfunction.

One thousand one hundred and twenty-eight candidates for liver transplantation were stratified into five urgency-of-need categories by the United Network for Organ Sharing (UNOS) criteria. Most patients of low-risk UNOS 1 status remained alive after 1 yr without transplantation; the mortality while waiting was 3% after a median of 229.5 days. In contrast, only 3% of those entered at the highest risk UNOS 5 category survived without transplantation; 28% died while waiting, the deaths occurring at a median of 5.5 days. The UNOS categories in between showed the expected gradations, in which at each higher level fewer patients remained as candidates throughout the 1-yr duration of study while progressively more died at earlier and earlier times while waiting for an organ. In a separate study of posttransplantation survival during the same time period, the best postoperative results were in the lowest-risk UNOS 1 and 2 patients (88% combined), and the worst results were those in UNOS 5 (71%). However, a relative risk cross-analysis showed that a negative benefit of transplantation may have been the result in terms of 1-yr survival for the low-risk elective patients, but that a gain in life extension was achieved in the potentially lethal UNOS categories 3, 4 and 5 (greatest for UNOS 3). These findings and conclusions are discussed in terms of total care of patients with liver disease, and in the context of organ allocation policies of the United States and Europe. Many of the earlier presentations at this Consensus Development Conference have focused on specific diseases and the wisdom of performing liver replacement for disorders that are apt to recur (such as cancer, hepatitis and alcoholic cirrhosis). Others have discussed limiting the operation to prime-of-life candidates, with exclusion of the very young or aged. Expansion of the donor pool has been proposed in the “splitting” of livers that are shared between two candidates or in the use of liver fragments from living donors. These subjects have been judiciously addressed in the context of organ shortage and allocation, leaving the all-important questions of patient disease severity and complexity almost untouched. To focus on this problem, Bronsther et al. (1) have analyzed elsewhere and we present here in more detail the dynamics in a collection of more than a thousand adult patients who were given candidacy in our program. The results may be useful in policy determination about organ allocation and in definition of the role of liver transplantation in the total armamentarium available to treat hepatic diseases.

Severe ischemia/reperfusion (IR) injury is associated with poor hepatic microperfusion. The aim of this study was to investigate the role of hepatic artery flow (HAF) and portal vein flow (PVF) in IR injury. From January 2004 to June 2008, 566 patients underwent orthotopic liver transplantation (OLT). The data were retrospectively reviewed via the transplant database. Patients with hepatic artery (HA) or portal vein (PV) thrombosis and retransplant patients were excluded. Intraoperative PVF and HAF values and graft weights were measured routinely, and the central venous pressure, mean arterial pressure, cardiac output, and cardiac index were recorded with hepatic blood flow measurements. Complete data were available for 312 primary OLT recipients (215 males and 97 females; mean age = 54 ± 10 years). The patients' follow-up ranged from 215 to 1746 days (705 ± 408 days). IR injury was defined by the aspartate aminotransferase (AST) level on postoperative day (POD) 2, and the patients were divided into 3 groups: (1) mild IR injury [AST500 U/L; n = 160 (51%)], (2) moderate IR injury [AST = 500-1000 U/L; n = 85 (27%)], and (3) severe IR injury [AST1000 U/L; n = 67 (21%)]. The demographics and pre-OLT variables (the Model for End-Stage Liver Disease score (MELD), platelet counts, PV thrombosis, transjugular intrahepatic portosystemic shunts, and shunts on computed tomography scans) were similar in all groups. The graft survival rate was 99% in group 1, 95.2% in group 2 (P = 0.02), and 92.3% in group 3 (P = 0.016). The patient survival rates were similar in the 3 groups. The cold ischemia time (CIT) was significantly higher in group 3 versus group 1 (P0.007). In the statistical analysis, low HAF, PVF, total liver blood flow (TLBF), and augmented HAF values were associated with a greater likelihood of elevated AST levels on POD 2. The strongest univariate predictors of AST were reduced augmented HAF (mL/minute/100 g) values (P0.001) and reduced TLBF (mL/minute/100 g) values (P0.001). In a covariate analysis with adjustments for CIT and donor variables, the blood flow parameters remained important predictors of graft function. In conclusion, this report demonstrates for the first time that reduced hepatic blood flow is a significant finding in patients with severe hepatic IR injury.

This review describes our program and its outcomes and then provides an in-depth focuses into many of the unique aspects of our practice that have been important to the success of the program. These include a global appreciation for the impact and various presentations of chronic portal hypertension. We have sought to better understand and describe the various effects it can have on local allograft hemodynamics and graft survival. Intraoperative blood flow measurements of the hepatic artery and portal vein are important. Postoperative follow-up with Doppler ultrasound has been essential for both partial and whole grafts. A better understanding of systemic and graft hemodynamics has changed our clinical practice with regards to the intra- and post-operative management of the hepatic artery and portal vein. We have also focused on the issue of hepatocellular carcinoma, one of the major indications for liver transplantation. We have sought to better understand the heterogeneous clinical presentations of this disease and how to best approach them in a multidisciplinary fashion. Finally, we describe the various methods we have utilized to increase the number of hepatic grafts available for our patients. We have aggressively utilized all forms of grafts; living and deceased; partial and whole; and extended and standard criteria donors. We have done this with the focus on living donor safety and then concentrated on finding the best graft for the individual patient in the context of the national allocation systems in which we all work.

Recurrence of hepatitis C virus (HCV) can be difficult to distinguish from acute cellular rejection (ACR) following liver transplantation. The Cylex Immune Function Assay (ImmuKnow) provides objective measure of recipient's immune function. The goal is to assess the ability of this assay to distinguish these similar conditions. A retrospective review was performed in 54 recipients with HCV. ImmuKnow assays were measured with allograft biopsies. Levels of adenosine triphosphate (ATP) release from CD4+ T cells (ng/mL) were compared with the following biopsy result classifications: 365 ± 130 with ACR (n = 11), 152 ± 100 with recurrent HCV (n = 26), 240 ± 71 with normal biopsies (n = 12), and 157 ± 130 with overlapping features of ACR and recurrent HCV (n = 5). Recipients with recurrent HCV had lower immune response than those with ACR (p0.0001).Using a cutoff level of 220, the sensitivity and specificity for distinguishing two conditions were 88.5% and 90.9%, respectively. When recipients with overlapping features had low immune response, three of four recipients' subsequent biopsies showed recurrent HCV. In conclusion, the ImmuKnow assay can be a sensitive and specific additional test for distinguishing recurrent HCV from ACR and may be useful for predicting which recipients may be most vulnerable to recurrent HCV.

The US Food and Drug Administration (FDA), concerned about the incidence of acute liver failure due to acetaminophen (Tylenol) overdose, has mandated new labeling on acetaminophen packaging. It is also considering (but has not enacted) reducing the maximum daily dose from 4 g (possibly to 3,250 mg), banning acetaminophen-narcotic combination products, and changing the current maximum single dose of 1 g to prescription status, making 650 mg the highest recommended nonprescription dose. We review the epidemiology, toxicology, and management of acetaminophen overdose and steps the FDA and physicians can take to prevent it.

Killer immunoglobulin-like receptors (KIRs) expressed on natural killer and natural killer T cells are involved in activation of these cells and can influence antiviral immunity in the liver. This study investigated the association between KIR genetic diversity and sustained virologic response (SVR) to Peginterferon and Ribavirin (Peg/RBV) therapy in liver transplant (LT) recipients with hepatitis C virus (HCV) recurrence. We tested KIR genotypes in 44 HCV-infected LT recipients treated with Peg/RBV for 48 weeks. Patients were categorized as having KIR genotypes A/A or B/x and analyzed for association with SVR. Fifteen of 44 (34%) patients had SVR. Only 2 of 18 (11%) who lacked KIR2DS2/KIR2DL2 achieved SVR compared to 13 of 26 (50%) who carried these two genes (odds ratio: 8.0, 95% confidence interval: 1.5-42.0, P = 0.008). The association between lack of KIR2DS2/KIR2DL2 and SVR remained significant after exclusion of 10 patients with non-genotype 1 HCV. No correlation was found with other activating or inhibitory KIR genes. Absence of KIR2DS2 and/or KIR2DL2 is associated with failure of Peg/RBV therapy in patients with recurrent HCV after LT. These findings support the role of natural killer and natural killer T cells in HCV clearance after LT and might be generalizable to treatment of HCV infection outside the setting of LT.

Background: Severe complex facial injuries are difficult to reconstruct and require multiple surgical procedures. The potential of performing complex craniofacial reconstruction in one surgical procedure is appealing, and composite face allograft transplantation may be considered an alternative option. The authors describe establishment of the Cleveland Clinic face transplantation program that led them to perform the first U.S. near-total face transplantation. Methods: In November of 2004, the authors received the world's first institutional review board approval to perform a face transplant in humans. In December of 2008, after a 22-hour operation, the authors performed the first near-total face transplantation in the United States, replacing 80 percent of the patient's traumatic facial deficit with a composite allograft from a brain-dead donor. This largest, and most complex, face allograft in the world included over 535 cm 2 of facial skin; functional units of full nose with nasal lining and bony skeleton; lower eyelids and upper lip; underlying muscles and bones, including orbital floor, zygoma, maxilla, alveolus with teeth, hard palate, and parotid glands; and pertinent nerves, arteries, and veins. Immunosuppressive treatment consisted of thymoglobulin, tacrolimus, mycophenolate mofetil, and prednisone. Results: The patient tolerated the procedure and immunosuppression well. At day 47 after transplantation, routine biopsy showed rejection of the graft mucosa without clinical evidence of skin or graft rejection. The patient's physical and psychological recovery went well. The functional outcome has been excellent, including optimal return of breathing through the nose, smelling, tasting, speaking, drinking from a cup, and eating solid foods. Conclusion: The functional outcome thus far at 8 months is rewarding and confirms the feasibility of performing complex reconstruction of severely disfigured patients in a single surgical procedure of facial allotransplantation.

Sialadenosis (sialosis) has been associated most often with alcoholic liver disease and alcoholic cirrhosis, but a number of nutritional deficiencies, diabetes, and bulimia have also been reported to result in sialadenosis. The aim of this study was to determine the prevalence of sialadenosis in patients with advanced liver disease. Patients in the study group consisted of 300 candidates for liver transplantation. Types of liver disease in subjects with clinical evidence of sialadenosis were compared with diagnoses in cases who had no manifestations of sialadenosis. The data were analyzed for significant association. Sialadenosis was found in 28 of the 300 subjects (9.3%). Among these 28 cases, 11 (39.3%) had alcoholic cirrhosis. The remaining 17 (60.7%) had eight other types of liver disease. There was no significant association between sialadenosis and alcoholic cirrhosis (P = 0.389). These findings suggest that both alcoholic and non-alcoholic cirrhosis may lead to the development of sialadenosis. Advanced liver disease is accompanied by multiple nutritional deficiencies which may be exacerbated by alcohol. Similar metabolic abnormalities may occur in patients with diabetes or bulimia. Malnutrition has been associated with autonomic neuropathy, the pathogenic mechanism that has been proposed for sialadenosis.

Splenic artery embolization (SAE) improves hepatic artery (HA) flow in liver transplant (OLT) recipients with so-called splenic artery steal syndrome. We propose that SAE actually improves HA flow by reducing the HA buffer response (HABR). Patient 1: On postoperative day (POD) 1, Doppler ultrasonography (US) showed patent vasculature with HA resistive index (RI) of 0.8. On POD 4, aminotransferases rose dramatically; his RI was 1.0 with no diastolic flow. Octreotide was begun, but on POD 5 US showed reverse diastolic HA flow with no signal in distal HA branches. After SAE, US showed markedly improved flow, RI was 0.6, diastolic flow in the main artery, and complete visualization of all distal branches. By POD 6, liver function had normalized. RI in the main HA is 0.76 at 2 months postsurgery. Patient 2: On POD 1, RI was 1.0. US showed worsening intrahepatic signal, with no signal in the intrahepatic branches and reversed diastolic flow despite good graft function. On POD 7, SAE improved the intrahepatic waveform and RI (from 1.0 to 0.72). Patient 3: Intraoperative reverse diastolic arterial flow persisted on PODs 1, 2, and 3, with progressive loss of US signal in peripheral HA branches. SAE on POD 4 improved the RI (0.86) and peripheral arterial branch signals. Patient 4: US on POD 1 showed good HA flow with a normal RI (0.7). A sudden waveform change on POD 2 with increasing RI (0.83) prompted SAE, after which the wave form normalized, with reconstitution of a normal diastolic flow (RI 0.68). In conclusion, these reports confirm the usefulness of SAE for poor HA flow but suggest that inflow steal was not the problem. Rather than producing an increase in arterial inflow, SAE worked by reducing portal flow and HABR, thereby reducing end-organ outflow resistance. Evidence of this effect is the marked reduction of the RI after the SAE to 0.6, 0.72, 0.86, and 0.68, in patients 1-4, respectively. SAE reduces excessive portal vein flow and thereby ameliorates an overactive HABR that can cause graft dysfunction and ultimately HA thrombosis.

Some chromosomal alterations can be associated with vascular abnormalities. For instance, Turner syndrome can be complicated by agenesis or hypoplasia of the portal venous system causing presinusoidal portal hypertension. Liver transplantation to treat this condition overcomes portal hypertension and reconstitutes the diminished hepatic function due to severe atrophy of the portal venous inflow.

Ligation of portosystemic shunts in patients with cirrhosis undergoing liver transplantation has been recommended to avoid insufficient portal vein (PV) flow. Shunts are not always recognized pretransplantation because intraoperative PV flow assessment is not routinely attempted. As a result of a posttransplantation PV thrombosis in a recipient with a large portosystemic shunt and a PV flow

Backgrounds/aims De-novo autoimmune hepatitis (AIH) after liver transplantation (LT) is rising. Yet there is scarcity of data on the characteristics and the long-term outcomes of this condition. The aim of this study is to investigate the clinical characteristics and long-term outcomes of patients with de novo AIH following LT.Methods Using transplant liver biopsy database, we identified all patients with de-novo AIH following LT at our institution between 2008 and 2013. Patients with hepatitis C virus infection were excluded. The diagnosis of de-novo AIH was made according to the classical and simplified criteria defined by the International Autoimmune Hepatitis Group. Clinical information was gathered from electronic medical records. H&E stained sections and histochemical stains from the liver biopsies revealed findings compatible with AIH. Results A total of nineteen patients with de-novo AIH were identified (58% female, median age of 46 years), with mean international autoimmune hepatitis score of 12.1. Underlying liver disease were primary sclerosing cholangitis (n=4), primary biliary cirrhosis (n=3), biliary atresia (n=3), drug induced liver failure (n=2), alcoholic hepatitis (n=2) and others (n=5). The interval period from the LT to diagnosis of de-novo AIH was 19.6 months (1.6-197.8), during which 11 (58%) patients developed at least one episode of acute cellular rejection prior to the diagnosis of de-novo AIH. All patients were successfully treated with corticosteroids and incremental dose in immunosuppression. All showed complete biochemical response to treatment but 9 (47.4%) patients relapsed upon tapering down corticosteroids. Patients were followed over 6.7 year (1.5-17) years post-LT. Eight (42%) patients progressed to cirrhosis of whom 3 (15%) patients expired and 2 (10%) required second LT due to complications of end stage liver disease. Conclusion The present study shows the long term clinical outcomes of the patients with de-novo AIH post-LT. Although most patients exhibit a good initial response to medical therapy, de-novo AIH post-LT is likely to recur and progress to liver cirrhosis. Therefore, we should consider denovo AIH in patients who show abnormal liver tests or graft dysfunction after LT.

Background: Nonalcoholic steatohepatitis (NASH) is the hepatic manifestation of obesity and can progress to liver cirrhosis even during childhood and early adulthood. The aim of this study was to determine the frequency of NASH as an indication for liver transplantation (LT) in children and young adults and to characterize patient and graft survival in this cohort using a comprehensive large national liver transplantation registry in the U.S. Methods: The study included all children and young adult patients (up to the age of 40 years) who underwent LT in the U.S. from the 1987-2012 United Network for Organ Sharing and Organ Procurement and Transplantation Network (UNOS/OPTN) database. We created a modified NASH category that included LT recipients who were given a primary diagnosis of NASH plus obese patients with primary diagnosis of cryptogenic cirrhosis (CC). KaplanMeier analysis was used to assess patient and graft survival. Results: A total of 330 patients were included (111 with NASH and 219 with CC and BMI ≥ 30 kg/m2). 52% were male, 68% were Caucasian, the mean BMI was 33.6 ± 6.3 and diabetes was present in 18%. Age at time of LT ranged between 4 and 40 years with a mean of 33.9 ± 6.6 years. 14 subjects were < 18 years of age at time of LT and 20 were between the ages of 18-25 years. A progressive increase in NASH as the primary indication for LT in young subjects is seen from 2001 to 2012 (Figure). Median follow-up after 1st LT was 45.8 months [10.7, 97.3]. During this time 30% of subjects (n = 100) died and 11.5% (n = 38) were re-transplanted including 13 for NASH recurrence. Conclusion: NASH can progress to end-stage liver disease requiring LT in childhood and early adulthood. A significant number of young patients transplanted for NASH cirrhosis required re-transplantation with one third being done for NASH recurrence.

In an attempt to more completely define the histopathologic features of the portal vein hyperperfusion or small-for-size syndrome (PHP/SFSS), we strictly identified 5 PHP/SFSS cases among 39 (5/39; 13%) adult living donor liver transplants (ALDLT) completed between 11/01 and 09/03. Living donor segments consisting of 3 right lobes, 1 left lobe, and 1 left lateral segment, with a mean allograft-to-recipient weight ratio (GRWR) of 1.0 +/- 0.3 (range 0.6 to 1.4), were transplanted without complications, initially, into 6 relatively healthy 25 to 63-year-old recipients. However, all recipients developed otherwise unexplained jaundice, coagulopathy, and ascites within 5 days after transplantation. Examination of sequential posttransplant biopsies and 3 failed allografts with clinicopathologic correlation was used in an attempt to reconstruct the sequence of events. Early findings included: (1) portal hyperperfusion resulting in portal vein and periportal sinusoidal endothelial denudation and focal hemorrhage into the portal tract connective tissue, which dissected into the periportal hepatic parenchyma when severe; and (2) poor hepatic arterial flow and vasospasm, which in severe cases, led to functional dearterialization, ischemic cholangitis, and parenchymal infarcts. Late sequelae in grafts surviving the initial events included small portal vein branch thrombosis with occasional luminal obliteration or recanalization, nodular regenerative hyperplasia, and biliary strictures. These findings suggest that portal hyperperfusion, venous pathology, and the arterial buffer response importantly contribute to early and late clinical and histopathologic manifestations of the small-for-size syndrome.

The "piggyback" technique for liver transplantation has gained worldwide acceptance. Still, complications such as outflow obstruction have been observed, usually attributable to technical errors such as small-caliber anastomosis of the suprahepatic vena cava, twisting, or kinking. Iatrogenic Budd-Chiari syndrome after piggyback liver transplantation has been reported as a consequence of obstruction involving the entire anastomosis (usually the 3 hepatic veins). Here we describe technical issues, clinical presentation, diagnosis, and treatment of 3 cases in which outflow obstruction affected only the right hepatic vein. In conclusion, all 3 patients developed recurrent ascites requiring angioplasty and/or stent placement across the right hepatic vein to alleviate the symptoms.

The donor was a 65-year-old male, who was declaredbrain dead following a massive intracranial bleed. Hismedicalhistoryincludeda10x8x9cmrightlobehepaticmasscompatiblewithagianthemangioma.Thiswascon-firmed by an abdominal ultrasound performed at the ad-mitting hospital and a prior CT scan provided by thefamily members. The patient was otherwise a good organdonor, with normal liver function tests and normal serumsodium level. In particular, there was no evidence of co-agulopathy, with a platelet count of 162,000 uL, pro-thrombintime12.0seconds,andINR1.2.Duringsurgeryon the donor, a large hemangioma was identified occupy-ing segments VIII and VII, representing approximately20% of the total liver volume. A smaller hemangiomameasuring 1.5x2cmwasnoted within the left lobe. Thesurrounding liver parenchyma was of normal color andsoft consistency, with normal vessels free of atherosclero-sis. The liver was recovered by a standard technique (14)and flushed with Histidine-Tryptophan-Ketoglutarate(HTK) solution.At this time, a decision was made to use the graft fortransplantation into a 53-year-old male with end-stageliver disease secondary to hepatitis C and hepatocellu-lar carcinoma outside of the Milan criteria. His tumorhad been unresponsive to 3 courses of radiofrequencythermal ablation but did respond to bilateral chemoem-bolization with mitomycin, adriamycin and cisplatin.Triple phase CT scans documented the response totreatment and ruled out liver vascular or extra hepaticinvasion. He had given informed consent for transplantwith an extended criteria liver donor. A standard ortho-topic liver transplant procedure

The model for end-stage liver disease (MELD) was developed to predict short-term mortality in patients with cirrhosis. It has since become the standard tool to prioritize patients for liver transplantation. We assessed the value of pretransplant MELD in the prediction of posttransplant survival. We identified adult patients who underwent liver transplantation at our institution during 1991–2002. Among 2,009 recipients, 1,472 met the inclusion criteria. Based on pretransplant MELD scores, recipients were stratified as low risk (≤15), medium risk (16–25), and high risk (>25). The primary endpoints were patient and graft survival. Mean posttransplant follow-up was 5.5 years. One-, 5- and 10-year patient survival was 83%, 72%, and 58%, respectively, and graft survival was 76%, 65%, and 53%, respectively. In univariable analysis, patient and donor age, patient sex, MELD score, disease etiology, and retransplantation were associated with posttransplantation patient and graft survival. In multivariable analysis adjusted for year of transplantation, patient age >65 years, donor age >50 years, male sex, and retransplantation and pretransplant MELD scores >25 were associated with poor patient and graft survival. The impact of MELD score >25 was maximal during the first year posttransplant. In conclusion, older patient and donor age, male sex of recipient, retransplantation, and high pretransplant MELD score are associated with poor posttransplant outcome. Pretransplant MELD scores correlate inversely with posttransplant survival. However, better prognostic models are needed that would provide an overall assessment of transplant benefit relative to the severity of hepatic dysfunction. Liver Transpl 12:440–447, 2006. © 2006 AASLD.

Despite improved survival after liver transplantation (OLTX) in HIV-positive individuals treated with highly active antiretroviral therapy (HAART), some transplant candidates do not survive to OLTX. To determine if pretransplant outcome is related to severity of liver disease and/or HIV infection, we prospectively evaluated 58 consecutive HIV-positive candidates seen at a single center from 1997-2002. Of the 58, 15 (25.9%) were transplanted, whereas 21 (36.2%) died before OLTX, a median one month of evaluation, with more than half of those (12 of 21, 57.1%) dying from infection. By contrast, of 1,359 HIV-negative candidates, 860 (63.3%) were transplanted, whereas 211 (15.5%) died before OLTX (P0.001). The cumulative survival following initial evaluation was significantly shorter among HIV-positive than HIV-negative candidates (880 vs. 1,427 days, P = 0.035, Breslow) but was not related to the initial pretransplant MELD score (16 vs. 15), INR (1.5 vs. 1.5), creatinine (1.3 vs. 1.3 mg/dL), or total bilirubin (6.6 vs. 5.7 mg/dL), respectively, all P0.05. Among untransplanted HIV-positive candidates, the 21 who died did not differ from the 22 surviving in initial MELD (15 vs. 13), CD4 (230 vs. 327/microL), HIV load (both400 copies/mL), HAART intolerance (10/21, 47.6% vs. 10/22, 45.4%), or HCV infection (16/21, 76.2% vs. 16/22, 72.3%), all P0.05. Further, the 21 did not differ from the 15 transplanted in pre-OLTX CD4, HIV load, or MELD score, all P0.05. In conclusion, pretransplant survival appears shorter in HIV-positive OLTX candidates and is unrelated to severity of liver or HIV disease. Further study is warranted to determine risk factors for poorer pretransplant outcomes.

Intrahepatic noncirrhotic portal hypertension can be idiopathic or associated with known toxic, developmental, vascular, or biliary tract diseases. Most patients are successfully managed medically or with shunting procedures. The goal of this study was to explore the reasons some patients require orthotopic liver transplantation (OLT). The clinical features, gross and microscopic liver explant pathology, and posttransplantation course in 16 patients who underwent OLT for intrahepatic noncirrhotic portal hypertension were studied. There were 11 men and 5 women with a mean age of 47 years. Clinical manifestations included gastrointestinal varices (n = 12), ascites (n = 8), encephalopathy (n = 3), and hepatopulmonary syndrome (n = 3). Cirrhosis was misdiagnosed clinically, radiographically and/or histologically in 13 patients (81%). Grossly, liver explants weighed a mean of 1,100 g, and 12 had a nodular appearance. Histologically, all 16 livers had portal tract vascular abnormalities, 15 had nodular regenerative hyperplasia (NRH), and 9 had incomplete septal cirrhosis. After OLT, mild NRH features were noted in 2 patients, and 1 of these patients developed evidence of portal hypertension. This study demonstrates that a subset of patients with intrahepatic noncirrhotic portal hypertension have severe symptoms requiring OLT. Accurate pre-OLT diagnosis is frequently difficult at advanced stages of the disease; 81% of our patients carried a diagnosis of cirrhosis. Morphologically, the explanted livers showed evidence of vascular abnormalities, NRH, and increased fibrosis, but not cirrhosis. Importantly, however, a diagnosis of cirrhosis is not required in this group of patients to qualify them for OLT, and these patients have good long-term graft function after OLT.

Background Tacrolimus has been increasingly used for liver transplantation during the last decade. The drug has immunological advantages in short- to medium-term follow-up. However, data on longitudinal follow-up are lacking. Aim The aim of the present report was to examine the impact of tacrolimus in primary adult and pediatric liver transplantation (LTx) patients. Material and Method One thousand consecutive primary LTx patients were performed under tacrolimus between August 1989 and December 1992 were followed up until August 2004. Mean follow-up was 13.4 ± 0.92 (range, 11.7–15) years. There were 600 males and 400 females with a mean age of 42.6 ± 20.2 years. There were 166 children (age 18 years or younger) and 834 adults, of whom 204 were older than 60 years (seniors). Results Four hundred ninety-seven (49.7%) patients died in the follow-up period. The overall 15-year actuarial patient survival rate was 51.4%. The survival rate for children was significantly better (81.3%) compared with adults (47.5%) and seniors (36.4%) ( P = .0001). One hundred fifty-one patients received a second LTx, 22 patients received a third LTx, and 4 patients received a fourth LTx. Over all 15 years the actuarial graft survival rate was 46.1%. At last follow-up, 69.1% of patients were off steroids. The majority of late deaths were due to age-related complications, recurrence of disease, and De novo cancers. Conclusion The data on longitudinal follow-up have shown actuarial survival for children to be significantly better than in adults and seniors. Graft loss from immunological causes are rare even with long-term follow-up.

Aim We monitored donor lymphoid chimerism (DLC) long term patterns by STR to investigate their clinical relevance to aGvHD. Methods 81 out of 879 liver transplant patients (2005-2013) who clinically suspected as aGvHD were tested for DLC. Short tandem repeat (STR) assay for DLC was run on the peripheral blood, T, NK, and CD8 + T cells. Cases with positive DLC in any preparation (>5%) were monitored until resolution of DLC or patient expiration. Results Three characteristic patterns of subset DLC were observed. The first pattern (5 patients) is characterized by low level D% that is detected only in CD8 + T cell on initial positive test (Fig. 1). In the second pattern, four patients on the initial positive DLC, had relatively higher CD8 + T cell D% combined with positive T cell D% (Fig. 1). These two patterns were associated with effective aGvHD control with complete resolution of DLC within a mean of 21 days. In the third pattern, four patients with positive DLC in all CD8 + T cells, NK cells and T cell were associated with longer duration for DLC resolution (114 days) (Fig. 2) and failure of treatment (Fig. 2). Conclusions Detection of DLC in both NK and CD8 + T cell preparations is associated with longer duration to DLC resolution and higher mortality rate. These results suggest that multi-subset DLC testing is a useful tool to support the diagnosis of aGvHD and predict the response to treatment.

Background: The colloid-based University of Wisconsin (UW) preservation solution has been used extensively in clinical pancreas transplantation. Experimental studies support the use of the crystalloid-based histidine-tryptophan-ketoglutarate (HTK) preservation solution for this purpose. Aim: We report our initial experience with HTK for pancreas allograft preservation and compare this to a contemporary experience with UW solution in conventional multiorgan deceased donors (

Hemolysis due to D incompatibility in the setting of liver transplantation is less frequent than that associated with ABO incompatibility, but can represent an equally adverse event. Approximately 10 percent of ABO-compatible liver transplants involve a D- donor and a D+ recipient.A case of severe D incompatibility resulting from liver transplantation in a 50-year-old O Rh+ man with end-stage liver disease who received an O Rh- liver allograft is reported. A declining hemoglobin level complicated the patient's postoperative course with laboratory evidence of anti-D-mediated hemolysis. Investigations revealed that the transplanted liver was from a female O Rh- donor with detectable antibodies against D, C, and K. The severity of the hemolytic anemia was such that the patient required two separate red blood cell (RBC) exchanges and intermittent RBC transfusions over the course of almost a year. In addition to the use of RBCs negative for D, C, and K, the patient underwent a variety of B-cell suppressive therapies including glucocorticosteroids, mycophenolate mofetil, and rituximab. A normalization of hemoglobin levels and a decrease in serum bilirubin did not occur until after a splenectomy on postoperative Day 321.This represents the sixth and most severe case reported of hemolysis resulting from D incompatibility in liver transplantation. When unexpected serologic findings are identified in a transplant recipient, obtaining more information on the donor may help guide transfusion support.

Liver transplantation is a well-established treatment for liver failure and for a selected group of patients with hepatic tumors. The growing teratoma syndrome refers to the phenomenon whereby germ cell tumors enlarge after chemotherapy despite complete eradication of malignant cells and normalization of serum tumor markers. We present the case of a young patient with rapidly growing teratomatous masses in his liver who was treated with liver transplantation from a live donor. We discuss his postoperative management, follow-up, and briefly review literature on the subject.

Chronic liver disease often leads to amenorrhea in women of childbearing age. There are several reports of successful pregnancy after liver transplantation (LTx) with cyclosporine A immunosuppression. Tacrolimus has been increasingly used in solid-organ transplantation, and the effect of the drug on pregnancy is still of interest to clinicians. This study updates our single-center experience.All pregnancies after LTx with tacrolimus immunosuppression were followed prospectively. Patients' clinical courses during pregnancy and labor along with gestational period and birth weight were catalogued. Changes in liver function, renal function, and immunosuppression also were recorded. The birth weight percentile was calculated on the basis of the gestational period using a standard chart.Thirty-seven mothers delivered 49 babies. Three mothers delivered three times, and six mothers delivered two times. Thirty-six mothers (97%) survived the pregnancy, and 36 allografts (97%) survived. The one death and graft loss was in a patient who demonstrated infra-aortic arterial graft, which clotted by the gravid uterus during labor. The patient developed a gangrenous liver and died before she could undergo retransplantation. The mean gestational period was 36.4+/-3.2 weeks, excluding two premature deliveries at 23 and 24 weeks gestation. Twenty-two babies (46.9%) were delivered by cesarean section, and the other babies were delivered vaginally. In addition to the two premature babies, one baby, who was born to a mother with Alagille syndrome, died from congenital birth defects. The rest of the newborns survived. The mean birth weight was 2,797+/-775 g, with 38 babies (78%) weighing more than 2,000 g. The mean birth weight percentile to gestational period was 54+/-23. Four babies (8.5%) had a birth weight percentile of less than 25, and 28 babies (59.6%) had a birth weight percentile greater than 50. Twelve patients demonstrated an increase in hepatic enzymes without jaundice during the pregnancy. All of them responded to augmentation of immunosuppression.The present report reconfirms the safety of tacrolimus during pregnancy after LTx. Preterm delivery and low birth weight seem to be a persistent problem in all solid-organ transplantation under any form of immunosuppression. However, toxemia of pregnancy and new onset of hypertension seem to be have a low occurrence with the use of tacrolimus.

Summary Background Insight into the mechanisms of organ engraftment and acquired tolerance has made it possible to facilitate these mechanisms, by tailoring the timing and dosage of immunosuppression in accordance with two therapeutic principles: recipient pretreatment, and minimum use of post-transplant immunosuppression. We aimed to apply these principles in recipients of renal and extrarenal organ transplants. Methods 82 patients awaiting kidney, liver, pancreas, or intestinal transplantation were pretreated with about 5 mg/kg of a broadly reacting rabbit antithymocyte globulin during several hours. Post-transplant immunosuppression was restricted to tacrolimus unless additional drugs were needed to treat breakthrough rejection. After 4 months, patients on tacrolimus monotherapy were considered for dose-spacing to every other day or longer intervals. Findings We frequently saw evidence of immune activation in graft biopsy samples, but unless this was associated with graft dysfunction or serious immune destruction, treatment usually was not intensified. Immunosuppression-related morbidity was virtually eliminated. 78 (95%) of 82 patients survived at 1 year and at 13–18 months. Graft survival was 73 (89%) of 82 at 1 year and 72 (88%) of 82 at 13–18 months. Of the 72 recipients with surviving grafts, 43 are on spaced doses of tacrolimus monotherapy: every other day (n=6), three times per week (11), twice per week (15), or once per week (11). Interpretation The striking ability to wean immunosuppression in these recipients indicates variable induction of tolerance. The simple therapeutic principles are neither drug-specific nor organ-specific. Systematic application of these principles should allow improvements in quality of life and long-term survival after organ transplantation.

Background and method. Posttransplantation acute pancreatitis (PTAP) is a rare but serious complication after pediatric liver transplantation (LTx). We performed a retrospective review in a large cohort of pediatric liver transplant recipients at a single institution to define the impact of this problem in children. Results. Between January 1986 and December 1999, 634 pediatric LTx were performed. Twenty-six patients developed serious acute pancreatitis. The mean age at transplantation was 7.7 years (9 months to 19 years), and the indications for transplantation were biliary atresia in seven, fulminant hepatic failure in six, chronic rejection in seven, and other etiologies in six patients. PTAP was more likely to occur early after LTx (61% within the first week), was associated with the presence of an infrarenal aortic graft in 14 (54%) of 26 patients, was more likely to occur after retransplantation (11/26 patients), and was associated with blood loss and prolonged surgery in four cases. Acute renal failure occurred in 15 (58%) of 26 patients. Mortality was 42% (11/26); causes of death were sepsis or multiple organ failure in nine and hemorrhage in two patients. Management of PTAP included antibiotics, sphincterotomy, debridement with drainage, hepatic arterial revascularization, and arterial ligation. Of the 14 patients with complicated pancreatitis, 5 were treated conservatively and died. Nine patients had extensive operative interventions and four survived (45%). Conclusions. Several risk factors such as retransplantation, extensive dissection at the time of LTx, and use of infrarenal arterial graft contribute to development of PTAP in children. Early exploration and debridement in patients with complicated pancreatitis may result in a better outcome. Retransplantation in the presence of clinical pancreatitis has a high failure rate.

Hepatitis C virus (HCV) is currently the most common etiology for liver transplantation (LTx) in the United States. A significant number of patients develop recurrent HCV after LTx. Although there is no completely satisfactory treatment for recurrent HCV, a combination of interferon-alpha (INF) and ribavirin remains the most widely used. Ribavirin is eliminated through the kidneys and tends to accumulate in the presence of renal dysfunction. The primary side effect of ribavirin is hemolysis. The goal of the present study was to correlate the incidence of hemolysis with renal function in LTx patients with recurrent HCV who were being treated with ribavirin. The incidence of hemolysis and the renal function were examined in 72 liver transplant patients (58 male and 14 female patients) with recurrent HCV receiving INF (3 million units, three times per week) and ribavirin (initial dose of 400 mg twice daily). Patients were grouped according to the decrease in the percentage of hematocrit after the introduction of ribavirin, with their baseline serum creatinine and creatinine clearance calculated using the Cockcroft-Gault formula. The decrease in the percentage of hematocrit after ribavirin treatment was also examined with respect to creatinine clearance as a continuous variable. In addition, for purposes of presentation, patients were analyzed in three groups: creatinine clearance of/= 70 mL/min (group A), creatinine clearance70 mL/min and/= 40 mL/min (group B), and creatinine clearance40 mL/min (group C). Forty-five (62.5%) patients experienced a decrease in hematocrit (Hct)/=15% after starting INF and ribavirin. The mean serum creatinine was 1.3 +/- 0.5 mg/dL (median, 1.3) in this group, and the mean calculated creatinine clearance was 71 +/- 29 mL/min (median, 66.47). In the 27 patients who did not show a significant decrease (15%) in hematocrit, the mean serum creatinine was 1.1 +/- 0.3 mg/dL (median, 1.0) and the mean creatinine clearance was 95 +/- 39 (median, 96) mL/min (P =.018). On continuous variable of calculated creatinine clearance, there was a trend in the decrease in hematocrit after ribavirin treatment compared with pretreatment (P =.09). However, the rate of hemolysis was significantly different in group A (53.7%), group B (70.8%), and group C (100%) (P =.042). Patients on INF and ribavirin therapy who experienced hemolysis had significantly higher serum creatinine levels and lower creatinine clearances compared with those who did not have hemolysis. The incidence of hemolysis was significantly associated with higher serum creatinine and decreased creatinine clearance. Because ribavirin is eliminated by the kidneys, this observation points to the need for adjustments in the dose of this agent in LTx patients, who tend to have some degree of renal dysfunction, to reduce the incidence of hemolysis. Further pharmacokinetic studies of ribavirin in LTx patients with varying degrees of renal function may allow the development of an algorithm for the safer use of ribavirin in HCV-positive LTx patients.

To evaluate the incidence of posttransplant lymphoproliferative disease (PTLD) and the risk factors and the impact of this complication on survival outcomes in a large cohort of liver transplant recipients at a single institution.Liver transplantation has been accepted as a therapeutic option for patients with end-stage liver disease since 1983, in large part due to the availability and reliance on the use of nonspecifically directed immunosuppression. However, as predicted and subsequently verified in 1968, an increased incidence of certain de novo malignancies has been observed, particularly with regards to lymphoid neoplasms. While many reports have confirmed and clarified the nature of PTLD, the literature is fraught with conflicting experience and outcomes with PTLD.Four thousand consecutive patients who underwent liver transplants between February 1981 and April 1998 were included in this analysis and were followed to November 2001. The effect of recipient age at the time of transplant, recipient gender, diagnosis, baseline immunosuppression, grading of PTLD, and association with Epstein-Barr virus were compared. The causes of death were also examined. Treatment for PTLD varied over the 20-year period, but all included massive reduction or elimination of baseline immunosuppression.The 1-year patient survival for liver transplant patients with PTLD was 85%, while the overall patient survival for the entire cohort was 53%. The actuarial 20-year survival was estimated at 45%. The overall median time to PTLD presentation was 10 months, and children had an incidence of PTLD that was threefold higher than adults. Patient survival was better in children, in patients transplanted in the era of tacrolimus immunosuppression, in patients with polymorphic PTLD, and in those with limited disease. Interestingly, neither the presence or absence of Epstein-Barr virus nor the timing of PTLD presentation appeared to influence overall patient survival. Patients transplanted for alcohol-related liver disease had a similar incidence of PTLD but had a higher risk of mortality.While PTLD continues to pose problems in patients receiving liver transplants, improvements in patient survival have been observed over time. While it is too early to assess the impact of new advances in prophylaxis, diagnosis, and treatment, such approaches are based on an increased knowledge of the pathophysiology of PTLD.