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Activation of the pancreatic lineage in the liver has been suggested as a potential autologous cell replacement therapy for diabetic patients. Transcription factors-induced liver-to-pancreas reprogramming has been demonstrated in numerous species both in vivo and in vitro. However, human-derived liver cells capable of acquiring the alternate pancreatic repertoire have never been characterized. It is yet unknown whether hepatic-like stem cells or rather adult liver cells give rise to insulin-producing cells. Using an in vitro experimental system, we demonstrate that proliferating adherent human liver cells acquire mesenchymal-like characteristics and a considerable level of cellular plasticity. However, using a lineage-tracing approach, we demonstrate that insulin-producing cells are primarily generated in cells enriched for adult hepatic markers that coexpress both albumin and mesenchymal markers. Taken together, our data suggest that adult human hepatic tissue retains a substantial level of developmental plasticity, which could be exploited in regenerative medicine approaches.

Introduction: This is a follow-up of a withdrawal study that we previously performed on 104 liver transplant patients in which immunosuppression was gradually withdrawn over a period of 3 years. Eighty-one patients were not able to be withdrawn (rejectors), and 23 patients were successfully weaned off immunosuppression (tolerants)., Methods: In this study, we present their follow-up after the end of the withdrawal study: we compared the results of the tolerant patients (n=23) with those of the rejectors (n=81). Follow-up was until February 2010., Results: Operational tolerant patients were off immunosuppression for an average of 7.27±0.28 years. Patient survival in the tolerant and the rejector groups was 63.66% and 74.25%, respectively (P=not significant). A patient in the rejector group received two retransplants for chronic rejection. In the rejector group, 19 patients presented 26 rejection episodes: clinically suspected (n=19) and biopsy-proven mild (n=4), moderate (n=2), and severe (n=1) rejection episodes. A tolerant patient had a moderate rejection episode of 5.3 years after immunosuppression withdrawal. In the rejector group, five patients received a kidney transplant and four more are on dialysis versus a tolerant patient on dialysis. Freedom from rejection in the tolerant and rejector groups was 95% and 73%, respectively (P<0.05), and freedom from renal replacement treatment was 83.33% vs. 44.58%, respectively (P=not significant)., Conclusions: Long-term outcomes of operationally tolerant liver transplant patients are at least as good as those of control patients. Operational tolerance is not a permanent state, and continuous vigilance is required to detect rejection episodes.

Introduction: Panel reactive antibodies (PRA) to class I and II HLA molecules have been associated with acute kidney graft rejection, but their role in small bowel transplantation has not been characterized., Methods: Since 1994, 324 SBT, alone or as multivisceral transplantation (MVT), have been performed in 286 patients. Routine and surveillance biopsies were performed to rule out or confirm acute rejection (AR), and PRA quantification was performed at varying intervals. We obtained data from 110 patients and 651 PRA measurements. While AR grade (mild to severe, grades 1-3) was determined by histopathological analysis, the status of no AR was determined also by clinical data. When biopsy samples or PRA measurements were frequent around an AR episode within periods of 7 days, the highest value was used., Results: A comparison could be made between 259 instances in which there was a PRA measurement and simultaneous rejection evaluation. Positive PRA showed association with AR (P < 0.001). The positive and negative predictive values were 44% and 79%, respectively. No correlation was found in the severity of rejection., Conclusion: The presence of increased levels of PRA is a risk factor of rejection in small bowel transplantation. Alloantibody-mediated injury to the graft contributes frequently to acute rejection of small bowel, and it is associated with cell-mediated immunity in variable proportion., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: Since March 2002, the United Network for Organ Sharing liver allocation policy has given extra priority to patients with hepatocellular carcinoma (HCC) who meet specific medical criteria. This study reviews our experience with liver transplantation for HCC under this system., Study Design: Between March 2002 and April 2009, 244 patients with HCC underwent primary liver or liver-kidney transplantation under the current allocation system at the University of Miami. Outcomes including HCC recurrence-free survival (RFS) and patient survival (PS) were assessed retrospectively. Clinical variables that predicted outcomes were analyzed., Results: The median time from listing to transplantation was 48 days. The median follow-up was 27.4 months, with an observed recurrence rate of 10.7%. The RFS rates at 1, 3, and 5 years after transplantation were 96.0%, 89.0%, and 83.6%, respectively. The PS rates at 1, 3, and 5 years after transplantation were 86.3%, 71.5%, and 61.7%, respectively. Among patients diagnosed with T2 HCC, a trend toward improved RFS was observed for those who received preoperative ablative therapy; PS was similar (p > 0.05). Outcomes (RFS and PS) for patients with T3 HCC were similar to those in patients with T2 HCC (p > 0.05). Patients with an alpha-fetoprotein >100 ng/mL had an RFS that was inferior to that in patients with an alpha-fetoprotein < or =100 ng/mL (p < 0.0001)., Conclusions: Under the current allocation system, transplantation for HCC results in excellent RFS; PS depends on factors other than HCC; the value of preoperative ablative therapy for patients with T2 HCC is uncertain; the current criteria could be expanded to include selected patients with T3 HCC; and an elevated AFP level is associated with an increased risk of HCC recurrence after transplantation., (Copyright 2010 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: The aim of this study was to evaluate the effect of liver transplantation on the spleen size, spontaneous splenorenal shunt (SRS) function, and platelet counts in patients with hypersplenism., Methods: Between December 2001 and February 2007, 462 adult patients underwent orthotopic liver transplantations (OLTX) at our institution. Of these patients, CT or MRI information was reviewed retrospectively in 55 patients. Volume measurements of the spleen and liver, spleen/liver volume ratio (S/L ratio), presence and size of SRS, and platelet counts were evaluated before and after OLTX., Results: Mean spleen volume decreased from 827 +/- 463 ml to 662 +/- 376 ml after OLTX (p < 0.01). Five (11%) patients returned to normal-range spleen size after OLTX. SRS was observed in 19 patients before OLTX (35%). The diameter of SRS also significantly decreased from 1.0 +/- 0.5 cm before OLTX to 0.7 +/- 0.5 cm after OLTX (p < 0.05). SRS disappeared in 16% of patients (3/19). S/L ratio significantly decreased from 0.65 +/- 0.33 to 0.38 +/- 0.17 (p < 0.01) after OLTX. Platelet counts significantly increased after OLTX (p < 0.01). Improvement of the platelet count in the group with postoperative S/L ratio >0.35 was not as good as that in the group with S/L ratio <0.35 (p < 0.01)., Conclusions: Spleen size and SRS size became significantly smaller after OLTX. However, patients with postoperative S/L ratio >0.35 tend to have lower platelet counts after OLTX.

Background: The role of preformed donor-specific antibodies (DSAs) as a barrier to isolated intestinal transplantation (ITx) remains ambiguous; thus, a positive cross-match has not been a contraindication to ITx., Objective: To report the case of a patient with Crohn's disease who underwent ITx and developed immediate antibody-mediated rejection on reperfusion of the allograft., Methods: Percent reactive antibody testing was performed using pretransplantation serum samples and at transplantation using bead-based assays (Luminex, Luminex Corp, Austin, Tex) and flow cytometry solid-phase assays (FlowPRA single-antigen beads (One Lambda, Inc, Canoga Park, Calif). Serologic tests, flow cytometry cross-matching, and flow cytometry assays of C4d-binding serum antibodies were also performed. Histologic and immunofluorescent analysis of biopsy specimens was performed., Results: HLA typing revealed no sharing of class I or II antigens between donor and recipient. Pretransplantation donor-specific antibodies (DSA) were present at transplantation. Cross-matching (performed during surgery) was positive for class I and II by serologic testing and flow cytometry. After reperfusion, the graft immediately developed severe ischemic injury and arteritis on mucosal biopsy specimens, with immunoglobulin deposition. The DSA C4d binding antibodies were also present. After intense immunosuppression and plasmapheresis, the graft and the biopsy histologic findings showed marked improvement (day 2). By day 7 posttransplantation, patient and graft status were stable. The patient has remained clinically stable for more than a year after transplantation., Conclusions: Pretransplant DSA in ITx can be a risk factor for immediate (hyperacute) but potentially reversible antibody-mediated rejection. Thus, pretransplantation DSA and cross-match results are critical components to be considered in patients awaiting or undergoing ITx.

A standardized grading scheme for the assessment of acute cellular rejection (ACR) in small-intestine transplantation was proposed in 2003 at the Eighth International Small Intestinal Transplantation Symposium. We have implemented the current grading scheme for ACR in small-bowel transplantation since October 2003. The pathologic diagnoses of those small-intestine biopsy samples, including ACR grade and other supplementary findings were evaluated. A total of 3484 small intestine biopsy samples from 155 patients were available for evaluation in this study. Frequency of grades 0, indeterminate, 1, 2, and 3 acute cellular rejection was 33.9%, 49.1%, 12.6%, 3.7%, and 0.8%, respectively. Duration of ACR episode strongly correlated with grade of ACR episode (P < .001). Other supplementary findings included acute vascular rejection component, 2.2%; increase in lymphoplasmacytic infiltrate in lamina propria, 15.7%; mucosal fibrosis, 0.4%; and regenerative changes, 0.3%. Our data substantiate that this grading system is reliable and useful for clinical decision making in bowel transplantation. We suggest that an assessment and quantification of supplementary findings be considered a component of the International Pathology Grading Scheme.

Introduction: The purpose of this study was to evaluate the correlation of plasma citrulline and rejection episodes in intestinal transplantation., Methods: From January 2007 until present, we performed citrulline assays on our small bowel patients. We investigated the correlation of these assays with the rejection status of the patients. The rejection status of the graft was defined based on graft biopsies., Results: Of 5195 citrulline samples, average serum citrulline levels decreased significantly when the patients presented a rejection episode. We found the following: no rejection, 17.38 microm/L; mild rejection, 13.05 microm/L; moderate rejection, 7.98 microm/L; and severe rejection, 6.05 microm/L. Our current emphasis is to determine the predictive power of citrulline with other biomarkers versus as a separate and isolated measurement., Conclusions: In our study, citrulline levels correlated significantly with the rejection status of the graft. Serial follow-up of the patients using this assay may alert us to the possibility of increased alloreactivity and rejection episodes.

Histopathological evaluation of the liver via biopsy remains the standard procedure for the diagnosis of both acute cellular rejection (ACR) and recurrent hepatitis C (RHC) after liver transplantation. Nevertheless, it is often difficult to diagnose ACR in hepatitis C virus-positive recipients because of changes in common and overlapping with RHC. The aim of this study was to identify potential target genes for ACR in recipients with RHC. We analyzed 22 liver biopsy samples obtained from 21 hepatitis C virus-positive recipients. The clinicopathological diagnosis based on biopsy examination was ACR-predominant with superimposed RHC in 9 samples (ACR group) and RHC without ACR (non-ACR group) in 13. Using oligonucleotide microarrays, we compared the transcriptional changes in the 2 groups and selected 2206 genes that were significantly modulated in ACR. We analyzed the regulatory networks in ACR with Ingenuity Pathway Analysis software, and we confirmed with quantitative real-time polymerase chain reaction the reproducibility of caspase 8, apoptosis-related cysteine peptidase and bone morphogenetic protein 2 up-regulation in another group of validation samples, representing 2 genes from the core network as the target genes for ACR. Our results demonstrated novel transcriptome patterns for ACR with concurrent RHC that were distinct from those of recipients with only RHC, suggesting that gene expression profiling may be useful in the diagnosis of ACR in recipients with hepatitis C.

Background: Transplantation of more than two livers for recurring graft failure has not been specifically addressed in the literature., Methods: A retrospective analysis was conducted from a total of 2527 overall liver transplants at our institution. Main indications for multiple retransplant included primary nonfunction, chronic rejection, hepatic artery thrombosis, and recurrent disease., Results: We identified 39 patients who received more than two grafts (32 received 3 grafts, 5 received 4 grafts, and 2 received 5 grafts). All patients required interposition arterial grafts from the aorta and hepatojejunostomy for the biliary reconstruction. Seventeen patients are still alive at last follow-up. Perioperative mortality rates after 3rd, 4th, and 5th liver graft were 25%, 14%, and 50%, respectively. Patient and graft survival rates were 72% and 56% at 1 year, respectively. Median length of stay was 27 days and median graft survival was 2.9 years., Conclusions: Selection of patients and a significant use of available resources are some of the important factors that clinicians need to take into account when dealing with multiple retransplantations. With such conditions, however, liver retransplantation of more than two grafts can be a life-saving procedure.

Purpose of Review: The field of intestinal transplantation continues to grow, both in terms of overall transplants performed each year and number of centers adopting this procedure. Numerous advances in technical and management procedures have resulted in improvements of patient and graft survival. This review focuses on the technical advances that have emerged over the last year., Recent Findings: Multiple variations of the original technique of intestinal transplantation are now utilized according to the patients' original diagnoses and/or degree of liver dysfunction. Multivisceral grafts can include both donor spleen and large intestine; preservation of the native spleen and pancreas is possible in some cases. Living donor intestinal transplantation is being described as alternative technique to minimize death on the waitlist., Summary: Constant evolution in the surgical aspects of intestinal transplantation parallels the improvements that have taken place in the medical management and immunosuppression. The transplant surgeon with full knowledge of all variations of intestinal transplant techniques will be able to tailor the type of surgery to each individual patient.

Liver transplantation has been reported in the literature as an extreme intervention in cases of severe and complicated hepatic trauma. The main indications for liver transplant in such cases were uncontrollable bleeding and postoperative hepatic insufficiency. We here describe four cases of orthotopic liver transplantation after penetrating or blunt liver trauma. The indications were liver failure, extended liver necrosis, liver gangrene and multiple episodes of gastrointestinal bleeding related to portal hypertension, respectively. One patient died due to postoperative cerebral edema. The other three patients recovered well and remain on immunosuppression. Liver transplantation should be considered as a saving procedure in severe hepatic trauma, when all other treatment modalities fail.

Abdominal wall transplantation is a type of composite tissue allograft that can be utilized to reconstitute the abdominal domain of patients undergoing intestinal transplantation. We have presented herein combined experience and long-term follow-up results of a series of abdominal wall transplants performed at 2 institutions. A total of 15 abdominal wall transplants from cadaveric donors were performed in 14 patients at the end of intestinal transplant surgery or, in 2 cases, a few days after the primary intestinal transplant. The vascular supply was through the inferior epigastric vessels, from the iliac vessels in 12 cases and via a microsurgical technique in 3 cases. Immunosuppression consisted of induction with alemtuzumab and maintenance treatment with tacrolimus monotherapy. Two grafts lost to vascular thrombosis were removed. Five patients are still alive, although all deaths were unrelated to the abdominal wall transplant. There were 3 episodes of abdominal wall graft rejection, treated with steroids; the abdominal wall graft and the intestinal grafts experienced rejection independent from each other. In summary, abdominal wall transplantation is a feasible technique for recipients of intestinal or multivisceral transplants, when the closure of the abdominal cavity by primary intention is technically impossible.

Graft rejection is a serious complication after intestinal and multivisceral transplantation. Classic anti-rejection strategies often focus on addressing the cellular component, however mounting evidence suggests that antibody mediated rejection may also play an important role in patient and graft survival. Bortezomib, a proteasome inhibitor used in the treatment of multiple myeloma, has been found to be useful in treating antibody mediated rejection in kidney transplant recipients. The following case illustrates how bortezomib was used to successfully reverse refractory rejection in a patient following multivisceral transplantation. While the rejection was able to be controlled, this patient's course was complicated by an aggressive viral infection after bortezomib therapy. Bortezomib may be a useful agent in the treatment of rejection after intestinal and multivisceral transplantation; however more data is needed to assess its impact on infectious complications in this complex group of patients.

Objective: A biochemical marker for detection of acute cellular rejection following small intestine transplantation has been sought. Citrulline, a non- protein amino acid synthesized mainly by functioning enterocytes, has been proposed. Trial sensitivity has been reportedly high but with low specificity. Thus, the goal was to determine, in a sufficiently large analysis, the significant value of citrulline level in the post-transplant setting, which would correlate with complications such as rejection and infection., Methods: Since March, 2004 2,135 dried blood spot (DBS) citrulline samples were obtained from 57 small intestine transplant recipients three months or more after post-transplant, i.e., once the expected period of recovery in the citrulline levels had occurred., Results: Using a <13 vs. > 13 micromoles/L cut off point, sensitivity of DBS citrulline for the detection of moderate or severe ACR was extremely high (96.4%). Furthermore, specificity estimates (given the absence of ACR and these particular infections), while controlling for time-to-DBS sample were reasonably high (54%-74% in children and 83%-88% in adults), and the negative predictive value (NPV) was >99%., Conclusion: Citrulline is a non-invasive marker to evaluate problems of the intestinal graft after three months post-transplant. Due to the high NPV, a moderate or severe ACR can be ruled out, based exclusively on knowledge of a high value for DBS citrulline.

Abstract Serum aminotransferase elevations are a commonly known adverse effect of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) therapy. However, hepatotoxic events have not been widely published with ezetimibe or the combination agent simvastatin-ezetimibe. We describe a 70-year-old Hispanic woman who developed fulminant hepatic failure necessitating liver transplantation 10 weeks after conversion from simvastatin 40 mg/day to simvastatin 10 mg-ezetimibe 40 mg/day. The patient's lipid panel had been maintained with simvastatin for 18 months before the conversion without evidence of hepatotoxicity. A routine laboratory work-up 10 weeks after conversion revealed elevated serum aminotransferase levels. Simvastatinezetimibe and escitalopram (which she was taking for depression) were discontinued, and other potential causes of hepatotoxicity were excluded. A repeat work-up revealed further elevations in aminotransferase levels, and liver biopsy revealed evidence of moderate-to-severe drug toxicity. She underwent liver transplantation with an uneventful postoperative course. Her aminotransferase levels returned to normal by postoperative day 23, and her 2-year follow-up showed no adverse events. Ezetimibe undergoes extensive glucuronidation by uridine diphosphate glucoronosyltransferases (UGT) in the intestine and liver and may have inhibited the glucuronidation of simvastatin hydroxy acid, resulting in increased simvastatin exposure and subsequent hepatotoxicity. To our knowledge, this is the first case report of simvastatin-ezetimibe-induced liver failure that resulted in liver transplantation. We postulate that the mechanism of the simvastatinezetimibe-induced hepatotoxicity is the increased simvastatin exposure by ezetimibe inhibition of UGT enzymes. Clinicians should be aware of potential hepatotoxicity with simvastatin-ezetimibe especially in elderly patients and should carefully monitor serum aminotransferase levels when starting therapy and titrating the dosage.

A technically difficult liver transplant was performed in a 68-yr-old male with Alveolar Echinococcosis causing end-stage liver disease. The pathology was extensive and included hepatic artery thrombosis, Budd-Chiari syndrome, and right hemidiaphragm invasion necessitating resection of this portion of diaphragm and direct donor cava anastomosis to the right atrium. The patient is now 21 months since transplant disease free with normal liver function.

Gas gangrene is a rare and devastating infectious process that can occur after liver transplantation, most often following hepatic artery thrombosis. We here report 3 cases of gas gangrene following orthotopic liver transplantation. Blood cultures were positive for Clostridium clostridiiforme in one case. In 2 other cases liver tissue from explanted specimens was positive for Enterobacter cloacae. Ultrasound demonstrated hepatic artery thrombosis and computed tomography imaging revealed diffuse liver necrosis with gas formation in each case. All 3 patients were successfully treated with a combination of antibiotics and emergent re-transplantation. We review previously published cases of gas gangrene after liver transplant and emphasize the importance of hepatic artery thrombosis in the development of this syndrome as well as the frequent involvement of non-clostridial organisms. Early diagnosis and aggressive combined medical and surgical treatment including re-transplantation are essential for successful treatment of these rare and catastrophic infections.

Background: The incidence of herpes zoster (HZ) infection in liver transplant recipients prior to the use of induction therapy with monoclonal antibodies has been reported as being 1.2-18%. We studied the occurrence of HZ in liver transplant recipients that received induction therapy with alemtuzumab (Campath 1H)., Material and Methods: This was a retrospective review of primary liver transplant recipients who received alemtuzumab as induction therapy at our center. HZ infection was diagnosed clinically as the presence of a characteristic vesicular rash in a dermatomal distribution without any further virological confirmation., Results: A total of 118 liver transplant recipients were treated with alemtuzumab between August 2002 and August 2005. Twelve patients developed HZ infection, and the cumulative probability of a patient developing HZ infection by 36 months post-transplant +/-1 SE was estimated as 16.5 +/- 5.0%. The median time for onset of the infection was 10.2 months (range 4.7-30.7) after the transplant. All patients had only one dermatomal distribution, and none developed systemic infection or complications such as postherpetic neuropathy. All patients except one were treated with systemic intravenous acyclovir. One patient received famciclovir. All of the patients had received ganciclovir during the post-transplant period but were not receiving any other antiviral medication at the time of the infection., Conclusion: Herpes zoster infection has previously been reported as a frequent complication of liver transplantation. Our study suggests that it occurs in approximately 16% of patients receiving induction therapy with alemtuzumab. Although alemtuzumab is a powerful immunosuppressive agent and there is still little information regarding its long-term safety when used in liver transplantation, our data do not suggest any increase in the occurrence and complications of HZ.

Background: Small intestinal allografts in multivisceral transplantation are felt to be more susceptible to acute cellular rejection (ACR) and chronic rejection (CR) when compared with other allografts although there is little direct evidence for this impression., Methods: A total of 48 cases of multiple allograft specimens (37 autopsy and 11 explanted allograft cases) from 41 patients were evaluated in this study. Histopathologic assessments were performed with special concern to ACR and CR in allografts. The numbers of allografts available for evaluation were liver 37, small intestine 47, stomach 41, pancreas 45, and large intestine 25., Results: Among 48 cases, 15 cases showed ACR (ACR case) and 12 showed CR (CR case) in at least one organ. In ACR cases, there was a statistically significant difference of organ-specific susceptibility to ACR among multivisceral allografts with the small intestinal allograft being the most susceptible (P<0.05). Severe ACR were observed only in small and large intestinal allografts. In CR cases, there was no statistically significant difference of organ-specific susceptibility to CR among multivisceral allografts with a tendency for the pancreas allograft to be the most susceptible (P=0.35)., Conclusions: Our study clearly indicated variation in organ susceptibility to ACR and CR. Small intestinal allografts were the most susceptible organ to ACR in frequency and severity. Pancreatic allografts may be more susceptible to CR in comparison with ACR.

Undetectable hepatitis C virus (HCV) RNA [RNA(-)] before liver transplantation (OLT) has been shown to decrease the rates of disease recurrence. We sought to determine whether RNA(-) subjects differ in post-OLT recurrence (virological/VR, histological/HR), graft failure (GF), or patient survival from RNA(+) patients using a retrospective review. From 1995 to 2004, a total of 49 patients were RNA(-) at OLT as a result of interferon-based therapy: 22 SVR and 27 with end-of-treatment response (ETR) transplanted when RNA(-) within 6 months of ET. Forty-eight RNA(+) patients were analyzed as controls. Virological recurrence (VR) was seen in 55% of RNA(-) subjects with no difference in HR between RNA(-) vs (+) groups, namely 36.7% versus 56.3% (P = .068), respectively. The RNA(+) subjects showed a lower time to HR (5.6 vs 11 months; P = .027). The SVR subjects displayed lower VR (36.4%) and histological recurrence (HR) (13.6%) compared to ETR (VR 70.4%, P = .023; HR 55.6%, P = .003) or RNA(+) (HR 56%, P = .0008). The SVR subjects, who were identified with a sensitive assay (SVR(S), lower limit <600 IU/mL) showed no VR, HR, or GF. The 1- and 5-year survivals were 87.8%/75.6% and 89.6%/77.8% for RNA(-) and (+) groups, respectively (P = .77). In conclusion, RNA(-)-transplanted patients displayed lower VR and longer time to HR. The SVR patients showed lower VR and HR compared to ETR and RNA(+) patients.

Background: Protocol endoscopy with biopsy is currently the gold standard of small bowel transplantation (SBTx) monitoring, however it is invasive, costly, needs skilled operator, may require anesthesia and may cause complications. We investigated fecal calprotectin level (FCL) as a candidate noninvasive marker for monitoring patients after SBTx., Methods: A pilot study was performed to test the use of FCL measurement in following up SBTx patients. Ileostomy effluents were collected at various postoperative days before endoscopy and biopsy. FCLs were measured by enzyme-linked immunosorbent assay and a cut-off level of 100 ng/mg was considered positive. The results were retrospectively evaluated in combination with clinical, endoscopic, and histopathological findings. FCLs are presented as median nanogram per milligram., Results: FCLs were measured in 122 samples that were obtained from 29 patients after SBTx. Only 1 of 69 positive FCL did not accompany abnormal findings. Retrospective evaluation showed that 11 samples from six patients (FCL: 217) coincided with rejection episodes, six samples from three patients (FCL: 125) coincided with viral enteritis, 51 samples from 21 patients (FCL: 207) coincided with nonspecific inflammation, 11 samples from two patients (FCL: 998) coincided with chronic intestinal ulceration, and finally 50 samples from 19 patients (FCL: 43) coincided with normal findings. No significant FCL difference was found between rejection, infection, and inflammation. FCL evolution in individuals showed that FCL can predict rejection days before histopathological diagnosis., Conclusion: FCL is a sensitive test for ongoing organic intestinal allograft pathologies. It might be useful as prescreening marker to avoid unnecessary endoscopies.

As the survival rate of the intestinal and multi-visceral transplant recipients continues to improve, an increasing number of these patients present for either elective or emergency surgery related or unrelated to transplantation. The aim of this review is to focus on clinical issues related to the anesthetic and perioperative management of the intestinal or multi-visceral transplant recipient for nontransplant surgery. Specific issues concerning perioperative assessment and medications, choice of anesthetic drugs and techniques, and postoperative care management are reviewed.

Background: Serum citrulline is a marker for acute cellular rejection (ACR) after intestinal transplantation; however, its clinical utility has not yet been established. The goal of this study was to determine clearcut serum levels beyond which the diagnosis of acute rejection could be supported or refuted, and predictors of citrulline levels posttransplant from which more accurate estimates of sensitivity and specificity could be obtained., Methods: Since March 2004, we obtained 2135 dried blood spot (DBS) citrulline samples from 57 intestinal transplant recipients at or beyond 3 months posttransplant. Stepwise linear regression was performed to determine the most significant multivariable predictors of the patient's DBS citrulline level., Results: Seven characteristics were associated with a significantly lower citrulline in multivariable analysis: presence of mild, moderate, or severe ACR; presence of bacteremia or respiratory infection; pediatric age; and time from transplant to DBS sample (P<0.00001 in each case). Using a <13 vs. > or =13 micromoles/L cutoff point, the sensitivity for detecting moderate or severe ACR and the negative predictive value were high (96.4% and >99% respectively). Specificity was 54% to 74% in children and 83% to 88% in adults., Conclusions: Citrulline levels <13 micromoles/L should alert the clinical team that a serious problem (rejection or infection) could be looming in a previously stable intestinal recipient. Levels > =13 micromoles/L practically rule out moderate or severe rejection.

Background: Subclinical rejection (SCR) is a known entity in various solid organ transplants but not in intestinal transplantation., Methods: The purpose of this study is to characterize the presence and effect of SCR in small intestinal transplantation (Itx). A total of 151 patients who underwent Itx and maintained a functioning graft for at least 3 months after Itx were investigated. The clinicopathological characteristics associated with a SCR episode within 3 months after Itx were analyzed. Cox regression with the landmark method (the landmark time being 3 months after Itx) was used for the analyses of overall graft survival and cause-specific hazard rate of SCR., Results: A total of 2744 small intestinal transplant biopsies within 3 months after Itx were available for retrospective evaluation; 171 cases (6.2%) were determined as SCR and 78 patients (51.7%) experienced SCR episode within 3 months after Itx. Adult patients were associated with a significantly higher occurrence of a SCR episode (P=0.001). Overall graft survival at 5 years posttransplant for patients experiencing SCR within 3 months posttransplant and for patients without SCR was 37.2% and 60.2%, respectively (P=0.009). Cause-specific hazard rate analysis showed that a SCR episode was associated with a significantly higher hazard rate of death due to infection (P=0.005)., Conclusions: A SCR episode in the initial postoperative period of Itx is a significant factor for unfavorable graft prognosis, likely representing alloimmune injury ultimately resulting in patient morbidity due to infection.

Objectives: To describe the effect of the splenic allograft in human multivisceral transplantation., Summary Background Data: We performed transplants of the spleen as part of a multivisceral graft in an attempt to decrease both the risk of infection from an asplenic state and the risk of rejection by a possible tolerogenic effect. To our knowledge, this is the first report of human splenic transplantation in a large series., Methods: All primary multivisceral recipients who received a donor spleen (N = 60) were compared with those who did not receive a spleen (N = 81)., Results: Thirty-five of 60 (58%) are alive in the spleen group, and 39 of 81 (48%) are alive in control group (P = 0.98). In univariate analysis, splenic recipients showed superiority in freedom-from-any rejection (P = 0.02) and freedom-from-moderate or severe rejection (P = 0.007). No significant differences were observed in analyses of infectious complications between the spleen and control groups. Both platelet and leukocyte counts became normal in splenic patients, whereas these counts were significantly increased in nonsplenic recipients. Observed incidence of graft versus host disease (GVHD) was 8.25% (5 of 60) in the spleen group and 6.2% (5 of 81) in the control group (P = 0.70). Increased incidence of autoimmune hemolysis was observed in the spleen group., Conclusions: Allograft spleen can be transplanted within a multivisceral graft without significantly increasing the risk of GVHD. The allogenic spleen seems to show a protective effect on small bowel rejection. Further investigation with longitudinal follow-up is required to precisely determine the immunologic and hematologic effects of the allograft spleen.

The frequency and significance of right hepatic artery injury associated with bile duct injury after laparoscopic cholecystectomy is unknown. Many reports suggest that a concomitant arterial injury worsens the outcome and prognosis of the bile duct injury even after an initially successful biliary repair. The optimal management of this complicated injury is controversial. We report a surgical technique to repair the right hepatic artery injury in these cases. We believe this technique is useful for surgeons who opt to repair the arterial injury at the time of biliary reconstruction, especially if it is performed soon after the injury occurred, before permanent damage to the liver and biliary system is established. To the best of our knowledge, this technique was not reported in the literature previously.

Background: Alloimmunization to red blood cell (RBC) antigens can significantly impact transfusion support of patients undergoing solid-organ transplantation. This study evaluated the incidence of clinically significant RBC alloantibodies (abs) in 2000 consecutive adults receiving liver (OLTX), intestinal (ITX) or multivisceral (MVT) transplants., Methods: From January 1991 to May 2006, 2000 patients underwent OLTX (n=1892), MVT (n=74), or ITX (n=34). Blood sample for serologic investigation was submitted to the transfusion service no later than 4 hr before surgery. The presence of clinically significant RBC abs before transplant with subsequent transfusion requirements, the incidence of delayed transfusion reactions, and de novo abs after transplant were evaluated., Results: One hundred fifteen patients (5.75%) had clinically significant RBC abs before transplant, with 56.7% directed against Rh system antigens. Forty-six (40%) had multiple abs. A mean of 18 packed RBC units (U) were transfused per patient. Patients requiring >20 U (n=34) or those with multiple abs received antigen-negative units for the first 5-10 U when antibody was still present, switched to antigen-unscreened units during massive blood loss and returned to antigen-negative units for the last 5-10 U transfused. Twelve patients (0.6%) developed de novo abs posttransplant. Twenty-two (1.1%) had delayed serologic transfusion reaction. All patients were successfully managed without delay in initiation of surgery or hemolytic complications., Conclusion: RBC alloimmunization can present a special challenge to solid-organ transplantation. Early serologic testing of the recipient pretransplant and prompt communication between the transfusion service and transplant team facilitates successful transfusion management of these patients.

Background: The reported incidence of adhesion related small bowel obstruction after abdominal organ transplantation is considerably lower than other abdominal procedures. The purpose of the study was to investigate the influence of immunosuppression on peritoneal adhesion formation after intestinal transplantation in rats., Methods: Four groups of rats (n = 6) underwent small bowel intestinal transplantation in syngeneic (Groups A, B) and allogeneic (Groups C, D) combinations. Groups B and D received tacrolimus immunosuppression 1 mg/kg/d. Animals were euthanized on postoperative day 7, and the total adhesion score (TAS), tissue hydroxyproline content (HPC), TGF-beta mRNA expression levels and histology were examined., Results: All of the animals in Group C showed severe histological (Grade III) acute cellular rejection. There were no histological signs of rejection in Group D. A significant reduction in TAS was observed in tacrolimus treated animals in both syngeneic and allogeneic combinations (Groups B and D), compared with controls (Groups A and C) (P < 0.001 and P < 0.01, respectively). TAS results correlated with the differences in TGF-beta levels that showed significant reduction when each immunosuppressed group was compared with its nontreated counterpart, i.e., (Groups B versus A, P < 0.05, and Groups D versus C, P < 0.01). TGF-beta levels were significantly high in the rejection group (C) and correlated with the intense adhesion formation that was demonstrated in that group. Group C was also the only group in which a significant elevation in HPC was demonstrated (P < 0.001)., Conclusion: Intense adhesion formation occurs during early posttransplant acute rejection. Postsurgical adhesion formation is significantly reduced in immunosuppressed rats after intestinal transplantation.

Objectives: Tissue damage caused by ischemia/reperfusion injury (IRI) of the intestine may lead to organ dysfunction in several clinical conditions, and is associated with increased incidence of chronic rejection after transplantation. Heme oxygenase-1 (HO-1) is a stress-inducible protein capable of modulating inflammation, oxidative stress, and cell death. The aim of the present study was to assess the effects of HO-1 upregulation on intestinal IRI., Methods: Lewis rats (seven groups, n=6 each) underwent intestinal warm ischemia induced by clamping the superior mesenteric artery and by ligating the inferior mesenteric artery for 60 min. After 120 or 240 min of reperfusion, tissue samples were collected for analysis. Cobalt protoporphyrin (CoPP) was administered IP at 10 or 20mg/kg 24h before IRI, to induce HO-1 upregulation. Control animals received vehicle alone. Tissue injury measurements included the following: histological changes, tissue myeloperoxidase (MPO) activity, nitrate/nitrite levels, and IL-6 levels., Results: A significant HO-1 upregulation was demonstrated in pre-treated animals (p<0.05, 95% CI: -0.84 to -0.05). Intestinal IL-6 mRNA expression levels were significantly reduced in animals treated with CoPP 20mg/kg after 240 min of IRI (p<0.05, 95% CI: 0.09-2.25). Significant reduction in MPO activity and NO products was observed in treated animals when compared to controls (p<0.01, 95% CI: 0.07-0.24 and p<0.01, 95% CI: 5.58-12.75, respectively)., Conclusions: Induction of HO-1 by CoPP administration before IRI was resulted in a significant reduction of intestinal tissue injury. Developing strategies to induce HO-1 upregulation before surgery will be important to reduce IRI in the clinical setting.

Background: In orthotopic liver transplantation (OLT) distinct causes of graft failure (GF) and death with a functioning graft (DFG) exist. Prognostic factors for one failure type may be distinctly different from those predictive of other types, and an accurate portrayal of these relationships may more clearly explain each factor's importance., Methods: A multivariable cause-specific hazard (CSH) rate analysis using Cox stepwise regression was performed among 877 adults who received primary OLT during 1996-2004 with tacrolimus+steroids as immunosuppression., Results: Older donor age (P=0.004) implied greater primary dysfunction GF, while primary sclerosing cholangitis (PSC; P=0.0002) implied greater vascular thrombosis GF. Recurrent nonmalignant liver disease GF was higher among hepatitis C virus patients (P<0.00001), and younger recipient age (P=0.005) implied greater death from recurrent (metastatic) hepatocellular carcinoma. African-American race (P<0.00001), PSC (P=0.003), and younger recipient age (P=0.005) were independently associated with greater GF due to chronic rejection. Older donor age (P=0.003) implied greater infection DFG, while older recipient age (P=0.003) and pretransplant diabetes (P=0.03) were independently associated with greater cardiovascular/cerebrovascular DFG. Finally, most of these cause-specific predictors were not significant in an overall Cox model for graft survival., Conclusions: The CSH approach should be more widely used in investigations of prognostic factors. The result of older donor age implying greater primary dysfunction GF and infection DFG but having no association with other failure types demonstrates that its impact is specific to the graft's early posttransplant functional status. In addition, while recipient age was an important prognosticator, its direction of association reverses depending upon the outcome being analyzed.

The field of intestinal transplantation has experienced a progressive increase in patient and graft survival over the last few years, leading to a parallel increase in the number of programs performing such type of surgical procedures. Indications for intestinal transplant include irreversible intestinal failure, compounded by potential life-threatening complications such as loss of intravenous access, liver failure or multiple episodes of infections. The type of graft that is required is highly individualized according to the patient's original diagnosis and status. Presence of short gut syndrome alone is indication for isolated intestinal transplant; liver failure mandates the use of a liver graft (liver-intestine or multivisceral transplant); intestinal dysmotility disorders with intact liver function require the use of a modified multivisceral graft. Most of the current immunosuppression protocols consist in induction immunosuppression and maintenance doses of tacrolimus. Rejection and infectious complications remain the most common causes of morbidity and mortality; it is therefore essential to closely monitor the intestinal graft to prevent such occurrences. Future developments include: the use of non-invasive markers of rejection; a refinement in surgical techniques; development of advanced immunosuppression protocols; expansion of living related transplant and multivisceral transplantation in selected patients.

Intestinal transplantation has evolved over the years with major improvements in patient and graft survival. Acute cellular rejection of the intestine, however, still remains one of the most challenging aspects of postoperative management. We analyzed retrospectively collected data from 209 recipients of primary intestinal grafts at our institution over the past 11 years. A total of 290 episodes of biopsy-proven rejection requiring clinical treatment were analyzed. Rejection episodes doubled in length, on average, with each increasing grade (mild, moderate, severe). We observed increased incidence of overall rejection and particularly severe rejection in recipients of isolated intestinal and liver-intestine grafts in comparison with multivisceral grafts. Two rejection history variables had a significant negative impact on graft survival: the occurrence of a severe rejection episode and a rejection episode lasting >or=21 days. The lower incidence rate of severe rejection in recipients of multivisceral grafts might be due to a combination of increased donor lymphatic tissue and larger load of donor-derived immune competent cells present in the graft. The development of more effective monitoring and treatment protocols to prevent the occurrence of severe and/or lengthy rejection episodes is of critical importance for intestinal graft survival.

Background: The aim of this study was to evaluate the efficacy of lamivudine (LAM) monoprophylaxis for patients with non-replicating hepatitis B virus (HBV) infection at orthotopic liver transplantation (OLT)., Methods: Among 128 liver recipients with HBV infection between 1994 and 2004 transplanted at our institution, 60 had non-replicating HBV infection at the time of OLT. Of those, 26 patients received LAM prophylaxis (monoprophylaxis group) and 34 patients received LAM and hepatitis B immunoglobulin (HBIG) prophylaxis (combination group) after OLT., Results: Median follow-up after OLT was 67 and 54 months, for monoprophylaxis and combination groups respectively. One and five yr patient/graft survival were 96/85% and 96/80% in monoprophylaxis group, and 85/79% and 67/55% in combination group. HBV DNA was re-detected or increased >10(5) IU/mL in four patients (15%) at 20-29 month in monoprophylaxis group and six (18%) at 4-35 months in combination group. Recurrent hepatitis was seen in two patients (8%) at 27 and 45 months and monoprophylaxis group and three (9%) at 21-35 months in combination group. The rate of recurrence was not statistically different between two groups., Conclusion: LAM monoprophylaxis seemed to be effective for OLT recipients with HBV infection who had non-replicating HBV at transplantation. HBIG administration may play a less valuable role in preventing HBV recurrence in this group of patients.

Catheter-related bacteremia (CRB), along with liver failure is the leading cause of mortality and morbidity in parenteral nutrition dependent children. Immunosuppressant therapy following transplantation increases the risk of CRB. Previous reports in pediatric cancer patients have described the use of antibiotic lock solutions (ABL) for prophylaxis of CRB. In our institution, we evaluated five children (ages between one and four yr old), three with intestinal transplantation and two with short gut syndrome, who were high risk for recurrent CRB defined by their incidence of bacteremias in the observation period (>2 CRB/six months or life-threatening CRB). These children received the prophylactic ABL protocol with tobramycin-tissue plasminogen activator, four h per day, on alternating ports for six to eight months. Each patient was his/her own historical control. We observed decreased incidence of CRB's (p < 0.05), days of hospitalization due to CRB's (p < 0.0001), the days of intensive care admissions due to CRB (p < 0.0001), as well as the total days of systemic antibiotic exposure (p < 0.001). Catheter survival during the ABL era was longer but not reaching statistical significance. There was no advantage in removing and later replacing the catheter to wire-guided exchange while on systemic antibiotics. One patient presented with break-through bacteremia, septic shock and died. None of the catheters were lost to occlusion/malfunction. ABL did not induce an increased resistance to tobramycin. These preliminary findings suggest that ABL can be used safely and effectively in parenteral nutrition dependent children with long-term central venous catheters.

Porto-caval hemitransposition (PCH) in liver transplantation allows revascularization of the liver when the porto-mesenteric axis is thrombosed. We, here, review our experience over an 11-year period. A total of 23 patients underwent liver transplantation using PCH. Immunosuppression was based on tacrolimus, with sirolimus used in case of renal insufficiency. Most common diagnoses were hepatitis C, Laennec's, Budd-Chiari and cryptogenic cirrhosis. Six patients needed splenectomy prior to transplant, 5 during transplant, 1 post-transplant, 11 had no splenectomy. Overall survival was 60% at 1 year and 38% at 3 years, with 10 of 23 patients currently alive and the longest survivor at 9.3 years. Most common cause of death was sepsis/multisystem organ failure, followed by pulmonary embolism. A total of 7/23 patients experienced post-operative gastrointestinal bleeding episodes, 6/23 patients developed thrombosis of the vena cava (median 162 days post-op). Post-operative ascites was noted in almost all patients. Renal dysfunction was commonly seen even after the first month post-transplant. PCH offers a feasible option for liver transplantation in those patients with complex thrombosis of the mesenteric and portal circulation.

The clinical outcome of LT has improved significantly with refinements in surgical skill and immunosuppressive agents. Over the past decade, nationally most LT centers have improved their standard care in LT. As a result, short-term survival after LT has increased remarkably. However, recurrence of original liver disease, chronic rejection, and the adverse effect of immunosuppressive agents still impose significant limitations on long-term survival. Here at the MTI, it is our mission to continue technical innovation, improve the management of hepatitis C patients, search for better immunosuppressive protocols, and work towards achieving tolerance after LT to improve the long-term outcome.

Intrahepatic cholangiocarcinoma (ICC) is well known to have a very poor prognosis. Aggressive surgical strategies in the treatment of ICC, including major hepatectomy, have been reported to afford patients the best chance for significant survival. Recent advancements in surgical techniques concerning live donor liver transplantation have dramatically improved the results of major hepatectomy. However, surgical treatment of biliary malignancy is complex and is known to increase the likelihood of blood transfusion. We describe a Jehovah's Witness patient with ICC and concomitant bile duct invasion who had a successful right trisectionectomy with bile duct resection, lymph node dissection, and Rouxen-Y hepatico-jejunostomy without blood transfusion. A multidisciplinary preparation was crucial in obtaining this positive outcome. Importantly, bloodless liver transection techniques with inflow clamping, meticulous dissection, and hemostasis should be utilized for major hepatectomy in a Jehovah's Witness. The success of this case may alert clinicians to consider a hepatectomy as a possible option in the treatment of ICC in a Jehovah's Witness.

We have shown in ex vivo studies in donor bone marrow-infused kidney transplant recipients, that chimeric cells of either donor or recipient origin taken from the recipient's bone marrow down-regulated the recipient's cellular immune responses. In the present study, we have now induced regulatory T cells from peripheral blood mononuclear cells (PBMC) of renal transplant recipients or laboratory volunteers by multi-stimulation with autologous immature dendritic cell (iDC) enriched populations derived from either bone marrow cells (BMC) of the (immunosuppressed) kidney transplant recipients or PBMC of the laboratory volunteers (i.e., ibDC and ipDC, respectively). These regulatory T cells, induced by ibDC and ipDC, were autoreactive and designated as TAb and TAp with similar phenotypes and functional profiles. They were largely CD4 + CD25high, CD45RA low and CD45RO high, and uniformly expressed intracellular CTLA-4, and message of IL-4, IL-10, Foxp3, and differentially expressed TGFbeta. Their proliferative responses to autologous mature dendritic stimulating cells (mDC) were approximately two-fold stronger than to allogeneic mDC, and to allogeneic mDC were significantly lower than those of (control) autologous TPBL, suggesting an anergic state. TAb and TAp were not cytotoxic to autologous cells expressing Epstein-Barr virus (EBV) antigens, but were able to inhibit (regulate) the effector phase of this TPBL response to both autologous and allogeneic EBV lymphoblasts. This regulation appeared to require cell-to-cell contact.

Background: Little is known about the long-term consequences of new-onset diabetes mellitus (NODM) after liver transplantation (LTX)., Methods: In a chart review between 1996 and 2004, we evaluated its incidence and possible effect on patient and graft survival. Inclusion criteria were: adult primary LTX; deceased donor LTX without combined organs; and dual immunosuppression with tacrolimus and corticosteroid. Patients who died within six months after LTX were excluded. For analytical purposes, each patient was classified into one of four groups: 1) preLTX diabetes mellitus (DM): established DM before LTX; 2) sustained NODM: NODM sustained > or =6 months; 3) transitory NODM: NODM temporarily existed > or =1 and <6 months; and 4) normal: no DM either pre- or postLTX. Patients who had NODM <1 month due to high-dose steroid (e.g., either immediate postLTX or rejection treatment) were considered as normal. Patient and graft survival was examined using Kaplan-Meier methodology., Results: In all, 778 patients met the inclusion/exclusion criteria: preLTX DM 159 (20.4%), sustained NODM 284 (36.5%), transitory NODM 108 (13.9%), and normal 227 (29.2%). Median follow-up was 57.2 months. There was a significant difference in patient (P = 0.012) and graft survival (P = 0.004) among the groups, with sustained NODM showing the poorest patient and graft survivals. Sustained NODM patients had a significantly higher rate of death due to infection, as well as graft failure due to chronic rejection and late onset hepatic artery thrombosis., Conclusion: NODM is a frequent complication with poor patient and graft survival after LTX.

We report a case of extensive acute thrombosis of portal vein and cava in a portocaval hemitransposition liver graft that was treated successfully with percutaneous pulse spray thrombolysis through a femoral vein access. The patient subsequently developed descending and sigmoid colon ischemic necrosis because of the venous thrombosis necessitating emergency colon resection. The patient had prolonged postoperative intensive care stay, but was eventually discharged in a good condition with normal liver function. Three month follow up demonstrated persistent normalization of hepatic function and normal duplex ultrasound.

Ground-glass hepatocytes have been described in Lafora's disease, fibrinogen deposition, hepatitis B, type IV glycogenosis, and alcohol aversion (cyanamide) therapy. We encountered ground-glass hepatocytes with intracytoplasmic inclusions in four liver biopsies from three transplanted patients who had none of the above-mentioned underlying diseases. One patient was a 4-year-old boy who had a kidney transplant for severe ureterovesical reflux. Patient 2 was a 52-year-old man who had two liver transplants because of hepatitis C. The third patient was a 7-month-old girl who underwent a multivisceral transplant because of necrotizing enterocolitis and liver failure induced by total parenteral nutrition. The patients developed liver abnormalities from 45 days to 4 years after their transplants. The livers showed conspicuous ground-glass hepatocytes in 90% of the children's samples and 30% of the adult liver cells. The cytoplasmic bodies stained strongly for Gomori methenamine-silver; they were positive for periodic acid-Schiff without diastase, but negative after diastase digestion. They were negative for colloidal iron and hepatitis B core and surface antigens. Electron microscopy revealed non-membrane bound aggregates of glycogen. Idiopathic ground-glass hepatocytes occur in transplanted patients and represent accumulation of altered glycogen. However, their clinical significance and cause are not entirely elucidated.

Background: Alemtuzumab (Campath-1H [C1H]) is a humanized monoclonal antibody directed against the CD 52 antigen that is present on the surface of T cells, B cells, natural killer cells and monocytes. We studied its application in intestinal transplantation., Methods: This is a retrospective review of adult patients who underwent intestinal transplantation between December 1994 and May 2005. Group 1: non-C1H group (n = 39); group 2: C1H group (n = 37). C1H was administered as an induction immunosuppression in four doses (0.3 mg/kg), or in two doses (30 mg/kg). Tacrolimus levels were maintained at low level (5-10 ng/dL). No maintenance steroids were given., Results: One-year survival of group 1 and group 2 patients were 57% and 70%, respectively. This difference is not statistically significant. Of 37 patients in group 2, 21 are alive. The incidence of rejection was lower in group 2 (P < .005). Average current tacrolimus level is 6.97 +/- 3.98 ng/dL. Seventeen patients (81%) are steroid free, and 15 (71%) are maintained solely on tacrolimus. There was no graft versus host disease in group 2., Conclusions: Our preliminary data suggest that C1H can provide effective immunosuppression for intestinal transplantation. Incidence of rejection was less with this regimen using low maintenance tacrolimus and minimal steroids.

Introduction: In a prospective protocol we studied whether serum citrulline level within 30 days of an acute rejection was predictive of the episode., Methods: An acute rejection episode was defined as the date of occurrence of any biopsy-proven rejection in which treatment was initiated until two successive biopsies showed no further rejection. We compared the mean citrulline level based on values determined within 30 days of the start of an acute rejection episode with the mean citrulline level measured on the same patient during a rejection-free period. Serum citrulline measurements were available immediately prior to the occurrence of rejection for 22 patients who experienced 37 episodes., Results: For the 12 episodes of mild rejection, the mean serum citrulline level +/- SE (standard error) was 15.0 + 2.3 micromol/L prior to rejection and 18.8 +/- 2.4 micromol/L during the rejection-free periods. A paired t test of the mean differences was not significant (P = 17). For the 25 episodes of moderate or severe rejection, the mean serum citrulline level was 12.4 +/- 1.1 micromol/L before rejection and 18.8 +/- 2.0 micromol/L during the rejection-free periods. A paired t test of the mean difference was statistically significant (P = .002)., Conclusions: Although further study of citrulline as a marker for the early detection of acute rejection episodes is needed, our hope is that its use will help to prevent some of these early episodes from evolving into full-blown moderate or severe grades of rejection.

Background: The role of the heterozygous PiZ state of alpha-1 antitrypsin deficiency (alpha1ATD) in the pathogenesis of chronic liver disease (LD) is still a matter of controversy., Aim: To determine the prevalence of alpha1ATD heterozygote states in a large population of patients with established LD compared with individuals with no LD, and to determine whether the prevalence of PiZ is increased in patients with more severe LD., Methods: A cross sectional case-control study among patients with and without LD. Blood samples were tested for alpha1AT levels and alpha1AT phenotype. The severity of LD was determined by clinical evaluation, lab tests, imaging studies and histopathology., Results: In total, 1405 patients were enrolled; 651 with, and 754 without LD. Out of them, 173 patients had decompensated cirrhosis requiring liver transplantation. PiMZ was significantly more prevalent in White patients (3.5%) compared with Hispanics (1.7%; P = 0.029). There was no difference in PiMZ prevalence between the total LD group and the group with no LD (2.1% vs. 1.7%; P = 0.64). Within the LD group, 5.7% of 173 patients with decompensated LD, listed for liver transplantation, had PiMZ, compared with 2.1% of 478 patients with less severe LD (P = 0.016). Similarly, there was a disproportionately higher prevalence of PiZ among hepatitis C virus (HCV) patients (5.6%) and patients with nonalcoholic fatty liver disease (NAFLD) (5.0%) with decompensated LD, compared with HCV patients (1.2%) and NAFLD patients (1.9%) with less severe LD (P = 0.044 and 0.017, respectively). Patients with cryptogenic cirrhosis, who were not considered NAFLD patients, did not have a higher prevalence of PiMZ compared with patients with LD of known etiologies (1.9% vs. 2.3%; P = 0.12)., Conclusions: We found no association between the heterozygous PiZ state of alpha1ATD and the presence of chronic LD in-general or the presence of cryptogenic cirrhosis. In contrast, patients with decompensated LD of any etiology had a significantly higher prevalence of PiMZ compared with patients with compensated LD. Furthermore, in patients with chronic LD due to HCV or NAFLD there was a significant association between the PiMZ heterozygous state and increased severity of LD and the need for liver transplantation. These interim results suggest that the PiMZ alpha1ATD heterozygous state may have a role in worsening LD due to HCV or NAFLD.