The potential risk of late severe adverse penicillamine-induced reactions raises the question of maintenance therapy in patients with WD who could be treated with safer drugs such as trientine or zinc. Penicillamine causes a diversity of dermatologic manifestations that include acute hypersensitivity reactions, dermopathies characterized by elastic fiber abnormalities including EPS and pseudo-pseudoxanthoma elasticum, autoimmune disorders such as pemphigus and penicillamine-induced lupus erythematosus-like syndrome, and miscellaneous dermatoses that result from undefined mechanisms (3). EPS is an uncommon potential complication of long-term therapy with penicillamine, characterized by transepidermal elimination of abnormal elastic fibers (4). EPS is more frequent in patients ages between 6 and 20 years, and the most common sites affected are face, neck, and upper limbs (4). The pathogenetic mechanism is not yet known, but 2 possible explanations for the role of penicillamine have been evidenced: according to the first explanation, the copper-dependent enzyme lysyl oxidase, which is required for cross-linking of collagen fibers, may be inhibited by the copper-chelating effect of the drug; conversely, according to the second explanation, penicillamine inhibits directly the cross-linking of collagen fibers, resulting in the deposition of abnormal elastic fibers. Such abnormal fibers are reported to cause a foreign body reaction affecting epidermis, which results in the typical aspect of EPS (5). Genetic factors are probably also involved (5). Studies have shown that approximately one quarter of patients with EPS are associated with an underlying systemic disorder, often a connective tissue disease such as Ehlers-Danlos syndrome and osteogenesis imperfecta (4). Therapeutic management of EPS is challenging, and at the moment there is no resolutive treatment. Some studies show that negative feedback occurs in case of topical and intralesional corticosteroids, cryotherapy, curettage, and oral isotretinoin treatment. Spontaneous resolution of the lesions within 36 months after cessation of penicillamine therapy has been described (5). Although the effectiveness of penicillamine in WD has long been documented and the overall prevalence of its severe adverse effects is low, the risk of some serious unpredictable adverse events with potential impact on survival (Goodpasture syndrome) or on external appearance with serious social consequences (EPS) emphasizes the question of maintenance therapy in patients with WD. Trientine, which is indicated especially in patients who are intolerant to penicillamine or have clinical features indicating potential intolerance, has a lower toxicity and seems to be a satisfactory alternative therapy. In contrast with copper chelation therapy, zinc treatment has few adverse effects and rarely leads to worsening of neurological symptoms. Although in adult patients, zinc monotherapy seems less effective than chelating agents in preventing the progression of liver disease and in terms of survival in the absence of liver transplantation, we recently demonstrated that zinc monotherapy is effective in controlling WD-related liver disease both as first-line and as maintenance treatment in pediatric patients with mild liver disease (6).

Biliary complications (BCs) still remain the Achilles heel of liver transplantation (LT) with an overall incidence of 10% to 35% in pediatric series. We hypothesized that (1) the use of alternative techniques (reduced size, split, and living donor grafts) in pediatric LT may contribute to an increased incidence of BCs, and (2) surgery as a first treatment option for anastomotic BCs could allow a definitive cure for the majority of these patients. Four hundred twenty-nine primary pediatric LT procedures, including 88, 91, 47, and 203 whole, reduced size, split, and living donor grafts, respectively, that were performed between July 1993 and November 2010 were retrospectively reviewed. Demographic and surgical variables were analyzed, and their respective impact on BCs was studied with univariate and multivariate analyses. The modalities of BC management were also reviewed. The 1- and 5-year patient survival rates were 94% and 90%, 89% and 85%, 94% and 89%, and 98% and 94% for whole, reduced size, split, and living donor liver grafts, respectively. The overall incidence of BCs was 23% (n = 98). Sixty were anastomotic complications [47 strictures (78%) and 13 fistulas (22%)]. The graft type was not found to be an independent risk factor for the development of BCs. According to a multivariate analysis, only hepatic artery thrombosis and acute rejection increased the risk of anastomotic BCs (P < 0.001 and P = 0.003, respectively). Anastomotic BCs were managed primarily with surgical repair in 59 of 60 cases with a primary patency rate of 80% (n = 47). These results suggest that (1) most of the BCs were anastomotic complications not influenced by the type of graft, and (2) the surgical management of anastomotic BCs may constitute the first and best therapeutic option. (C) 2014 AASLD.

Progressive liver allograft fibrosis (LAF) is well known to occur long term, as shown by its high prevalence in late posttransplant liver biopsies (LBs). To evaluate the influence of clinical variables and immunosuppression on LAF progression, LAF dynamic was assessed in 54 pediatric liver transplantation (LT) recipients at 6 months, 3 and 7 years post-LT, reviewing clinical, biochemical data and protocol LBs using METAVIR and the liver allograft fibrosis score, previously designed and validated specifically for LAF assessment. Scoring evaluations were correlated with fibrosis quantification by morphometric analysis. Progressive LAF was found in 74% of long-term patients, 70% of whom had unaltered liver enzymes. Deceased grafts showed more fibrosis than living-related grafts (p = 0.0001). Portal fibrosis was observed in correlation with prolonged ischemia time, deceased grafts and lymphoproliferative disease (p = 0.001, 0.006 and 0.012, respectively). Sinusoidal fibrosis was correlated with biliary complications (p = 0.01). Centrilobular fibrosis was associated with vascular complications (p = 0.044), positive autoantibodies (p = 0.017) and high gamma-globulins levels (p = 0.028). Steroid therapy was not associated with reduced fibrosis (p = 0.83). LAF could be viewed as a dynamic process with mostly progression along the time. Peri- and post-LT-associated factors may condition fibrosis development in a specific area of the liver parenchyma.

p T , under mono‐ and infratherapeutic calcineurin inhibition, may constitute an optimal condition combining graft acceptance with low IS load and minimal IS ‐related toxicity. We reviewed 171 pediatric (<15.0 yr) survivors beyond one yr after LT , transplanted between April 1999 and June 2007 under tacrolimus‐based regimens (median follow‐up post‐ LT : 6.0 yr, range: 0.8–9.5 yr). Their current status regarding IS therapy was analyzed and correlated with initial immunoprophylaxis. p T was defined as tacrolimus monotherapy, with mean trough blood levels <4 ng/mL during the preceding year of follow‐up, combined with normal liver function tests. The 66 children transplanted before April 2001 received a standard tacrolimus–steroid regimen. Beyond April 2001, 105 patients received steroid‐free tacrolimus–basiliximab or tacrolimus–daclizumab immunoprophylaxis. In the latter group, 43 (41%) never experienced any acute rejection episode and never received steroids. In the long term, a total of 79 recipients (47%) developed p T (n = 73) or IS ‐free operational tolerance (n = 6), 27 of them belonging to the 43 steroid‐free patients (63%). In contrast, only 52/128 (41%) children treated with steroids subsequently developed prope/operational tolerance (p = 0.012). Steroid‐free tacrolimus‐based IS seems to promote long‐term graft acceptance under minimal/no IS . These results constitute the first evidence that minimization of IS , including steroid avoidance, might be tolerogenic in the long term after pediatric LT .

Until recently, liver transplantation (Ltx) was the only available treatment for familial amyloidotic polyneuropathy (FAP), but in the last years several pharmaco-therapeutic approaches have emerged hoping to halt disease progression.In the present study, Ltx as the golden standard of treatment is evaluated in a 20 years perspective by analysis of the FAP world transplant registry (FAPWTR).From April 1990 until December 2010, data from 78 liver transplant centers in 19 countries have been accumulated.Approximately 125 liver transplants are performed yearly worldwide.The Registry holds a total of 1940 patients undergoing 2127 Ltx.561 patient deaths were reported.Eighty-eight Ltx were performed in combination with a heart or a kidney.Patients undergoing combined Ltx were generally older than those only subjected to Ltx and with a non-Val30Met mutation.The overall 20 year survival after tx, all mutations included, was 55.3%.Expected mortality rate decreased on average by approximately 4% per year between 1990 and 2010.In a multivariate analysis modified body mass index (mBMI), early onset of disease, disease duration before Ltx and Val30Met versus non Val30Met were independent significant factors for survival after Ltx.Survival of patients with onset of disease after age 50 was significantly reduced when compared to early onset patients, and most pronounced in the male subgroup.Thus, expected mortality rate in late onset male patients was 137% of that of late onset female patient mortality (p<0.05).Early onset patients (all mutations) had an expected mortality rate of 38% of that of the late onset group (p<0.01).Furthermore, Val30Met patients had an expected mortality rate of 61% of that of non Val30Met patients (p<0.01).With each year of increase in duration of disease before Ltx, the expected mortality increased by 11% (p<0.01).Overall, with each unit of increase in mBMI at Ltx, the expected mortality decreased by 0.12% (p<0.01).Twenty-two percent of the death causes were related to cardiovascular disease, thus significantly more common than usually seen in Ltx for end stage liver disease.Conclusion: Long term survival after Ltx for FAP is excellent.A good nutritional status, short duration of disease at the time of Ltx and early onset of disease were significant independent factors for survival.Val30Met patients had significantly better outcome when compared to non-Val30Met patients.The risk of delaying Ltx by testing alternative treatments needs consideration.

The existing systems for scoring fibrosis were not developed to evaluate transplanted livers. Our aim was to design and validate a novel fibrosis scoring system specifically adapted to assess liver allograft fibrosis (LAF). Clinical data, histology, transient elastography (TE) and AST/platelet ratio index (APRI) were reviewed in 38 pediatric liver transplant (LT) recipients. Protocol liver biopsies performed at 6 months and 7 years post-LT were reviewed by three pathologists who assessed LAF using the METAVIR and Ishak systems. LAF was also scored separately in portal (03), sinusoidal (03) and centrolobular areas (03). Scoring evaluations were correlated with fibrosis quantification using morphometry, and also with TE and APRI. Statistical correlations between morphometry and METAVIR were 0.571 (p < 0.000) and 0.566 (p < 0.000) for the Ishak system. The novel score (09) for separate assessment of portal, sinusoidal and centrolobular fibrosis showed a better correlation with morphometry (0.731; p < 0.000) and high intra-/interobserver agreement (0.966; p < 0.000 and 0.794; p < 0.000, respectively). No correlation was found between TE or APRI and morphometry or the three histologic scores. In conclusion, this novel semiquantitative fibrosis scoring system seems to more accurately reflect LAF than the existing scoring system and may become a practical tool for staging fibrosis in LT.

Background and Objective: Portal vein (PV) complications are the most frequent vascular complications in pediatric liver transplant (LT). We hypothesized that pre-LT liver hemodynamic parameters and PV reconstruction technique could predict the risk of PV complications post-LT.Methods: Three hundred seventy-three children had a primary LT. A detailed ultrasound study of the pre-LT native liver hemodynamics was available in 198 cases, with details of PV anastomosis available for 197 of these: end-to-end anastomosis (n = 146, 74%), interposition vein graft technique (n = 28, 14%), or portoplasty (latero-lateral anastomosis of vein graft and recipient PV) (n = 23, 12%).Results: Overall 5-year patient survival rate was 90%. Among the 198 patients with pre-LT hemodynamic data, 79 (40%) had PV hypoplasia (diameter <= 4 mm), 64 (32%) had a pathological portal flow (nonhepatopetal flow), and 47 (24%) had an arterial resistance index (ARI) >= 1. Abnormal hemodynamics were mostly observed in biliary atresia (BA). Among these 3 parameters, only ARI >= 1 was significantly correlated with a higher rate of PV complications post-LT (P = 0.041). PV complication-free survival at 5 years were 91% for end-to-end anastomosis, 91% for portoplasty, and 62% for interposition vein graft technique (P = 0.002). At multivariate analysis, the use of an interposition vein graft was the only factor to be significantly associated with a higher rate of PV complications post-LT (P = 0.003).Conclusions: PV hypoplasia with liver hemodynamic disturbances was mainly observed in BA. Hepatic ARI >= 1 might be a good predictor of PV complications post-LT. Latero-lateral portoplasty seemed to provide the best results when end-to-end anastomosis is not feasible.

In our recent liver transplant (LT) experience, as much as 38% of patients were transplanted during infancy ( 1 yr post-LT), with a documented median follow-up of 6.0 yrs. In these, prope tolerance was defi ned as tacrolimus monotherapy, with mean trough blood levels 4ng/ml during the preceding year, combined with normal liver tests; operational tolerance was defi ned as stable immunosuppression withdrawal (>1yr). Results: Among the 75 children transplanted as infants, the 1- and 5-yr patient survival rates were 97% and 93%, versus 93% and 92% for children transplanted beyond 1 year of age, respectively (NS); the corresponding graft survival rates were 95% and 90%, versus 88% and 84% (NS). At 5 yrs, no signifi cant difference was observed in term of hepatic artery thrombosis rate ( 1yr: 4%, NS) or biliary complication rate ( 1yr: 22%, NS). Only the 5-yr rate of portal vein complication was signifi cantly higher in infants ( 1yr: 4%, p=0.01). Regarding the immunological issues, the 5 yr rate of acute rejection was comparable in both groups ( 1yr: 61%, NS); similarly, no difference was found for chronic rejection ( 1yr: 4%, NS). Among the 168 long-term survivors post-LT, 38/68 recipients transplanted as infants became prope/operationally tolerant (56%), compared to 41/100 children transplanted beyond 1 yr of age (41%) (p=0.058). Moreover, steroid avoidance and living related LT were both signifi cantly associated with later occurrence of a prope/operational tolerance (p=0.011 and p=0.01, respectively). Conclusions: (1) No signifi cant impact of recipient age on overall patient/ graft outcome could be evidenced; (2) transplanted infants seemed to have increased rate of portal complications, possibly related to portal vein hypoplasia; (3) despite similar rejection rates, infants showed a trend toward enhanced allograft tolerance in the long-term.

In this study, the epidemiology and outcome of graft loss following primary pediatric liver transplantation (LT) were analysed, with the hypothesis that early retransplantation (reLT) might be associated with lower immunologic risks when compared with late reLT. Between March 1984 and December 2005, 745 liver grafts were transplanted to 638 children at Saint-Luc University Hospital, Brussels. Among them, a total of 90 children (14%) underwent 107 reLT, and were categorized into two groups (early reLT, n = 58; late reLT, n = 32), according to the interval between either transplant procedures (< or >30 days). Ten-year patient survival rate was 85% in recipients with a single LT, vs. 61% in recipients requiring reLT (P < 0.001). Ten-year patient survival rates were 59% and 66% for early and late reLT, respectively (P = 0.423), the corresponding graft survival rates being 51% and 63% (P = 0.231). Along the successive eras, the rate of reLT decreased from 17% to 10%, whereas progressive improvement of outcome post-reLT was observed. No recurrence of chronic rejection (CR) was observed after reLT for CR (0 of 19). Two children developed a positive cross-match at reLT (two of 10, 20%), both retransplanted lately for CR secondary to immunosuppression withdrawal following a post-transplant lymphoproliferative disease. In summary, the results presented could not evidence better results for late reLT when compared with early reLT. The former did not seem to be associated with higher immunologic risk, except for children having withdrawal of immunosuppression following the first graft.

Over the last half century, kidney and liver transplantation have been recognized as the treatment of choice for adult and children with end-stage renal or liver failure. Infants present a relative naïve immune system, but they are capable of mounting both cellular and humoral immune responses to the foreign antigens presented by the allograft. Immune monitoring is a way of measuring functional and molecular correlates of immune reactivity which may provide clinically useful information for identifying patients who have an increase risk of acute rejection prior to clinical symptoms or develop transplant tolerance. However, although numerous assays have been shown to predict rejection, to date no assays have been demonstrated to detect or predict transplantation tolerance. This is a summary of the published literature on promising antigen-specific and non-antigen-specific assays used for immunological monitoring in solid organ transplantation. This work also attempts to review their applicability to pediatric transplantation, specifically, pediatric kidney and liver recipients.

The validation of reliable, non-invasive immunological assays evaluating anti-donor responsiveness in allograft recipients would provide a clinically relevant tool for the early detection of ongoing rejection process as well as for the identification of operational tolerance in the long term. A sequential approach towards immunological monitoring of allografts is proposed in this review: (i) investigations exploring the initial donor-recipient alloresponses, including the analysis of the cytokine network; (ii) investigations regarding graft acceptance and operational tolerance in long-term transplant patients, consisting in the analysis of regulatory T cells and of circulating precursors of dendritic cells, in the measurement of T cell alloreactivity as well as in the study of T cell receptor repertoires. Beside the conventional in vivo and in vitro immunological techniques, the potential applications of molecular imaging in transplantation also deserve further exploration, with particular respect to allograft immune monitoring. Enforced collaboration between transplant clinicians and immunologists will be required to develop the translational research protocols required for the development of immunological monitoring, within an international multicentric network.

Timely access to a living donor (LD) reduced pretransplant mortality in pediatric liver transplantation (LT). We hypothesized that this strategy may provide better posttransplant outcome. Between July 1993 and April 2002, 235 children received a primary LT from a LD (n = 100) or a deceased donor (DD) (n = 135). Demographic, surgical and immunological variables were compared, and respective impact on posttransplant complications was studied using a multivariate analysis. Five-year patient survival rates were 92% and 85% for groups LD and DD, respectively (p = 0.181), the corresponding graft survival rates being 89% and 77% (p = 0.033). At multivariate analysis: (1) type of donor (DD) was correlated with higher rate of artery thrombosis (p < 0.012); (2) biliary complication rate at 5 years was 29% and 23% for groups LD and DD, respectively (p = 0.451); (3) lower acute rejection incidence could be correlated with type of donor (DD) (p = 0.001), and immunosuppressive therapy (tacrolimus) (p < 0.001). We conclude that (1) according to the multivariate analysis, LT with LD provided similar patient and graft outcome, when compared to DD; (2) a higher rate of artery thrombosis and a lower rate of rejection were observed in group DD; (3) this study confirms the efficacy of tacrolimus for immunoprophylaxis, whatever the type of organ donor is.