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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of the coronavirus disease 2019 (COVID-19) pandemic. Besides virus intrinsic characteristics, the host genetic makeup is predicted to account for the extreme clinical heterogeneity of the disease, which is characterized, among other manifestations, by a derangement of hemostasis associated with thromboembolic events. To date, large-scale studies confirmed that genetic predisposition plays a role in COVID-19 severity, pinpointing several susceptibility genes, often characterized by immunologic functions. With these premises, we performed an association study of common variants in 32 hemostatic genes with COVID-19 severity. We investigated 49,845 single-nucleotide polymorphism in a cohort of 332 Italian severe COVID-19 patients and 1668 controls from the general population. The study was conducted engaging a class of students attending the second year of the MEDTEC school (a six-year program, held in collaboration between Humanitas University and the Politecnico of Milan, allowing students to gain an MD in Medicine and a Bachelor’s Degree in Biomedical Engineering). Thanks to their willingness to participate in the fight against the pandemic, we evidenced several suggestive hits (p &lt, 0.001), involving the PROC, MTHFR, MTR, ADAMTS13, and THBS2 genes (top signal in PROC: chr2:127192625:G:A, OR = 2.23, 95%CI = 1.50–3.34, p = 8.77 × 10−5). The top signals in PROC, MTHFR, MTR, ADAMTS13 were instrumental for the construction of a polygenic risk score, whose distribution was significantly different between cases and controls (p = 1.62 × 10−8 for difference in median levels). Finally, a meta-analysis performed using data from the Regeneron database confirmed the contribution of the MTHFR variant chr1:11753033:G:A to the predisposition to severe COVID-19 (pooled OR = 1.21, 95%CI = 1.09–1.33, p = 4.34 × 10−14 in the weighted analysis).

Aim The aim of the present study was to investigate the influence of the cytochrome P450 (CYP) 3A4/5 genotype in paediatric liver transplant recipients and donors, and the contribution of age and gender to tacrolimus disposition on the first day after transplantation. Methods The contribution of the CYP3A4/5 genotype in paediatric liver transplant recipients and donors to the tacrolimus blood trough concentrations (C0) and the tacrolimus concentration/weight-adjusted dose ratio on day 1 was evaluated in 67 liver-transplanted children: 33 boys and 34 girls, mean age 4.5 years. Results Donor CYP3A5 genotype appears to be significantly associated with tacrolimus disposition on the first day after liver transplantation (P < 0.0002). Other physiological factors, such as recipient age and donor gender may also play a role and lead to significant differences in tacrolimus C0 and tacrolimus concentration/weight-adjusted dose ratio on day 1. However, according to the general linear model, only recipient age appears to be independently associated with tacrolimus disposition on the first day after liver transplantation (P < 0.03). Indeed, there was a faster tacrolimus metabolism in children under 6 years of age (P < 0.02). Conclusions Donor CYP3A5 genotype, recipient age and, to a lesser extent, donor gender appear to be associated with tacrolimus disposition on day 1 after transplant. This suggests that increasing the starting tacrolimus doses in paediatric patients under 6 years of age who receive a graft from a male extensive metabolizer may enhance the possibility of their tacrolimus levels reaching the therapeutic range sooner.

Albeit accepted in the trauma setting, use of peri-hepatic gauze packing has been rarely reported during liver transplantation.To assess the results of packing in liver transplantation.We reviewed clinical characteristics, intraoperative events and postoperative outcome of consecutive adult liver transplantation recipients between 2003 and 2013. Patients treated with packing were compared to no-packing patients and to matched controls selected using a propensity score.Of 1396 recipients, 107 were treated with packing for peri-hepatic bleeding (76.6%), allograft damage (12.1%) or partial outflow obstruction (11.2%). Urgent reoperation for ongoing haemorrhage was required in 6 (5.6%). Correction of haemodynamic and coagulation parameters was constantly achieved. Overall, patient (90% vs. 98%, p0.001) and graft (83.2% vs. 94.7%, p0.001) 3-month survival was significantly reduced in packing patients. However, after matching, no significant difference was observed in patient (89.3% vs. 95.2%, p=0.12) and graft (83.5% vs. 92.2%, p=0.06) 3-month survival. Patient survival was associated with recipient age (HR 2.59; p=0.04) and donor age × recipient MELD (HR 2.04; p=0.02), but not with packing (HR 1.81; p=0.29).In our experience, packing was a valuable adjunct to conventional means of haemostasis during liver transplantation and, after accounting for confounding covariates, was not associated with inferior outcomes.

As graft survival in pediatric LT is often affected by progressive fibrosis, numerous centers carry out protocol liver biopsies. Follow-up biopsy protocols differ from center to center, but all biopsies are progressively spaced out, as time from transplant increases. Therefore, there is a need for non-invasive techniques to evaluate graft fibrosis progression in those children who have no clinical or serological signs of liver damage. Indirect markers, such as the APRI, should be relied on with caution because their sensitivity in predicting fibrosis can be strongly influenced by the etiology of liver disease, severity of fibrosis, and patient age. A valid alternative could be TE, a non-invasive technique already validated in adults, which estimates the stiffness of the cylindrical volume of liver tissue, 100-fold the size of a standard needle biopsy sample. The aims of this study were to evaluate the reliability of TE in children after LT and to compare both the TE and the APRI index results with the histological scores of fibrosis on liver biopsies. A total of 36 pediatric LT recipients were studied. All patients underwent both TE and biopsy within a year (median interval -0.012 months) at an interval from LT of 0.36 to 19.47 years (median 3.02 years). Fibrosis was assessed on the biopsy specimens at histology and staged according to METAVIR. There was a statistically significant correlation between TE stiffness values and METAVIR scores (P = .005). The diagnostic accuracy of TE for the diagnosis of significant fibrosis (F ≥ 2) was measured as the area under the curve (AUROC = 0.865), and it demonstrated that the method had a good diagnostic performance. APRI was not so accurate in assessing graft fibrosis when compared to METAVIR (AUROC = 0.592). A liver stiffness cutoff value of 5.6 kPa at TE was identified as the best predictor for a significant graft fibrosis (METAVIR F ≥ 2) on liver biopsy, with a 75% sensitivity, a 95.8% specificity, a 90% positive predictive value, and an 88.5% negative predictive value. These data suggest that TE may represent a non-invasive, reliable tool for the assessment of graft fibrosis in the follow-up of LT children, alerting the clinicians to the indication for a liver biopsy, with the aim of reducing the number of protocol liver biopsies.

Tacrolimus is an immunosuppressor used to treat patients undergoing liver transplantation. TDM of hematic tacrolimus by liquid chromatography became standard practice, but it does not necessarily reflect its concentration at its active site. Our aim was to validate a new method for tacrolimus quantification into target cells (peripheral blood mononuclear cells, PBMCs) and testing it on 100 real samples from 37 pediatric patients.PBMCs were collected using cell-preparation-tubes; cells number and MCV were evaluated. Tacrolimus was quantified using UPLC-MS/MS coupled with a new automated on-line SPE platform. Chromatographic run was performed on an Acquity UPLC(®) BEH C18 1.7 μm (2.1 mm × 50 mm) column for 5 min, with a gradient of water and methanol (both with 2 mM/L ammonium acetate and 1 mL/L formic acid). XBridge(®) C8 10 μm (1 mm × 10 mm) SPE cartridges were used. The internal standard was 6,7-dimethyl-2,3-di(2-pyridyl)quinoxaline.Full validation following FDA guidelines was performed: the method showed high sensitivity and specificity (LLOQ of 0.010 ng; LLOD of 0.005 ng). Intra- and inter-day imprecision and inaccuracy were15%. A positive and stable matrix effect was observed, with a good recovery for tacrolimus. All drug amounts in real samples resulted within the calibration range and calibration curves were linear (r(2)=0.998). Concentrations from each patient were standardized using their evaluated MCV: intra-PBMCs concentration was meanly 12.7 times higher than the hematic one.This method might be eligible and useful for a clinical routine use, giving more reliable data on drug concentration at the active site.

Background Pediatric acute-liver-failure due to acetaminophen (APAP) administration at therapeutic dosage is rare, while viral infections and metabolic defects are the prevalent causes. Yet, as acetaminophen is routinely used in febrile illnesses, it may be mistakenly held responsible for the acute liver damage. Case presentation An 11 month old boy had been on acetaminophen for 10 days (total dose 720 mg = 72 mg/kg) when he developed acute-liver-failure with encephalopathy. As he rapidly improved on N-acetylcysteine (NAC) infusion, it was concluded that chronic acetaminophen administration in an infant had lead to acute-liver-failure even at therapeutic doses, that N-acetylcysteine infusion had been life-saving and should be immediately started in similar circumstances. The child, however, had two further episodes of acute liver damage over a 34-month period, without having been given acetaminophen, as the parents carefully avoided using it. His clinical, laboratory and radiological findings between the acute episodes were unremarkable. His features and skeletal surveys were not suggestive of a syndromic condition. He then went on to suffer another episode of acute-liver-failure with multi-organ failure, necessitating an urgent liver transplant. All efforts to come to a diagnosis for the causes of his recurrent episodes of liver failure had been unsuccessful, until a biallelic mutation in the NBAS gene was reported to be associated with recurrent acute-liver-failure in children. The boy’s DNA analysis revealed compound heterozygous pathogenic mutations in the NBAS gene. Liver failure episodes in these patients are triggered and worsened by fever, most likely due to thermal susceptibility of hepatocytes, hence APAP, rather than being a culprit, is part of the supportive treatment. Conclusions We suggest that, in acute-liver-failure with a history of acetaminophen exposure at therapeutic dosage, clinicians should not be contented with administering NAC, but should consider an alternative etiology, above all if the episodes are recurrent, and actively start supportive and antipyretic treatment while seeking the advice of a specialist unit.

The aim of this study is to evaluate the safety and efficacy of percutaneous treatment of biliary strictures after paediatric liver transplantation. In the period between October 1999 and October 2010, a total of 92 transplants in 86 children were performed at our Liver Transplant Centre. Eighteen patients had anastomotic biliary strictures (in four cases associated with intrahepatic bile duct stenosis). Percutaneous treatment (transhepatic biliary drainage and conventional/cutting balloon dilatation) was proposed as a first approach in 13/18 patients. Strict radiation protection precautions were taken in accordance with the ALARA (as low as reasonably achievable) principle. Mean follow-up time was 2,364 days. Surgical correction was required in 3/13 patients; in 8/13 cases, there was complete disappearance of clinical symptoms without bile duct dilatation; in one case, an asymptomatic persistent bile duct dilatation was detected while in the other case, the liver is currently in cirrhotic degeneration (69 % clinical success including the asymptomatic patient with biliary dilatation). Two of the five patients who were initially treated with surgery required percutaneous revision (clinical success of 100 %). There were two cases of long-term restenosis and two cases of transient haemobilia. Percutaneous procedures are safe and effective therapeutic options for the treatment of biliary strictures after paediatric liver transplantation.

Hepatoblastoma (HB) is the most common liver cancer in infants younger than 3 years. Its onset has been associated with other genetic syndromes and some genetic and biochemical markers has been identified recently in this neoplasia. Nevertheless the patients have a poor prognosis and the resection or transplantation remains the only effective therapeutic approach. The identification of non-invasive markers may represent an innovative approach and may contribute to a more accurate histological classification of this tumor. We previously demonstrated that some microRNAs are helpful in discriminating HB from hepatocellular carcinoma. In this study, we describe the involvement of the two forms of microRNA-483 (-3p and -5p) in a selected cohort of HB patients who underwent surgical resection or liver transplantation. Differently from other liver diseases we observed that the quantitative expression of the two forms did not significantly changed among patients. Furthermore, 3p/5p ratio was different between HB and non-HB samples, being positive in the latter and negative in HB samples. Influence of concomitant treatments in the expression of miR-483 (i.e. chemotherapy, and immunosuppressive drugs) was also evaluated and no changes were found in the follow-up. In conclusion the expression and function of miR-483-3p/5p in HB still remains unclear and further studies are needed to elucidate the possible mechanisms that regulate the different strand selection between the two forms of microRNA-483 in patients affected by HB. We deem that the analysis of microRNA-483 different forms could be useful for the molecular identification of HB patients and the discrimination with non-HB patient.

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 ( 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.

The risk of disease recurrence after a kidney transplant is high in patients with atypical hemolytic uremic syndrome (aHUS) and mutations in the complement factor H (FH) gene (CFH). Since FH is mostly produced by the liver, a kidney transplant does not correct the genetic defect. The anti-C5 antibody eculizumab prevents post-transplant aHUS recurrence, but it does not cure the disease. Combined liver–kidney transplantation has been performed in few patients with CFH mutations based on the rationale that liver replacement provides a source of normal FH. We report the 9-year follow-up of a child with aHUS and a CFH mutation, including clinical data, extensive genetic characterization, and complement profile in the circulation and at endothelial level. The outcome of kidney and liver transplants performed separately 3 years apart are reported. The patient showed incomplete response to plasma, with relapsing episodes, progression to end-stage renal disease, and endothelial-restricted complement dysregulation. Eculizumab prophylaxis post-kidney transplant did not achieve sustained remission, leaving the child at risk of disease recurrence. A liver graft given 3 years after the kidney transplant completely abrogated endothelial complement activation and allowed eculizumab withdrawal. Liver transplant may definitely cure aHUS and represents an option for patients with suboptimal response to eculizumab.

With conventional dietary treatment, the clinical course of methylmalonic acidemia due to cobalamin-unresponsive methylmalonyl-CoA mutase (MCM) deficiency is characterized by the persistent risk of recurrent life-threatening decompensation episodes with metabolic acidosis, hyperammonemia, and coma. Liver transplant has been proposed as an alternative treatment and anecdotally attempted in the last 2 decades with inconsistent results. Most criticisms of this approach have been directed at the continuing risk of neurologic and renal damage after transplant. Here, we report the perioperative and postoperative clinical and biochemical outcomes of 2 patients with severe MCM deficiency who underwent early liver transplant. In both cases, liver transplant allowed prevention of decompensation episodes, normalization of dietary protein intake, and a marked improvement of quality of life. No serious complications have been observed at 12 years’ and 2 years’ follow-up, respectively, except for mild kidney function impairment in the older patient. On the basis of our experience, we strongly suggest that liver transplant should be offered as a therapeutic option for children with cobalamin-unresponsive MCM deficiency at an early stage of the disease.

Lafosse A, de Magnee C, Brunati A, Bayet B, Vanwijck R, Manzanares J, Reding R. Combination of tissue expansion and porcine mesh for secondary abdominal wall closure after pediatric liver transplantation. Abstract: We report the case of a two and a half yr boy hospitalized in our Pediatric Transplantation Unit for portal vein thrombosis following liver transplantation. After performing a meso-Rex shunt, abdominal wall closure was impossible without compressing the portal flow. A combination of two techniques was used to perform the reconstruction of the muscular fasciae and skin layers. The association of tissue expanders and porcine mesh (Surgisis(®) ) allowed complete abdominal wall closure with good functional and esthetic results. Use of both techniques is a useful alternative for difficult abdominal closure after liver pediatric transplantation.

s / Digestive and Liver Disease 46 (2014) e71–e84 e73 QUANTIFICATION OF TACROLIMUS IN PBMCS SAMPLES IN PEDIATRIC LIVER TRANSPLANT PATIENTS AND CORRELATION WITH TACROLIMUS WHOLE BLOOD CONCENTRATION Michele Pinon1,∗, Pier Luigi Calvo1, Antonio D’Avolio2, Debora Pensi2, Andrea Brunati3, Roberto Canaparo4, Amedeo De Nicolo2, Giulia Carbonaro3, Alessia Cerrina3, Giovanni Di Perri2, Renato Romagnoli3, Cristiana Barbera1, Mauro Salizzoni3 1 Department of Pediatric Gastroenterology and Hepatology, Regina Margherita Children’s Hospital, Azienda Ospedaliera Citta della Salute e della Scienza, University of Turin, Turin, Italy 2 Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy 3 Liver Transplantation Center, Azienda Ospedaliera Citta della Salute e della Scienza, University of Turin, Turin, Italy 4 Department of Drug Science and Technology, University of Turin, Turin, Italy Objective: Therapeutic drug monitoring (TDM) of tacrolimus in whole blood is essential to optimize clinical outcomes and reduce toxicity. However, the relationship between blood concentrations and therapeutic efficacy is unclear, probably because it does not reflect tacrolimus concentration at the active site. In this preliminary study, our aims were to validate a newmethod for tacrolimus quantification into the target cells (peripheral blood mononuclear cells, PBMCs), in a cohort of 24 pediatric liver recipients after a median follow-up of 5.23 years. Moreover, we analyzed the influence of ABCB1 (3435C>T and 1199A>G), CYP3A*3 and CYP3A4*22 polymorphisms on the intralymphocyte distribution of tacrolimus. Methods: PBMCs were collected using CPT tubes; cells count and the mean cellular volume were evaluated with a coulter counter. Tacrolimus concentration was quantified, after cell lyses, using ultra performance liquid chromatographywith tandemmass inpositive ionmode, coupledwith thenewautomatedon-line solid phase extraction technology. Results: A median value of 49.5ng/mL (range 14.4–358.9) of tacrolimus PBMCs concentration was found, corresponding to a 12.7-fold wider range than the whole blood levels simultaneously analyzed. Although a significant correlation with mean tacrolimus blood levels could be observed, tacrolimus intracellular accumulation tended to be higher in ABCB1 G/A, although not statistically significantly, and in CYP3A5*3/*3 recipients. Conclusions:Although tacrolimus PBMCs concentration cannot be considered as a routine test yet, this method could bemore predictive of efficacy and toxicity of immunosuppressive therapy than whole blood levels. Further studies are required to evaluate the relationship with clinical outcomes. http://dx.doi.org/10.1016/j.dld.2014.07.025 LIVING DONOR LIVER TRANSPLANT (LDLT): THE PATIENT PERSPECTIVE Andrea Pietrobattista1,∗, Manila Candusso1, Maria Sole Basso1, Chiara Grimaldi2, Fabrizio Di Francesco2, Lidia Monti3, Jean De Ville De Goyet2, Giuliano Torre1 1 USC Epatogastroenterologia e Nutrizione, Ospedale Pediatrico Bambino Gesu, Roma, Italy 2 USC Chirurgia epato-biliare, Ospedale Pediatrico Bambino Gesu, Roma, Italy 3 USC Radiologia, Ospedale Pediatrico Bambino Gesu, Roma, Italy Objective: To evaluate the outcome of living liver donor transplantation in children. Methods: Retrospective analysis. Results: We performed 23 LDLTs out of 105 transplants in the past 5 years inRome, and thenumberhas been increasing; themain indication is cirrhosis in biliary atresia (20 cases, 87%) but it has been performed also in metabolic diseases such as primary oxalosis, MSUD and propionic academia. No recipient died, themean age at transplantwas 29.3months (SD 28.6, r. 6–132), themeanweight 13kg (SD6.7, r. 5.5–30.3), after amean144daywaiting list time (SD 250, r. 0–1040); the mean PELD score was 20 (SD 12, r. 0–38). The mean ischemic time was 244min in LDLT vs 517.3min in cadaveric transplants. The mother was the donor in 13 children, in one a relative; no death. Surgical complications occurred in 8 children (34.7%), 2 out of these in one baby; the rate is similar in cadaveric recipients (33.7%), Rejectionwasdiagnosed in47.8%of cases, biliary stenosis in 2 cases, resolved by percutaneous biliary drainage (1) and by surgery (1); one child reported portal thrombosis, treated by Meso-Rex shunt. No living donor reported any complication. Conclusions: LDLT is an important tool in dealing childrenwith end-stage liver disease, mainly if cadaveric donors are lacking; it could be a safe choose even in metabolic disorders, with an heterozygote donor. http://dx.doi.org/10.1016/j.dld.2014.07.026

A case of liver transplantation for HCC complicating BA in an eight-month old infant is reported. HCC in BA is extremely rare. Screening of AFP and ultrasonographic examination should be performed regularly in patients with secondary biliary cirrhosis for early detection of HCC.

We report the outcome of liver transplantation (LT) in the only surviving patient with lathosterolosis, a defect of cholesterol biosynthesis characterized by high lathosterol levels associated with progressive cholestasis, multiple congenital anomalies and mental retardation. From her diagnosis at age 2 she had shown autistic behavior, was unable to walk unaided and her sight was impaired by cataracts. By age 7 she developed end-stage liver disease. After a soul-searching discussion within the transplantation team, she was treated with LT as this represented her only lifesaving option. At 1-year follow-up, her lathosterol levels had returned to normal (0.61 mg/dL from 13.04 ± 2.65) and her nutrition improved. She began exploring her environment and walking by holding onto an adult's hand and then independently. Her brain magnetic resonance imaging (MRI) had shown a normal picture at age 1, whereas a volume reduction of white matter with ex vacuo ventricular dilatation and defective myelinization were observed before transplant. At 5-year follow-up, a complete biochemical recovery, an arrest of mental deterioration and a stable MRI picture were achieved, with a return to her every day life albeit with limitations. Timely liver transplant in defects of cholesterol biosynthesis might arrest the progression of neurological damage.

Severe hepatic trauma is a rare indication for liver transplantation (LT). We report our single-center experience of LT for hepatic trauma. Four new cases are discussed in light of a literature review in order to depict the pathways leading from hepatic trauma to LT and to assess the outcomes of this practice. LT is generally indicated in case of uncontrollable hemorrhage, acute liver failure, or post-traumatic late sequelae. Hepatic vessels thrombosis, sepsis, major hepatic resections, and a late referral are factors associated with the progression toward irreversible liver failure. Considering all reported cases, early patient and graft survival reached 68% and 62%, respectively, but in the last decade both have improved to 84%. LT after severe hepatic trauma is a sustainable practice considering the current good outcomes and the ineluctable death of these patients without LT.

The authors retrospectively reviewed the results obtained with percutaneous treatment of portal stenosis. In November 2005 and March 2008, two patients, 15 and 32 months old, underwent portal vein angioplasty at our centre. Both procedures were performed after ultrasound-guided portal vein puncture and measurement of pre- and postanastomotic pressure gradients. The diameters of the angioplasty catheters ranged from 5 to 10 mm and no stents were used. In both cases, it was possible to cross the stenoses, perform angioplasty and obtain an immediate reduction of the pressure gradients. There were no major complications after the procedure. In the first patient, percutaneous treatment allowed us to postpone surgical revision of the anastomosis; in the second case, angioplasty had to be repeated twice over a period of 4 years to finally achieve regular patency of the anastomosis and function of the graft. Percutaneous treatment of portal stenosis after paediatric liver transplantation is a safe and feasible treatment; if balloon dilatation does not guarantee functional recovery of the organ, it allows surgical revision to be postponed to a later date when the clinical condition is more stable.

new arguments for answering those questions. 3 First, given the dismal natural course of the disease in spite of rigorous medical management, we are persuaded that the organ transplant approach should be considered in all patients with neonatal-onset, cobalamin-unresponsive MMA. In our patients, timely liver transplantation allowed an excellent clinical course both perioperatively and in the long-term, consistent with the results by Niemi et al. Second, we are convinced that transplantation should be performed early, ideally within the first year of life, thereby avoiding repeated metabolic decompensations and the consequent neurologic deterioration. Third, we believe that isolated liver transplantationshould bethe preferred option,asit providesthe greatest mutase enzyme activity (5-fold greater than kidney transplantation), sufficient for preserving renal function and avoiding, or at least delaying, the need for kidney transplantation. In light of these independent reports, early liver transplantation currently appears to be the best therapeutic option in patients with severe MMA. Although not fully curative, this approach will ensure healthier clinical outcome with respect to traditional medical management.

We report the case of a two and a half yr boy hospitalized in our Pediatric Transplantation Unit for portal vein thrombosis following liver transplantation. After performing a meso-Rex shunt, abdominal wall closure was impossible without compressing the portal flow. A combination of two techniques was used to perform the reconstruction of the muscular fasciae and skin layers. The association of tissue expanders and porcine mesh (Surgisis(®)) allowed complete abdominal wall closure with good functional and esthetic results. Use of both techniques is a useful alternative for difficult abdominal closure after liver pediatric transplantation.

Ectopic adrenocorticotrophic hormone (ACTH) secretion is a rare cause of Cushing syndrome in paediatric age, due to tumours arising from different tissues. To date, only 11 reports of ACTH-secreting pancreatic tumours in children and adolescents exist in the literature. We present a paediatric case of Cushing syndrome caused by ectopic ACTH secretion. This was caused by a large acinar cell carcinoma that developed in the pancreas of a 3-year-old girl.

The use of a novel biological mesh for surface hemostasis is described in pediatric liver transplantation with alternative techniques. The putative benefits of TachoSil are discussed, particularly in the context of children with impaired coagulation, including fulminant hepatic failure.

Aim Our goal was to evaluate the outcome of HCV(+) recipients after liver transplantation (LT) using HCV(+) donors and the interaction between donor and recipient viral strain. Methods We performed a retrospective analysis of 21 LT performed between 1998 and 2004 using livers from HCV(+) donors in HCV(+) recipients. Two hundred thirty-seven patients with HCV cirrhosis who underwent LT with livers from HCV(−) donors were the control group. Ishak score (IS) was evaluated for all HCV(+) grafts. The considered variables included donor age, hepatic enzymes, intensive care unit stay, HCV genotype, ischemia time, recipient age, UNOS status, Child score, HCV genotype (before and 6 months after LT) and IS (after LT). We analyzed patient, graft, and disease-free survival. Results HCV(+) donors were significantly older than HCV(−) donors. The cumulative 5-year patient and graft survivals and disease free intervals were not different between groups. IS grading was more than 2/18 in two cases; the only graft with a staging score over 2/6 was retransplanted for early nonfunction. In two cases, different HCV genotypes were matched and donor strain took over the recipient strain. In one patient, donor genotyping 2a-2c took over recipient genotyping 1b and 9 months after LT recurrent hepatitis was documented, but antiviral therapy cleared HCV. Conclusions Livers from HCV(+) donors can safely be used in HCV(+) recipients. Hepatic biopsy must always be performed; livers with bridging fibrosis should not be used. The takeover of one strain by another may change the prognosis of the patient if the predominant strain is more sensitive to antiviral therapy.

Aim. Calcineurin inhibitors (CI) are associated with significant morbidity in transplant recipients. The aim of this study was to evaluate the effectiveness and safety of mycophenolate mofetil (MMF) monotherapy in liver transplantation (LT). Methods. We analysed 32 patients (24 males, 8 female, of mean age 55.7 years) who underwent LT between 1994 and 2003. In 29 patients immunosuppressive therapy was cyclosporine; in three patients it was tacrolimus. Eleven patients were submitted for LT due to hepatitis B cirrhosis; eight for hepatitis C cirrhosis, six for alcoholic cirrhosis, and seven for other diseases. In these patients, MMF was added gradually, simultaneously reducing the dosage of CI up to complete withdrawal. We considered the efficacy (decrease in serum creatinine) and the incidence of complications (acute and chronic rejection, leukopenia, diarrhea). Results. Patients were converted to MMF after a median of 50 months after LT. MMF monotherapy was started after a median of 9 months in association with CI. Indications for switch to MMF monotherapy were adverse effects of CI (renal disfunction in 30 patients) and de novo tumoral evidence after LT in two patients. Median dosage of MMF was 750 mg twice daily (500-1500 mg). There was a statistically significant decrease in serum creatinine levels (2.02-1.7 mg/dL; P = .0001). Side effects were: leukopenia in five of 32 patients (15.6%), diarrhea in four of 32 patients (12.5%), and one acute rejection. Conclusion. MMF monotherapy improved renal function and was not associated with a significant risk of allograft rejection. Side effects were mild with dose regimens up to 750 mg twice daily.

The first Italian liver transplant center to reach the goal of 1000 procedures was Turin. The paper reports this single-center experience, highlighting the main changes that have occurred over time. From 1990 to 2002, 1000 consecutive liver transplants were performed in 910 patients, mainly cirrhotics. Surgical technique was based on the preservation of the retrohepatic vena cava of the recipient. The veno-venous bypass was used in 30 cases only and abandoned since 1997. Operating time, warm ischemia time and length of hospital stay significantly decreased over the years, while operating room extubation became routine. Immunosuppression pivoted on cyclosporine A. Management of retransplantations, marginal grafts, and of HCV-positive, HBV-positive and hepatocellular carcinoma recipients were optimized. Median follow-up of the patients was 41 months. Overall survival rates at 1, 5 and 10 years were 87%, 78% and 72% respectively. Survival rates obtained in the second half of the cases (1999-2002 period) were significantly better than those obtained in the first half (1990-1998 period) (90% vs. 83% at 1 year and 81% vs. 76% at 5 years respectively). Increasing experience in liver transplant surgery and postoperative care allowed standardization of the procedure and expansion of the activity, with parallel improvement of the results.

Aim The impact of new-onset diabetes (NOD) posttransplantation has been underestimated in the past. The aim of this study was to evaluate the incidence of diabetes after liver transplantation. Methods We retrospectively analyzed the incidence of NOD in 899 patients transplanted in our center. According to International Consensus 2003 Guidelines, criteria for diagnosis of diabetes were: fasting plasma glucose ≥126 mg/dL, symptoms of diabetes plus casual plasma glucose concentrations ≥200 mg/dL, and 2-hour plasma glucose levels ≥200 mg/dL during an oral glucose tolerance test. We considered only patients with follow-up over 10 months. We evaluated the risk factors correlated with NOD (age, hepatitis C virus [HCV] positivity, tacrolimus vs cyclosporine, steatosic graft), and the outcomes of diabetic patient and their grafts. Results The incidence of NOD was 10.8% (90/830 patients). Sixty nine patients were diabetic before transplantation. Recipient age >45 years (14.7% vs 6.8%, P = .002, OR = 2.4) and HCV positivity (15.5% vs 7.8%, P = .001, OR = 2.2) significantly correlated with NOD. Multivariate analysis confirmed these variables to be independently associated with diabetic risk. Tacrolimus was associated with an increased risk of NOD (16.2% in HCV-negative patients, 25% in HCV-positive patients), but this difference was not statistically significant. Steatotic grafts (>10%) were associated with an increased risk of NOD (28.6% vs 10%, P = .001, OR = 3.6). The outcome of patients and grafts in the group of diabetic patients was not significantly different from all other patients. Conclusions The incidence of NOD was more relevant in patients older than 45 years and/or HCV-positive. A steatotic graft was an important risk factor, and the match with high-risk patients should be avoided.

The indications for sequential liver and kidney transplantation have not been well defined. Two categories of patients may benefit from this procedure: patients with primary renal disease associated with hepatic disorders (glomerulonephritis, tubulointerstitial nephritis, metabolic diseases, and structural diseases) and patients who develop renal failure after liver transplantation. Chronic renal failure is a frequent long-term complication after liver transplantation. End-stage renal disease develops in 2% to 10% of cases by 10 years after transplantation. Kidney transplantation appears to be a better option than dialysis for the treatment of end-stage renal disease after liver transplantation. In contrast, survival rates, after kidney transplantation are significantly lower among liver transplant patients than primary-only kidney transplant recipients. Considering the donor shortage, kidney transplantation should be cautiously considered in liver transplantation patients. New immunosuppressive drugs and protocols are needed to reduce chronic renal failure after liver transplantation.

Liver transplantation involving living-related donors has been adopted in many centers as a way of relieving organ shortage. This study reviewed the anesthetic considerations for donor operations at our institution in relation to intraoperative blood transfusion, complications, and postoperative liver function test results. From January 1990 to May 2001, 30 living-related liver transplantations were performed at Baskent University Hospital, Ankara. The donor data used for analysis were retrospectively obtained through chart review, anesthesia records, and the computerized hospital database. Left lobectomy was performed in 19 cases, and left lateral segmentectomy in 11 cases. Intraoperatively, the average volume of intravenous fluids used was 6431±468 ml, and the average amount of blood transfused was 2.1±0.4 units. The mean postoperative hospital stay was 11.5±1.3 days. The only intraoperative complication observed in these 30 donors was severe bleeding during retrohepatic vena cava dissection in one of the cases. The postoperative complications related to anesthesia were one case each of shoulder pain, neuropraxia, and compartment syndrome. The levels of total and direct bilirubin, aspartate aminotransferase, and alanine aminotransferase peaked within the first 2 postoperative days (2.19±0.36 mg/dl, 1.02±0.18 mg/dl, 245.7±26.6 U/l, 313.5±51.9 U/l, respectively). In all 30 donors, these levels had normalized by 1 month after surgery. Maximal efforts must be applied in the anesthetic approach to minimize donor complications in living-related liver transplantation; however, this will not completely eliminate some risks to the donor.

Case report: We report the case of an 80-day-old infant referred to our department with refractory severe dermatitis, resembling Acrodermatitis Enteropathica (AE), associated with moderate failure to thrive. She had been hospitalized in a different clinic when she was 50 days old. During that time she was treated with oral steroids for suspected atopic dermatitis with no lasting benefits. The baby had been exclusively breast fed. At admission, the patient was well below the 3rd percentile for weight and at the 25th percentile for length, while the respective percentiles at birth were both at the 50th. Dermatological examination revealed erythematous, scaly plaques with crusts and ulcerations, predominantly in the diaper area, perioral area and extremities. Mucous membranes and nails were not involved. Laboratory tests revealed anemia, hypoalbuminemia and zinc deficiency. Laboratory abnormalities included the following: albumin minimum values of 16.2 and 19.2 g/dl (38–54 g/dl), haemoglobin minimum values of 5.5 and 6.7 g/dl (10–13 g/dl). Two albumin infusions and two blood transfusions were required. A sweat test was done but the amount of sweat collected was insufficient for an accurate result, influenced by the skin condition. However, stools were positive for fat analysis; steatocrit was 28% ( 5 U/g). With the suspect of CF pancreatic enzyme supplementation was started and was associated with clinical and laboratory findings improvement. The dermatitis showed a gradual resolution, preceded by an extensive desquamation. Finally, mutation analysis for CF showed homozygous mutation 508. After three months of therapy, the patient’s weight increased from the 3rd to the 25th percentile, the dermatitis had completely resolved and laboratory findings had improved. Conclusions: Skin manifestations of CF are under-estimated; however, dermatitis can be the presenting sign of the disease, prior to pulmonary and gastrointestinal symptoms. AE-like dermatitis may concur and allows a correct and early diagnosis in atypical presentations of CF, particularly in association with other symptoms such as failure to thrive or laboratory findings such as anemia and hypoalbuminemia. Even in cases of negative neonatal screening, further investigations such as the sweat test and/or genetic analysis may be required if there are symptoms suggestive of CF. It is important to offer genetic counselling to parents with a family history of CF so that they are aware of the possibility of performing CF carrier screening and prenatal diagnosis.