[Expert consensus of perioperative management in pediatric liver transplantation].

Pediatric liver transplantation (PLT) is an effective strategy of treating various acute or chronic end-stage liver diseases and inherited metabolic diseases in children.PLT has been applied in many transplant centers nationwide and has achieved satisfactory results.However,the development of transplant centers is uneven,and there is a lack of consensus and standards within the industry.In order to reduce post-operative complications,accelerate post-operative recovery,and improve the short-and long-term quality of life of children,the Enhanced Recovery After Surgery Committee of Chinese Research Hospital Association organized multidisciplinary experts to summarize the progress of domestic and international research,and formulated a perioperative consensus on PLT based on the principles of evidence-based medicine.The consensus provides recommendations for perioperative PLT from three aspects:preoperative assessment and preparation,intraoperative management and postoperative management,in order to provide reference guidelines for centers that are conducting or preparing to conduct PLT.

Differential Intraoperative Effect of Liver Transplant in Different Inborn Errors of Metabolism.

Liver transplant (LT) is a therapeutic option for a growing number of inborn errors of metabolism (IEM), including some disorders not confined to the liver. Clinical advantages of LT in maple syrup urine disease (MSUD), methylmalonic acidemia (MMA), and argininosuccinic aciduria (ASA) have been reported. However, no information on the early metabolic effect of LT after portal reperfusion is available in these disorders. Here we describe the intraoperative differential metabolic outcome of LT in MSUD, MMA, and ASA. In these IEM, LT promptly cleared toxic metabolites to safe concentrations. In MSUD, leucine concentration reached physiological concentration within 12 hours after portal reperfusion. In MMA and ASA, LT allowed faster clearance of methylmalonate and argininosuccinate, respectively, both dropping by ∼90% within the first hour after portal reperfusion. The early biochemical benefits of LT in MSUD, MMA, and ASA demonstrate its immediate effectiveness in protecting patients from intercurrent metabolic decompensations.

Analysis of fragment size distribution of cell-free DNA: A potential non-invasive marker to monitor graft damage in living-related liver transplantation for inborn errors of metabolism.

Graft-derived-cell-free DNA (Gcf-DNA) in plasma is a promising biomarker to monitor graft-rejection after liver transplantation (LTx). However, current methods of measuring Gcf-DNA have several limitations including high cost, long turnaround-time and the need to request donor's genetic information. In this study, eleven patients diagnosed with different inborn errors of metabolism (IEMs) who required living-related LTx were enrolled in order to establish a potentially useful noninvasive method to monitor graft damage. Circulating cell-free DNA (cfDNA) was extracted from plasma specimens serially collected at specific time points (day 0, day 1, day 7, day 14, day 30, day 60) after LTx. The distribution of Gcf-DNA fragment sizes was measured using sequencing read lengths and quantified by using Y-chromosome capture methodology in seven sex-mismatched recipients. In the analysis of fragment size distribution, we observed Gcf-DNA exhibited smaller fragment sizes than the recipient-cfDNA. Based on this phenomenon, two fragment sizes (105-145 bp, 160-170 bp) of the cfDNA pool were extracted to enrich Gcf-DNA. Accordingly, the ratio of short fragments to long fragments (S/L-Frag) in cfDNA was calculated. A high S/L-Frag ratio pointed towards an early trend of graft injury when compared to two routine liver function enzymes (ALT and AST) and Gcf-DNA, and it significantly correlated with ALT (P < 0.0001) and AST (P < 0.0001) during full-blown rejection. In conclusion, we established the Gcf-DNA size profile in patients who have undergone living-related LTx and established a potential biomarker to monitor graft function after LTx.

Domino Liver Transplantation: Where are we Now?

BACKGROUND: Domino transplant occurs when a recipient explanted graft is used for a second recipient. INTRODUCTION: The first experience came from thoracic surgery by the observation that many patients during heart-lung transplantation actually showed a functional heart that could be employed in other subjects with a good result. RESULTS: This concept was then extended to the field of liver transplantation. At present, some patients transplanted for an inborn metabolic disease may be considered as excellent domino liver donors. CONCLUSION: The results, limitations, clinical challenges and the donor and recipient features of domino liver transplantation are discussed in this manuscript.

Auxiliary Partial Orthotopic Liver Transplantation for Selected Noncirrhotic Metabolic Liver Disease.

Auxiliary partial orthotopic liver transplantation (APOLT) in selected noncirrhotic metabolic liver diseases (NCMLDs) is a viable alternative to orthotopic liver transplantation (OLT) as it supplements the function of the native liver with the missing functional protein. APOLT for NCMLD is not universally accepted due to concerns of increased technical complications and longterm graft atrophy. Review of a prospectively collected database of all pediatric patients (age ≤16 years) who underwent liver transplantation for NCMLD from August 2009 up to June 2017 was performed. Patients were divided into 2 groups: group 1 underwent APOLT and group 2 underwent OLT. In total, 18 OLTs and 12 APOLTs were performed for NCMLDs during the study period. There was no significant difference in the age and weight of the recipients in both groups. All APOLT patients needed intraoperative portal flow modulation. Intraoperative peak and end of surgery lactate were significantly higher in the OLT group, and cold ischemia time was longer in the APOLT group. There were no differences in postoperative liver function tests apart from higher peak international normalized ratio in the OLT group. The incidence of postoperative complications, duration of hospital stay, and 1- and 5-year survivals were similar in both groups. In conclusion, we present the largest series of APOLT for NCMLD. APOLT is a safe and effective alternative to OLT and may even be better than OLT due to lesser physiological stress and the smoother postoperative period for selected patients with NCMLD.

Surgical consequences in infants with delayed diagnosis of congenital chloride diarrhea.

Despite the usual typical presentation, congenital chloride diarrhea (CCD) poses multiple diagnostic challenges. It has an incidence of 1/5000 in Saudi Arabia. CCD can mimic intestinal obstruction and result in avoidable surgical interventions. Contributing factors are abdominal distension and the watery (urine-like) diarrhea that is often interpreted as delayed passage of meconium. Surgical interventions would unnecessarily increase the morbidity. Therefore, a high index of suspicion and educating neonatologists, general pediatricians, and pediatric surgeons regarding this diagnostic entity is essential. Here we describe five such cases.

Anesthetic Management of Patients With Inborn Errors of Metabolism.

Inborn errors of metabolism (IEM) are characterized by the body's inability to convert food into energy. The pathogenetic mechanism is based on defects in a variety of cellular enzymes. In addition to impairment of energy generation, accumulation of substrates may occur, which can deposit in tissue and lead to organ dysfunction. IEM can have profound implications for perioperative management, including difficult airway management, cardiac dysfunction, aspiration risk, seizures, and metabolic dysregulation. For the anesthesiologist, comprehensive knowledge is difficult to attain because of the heterogeneity of this group and the low prevalence of specific diseases. The first part of this article reviews intermediary metabolism, whereas the second part aims to highlight important aspects in perioperative management of patients with IEM. Instead of reviewing each single disorder within the vast group of IEM, we provide a conceptual framework that will facilitate the understanding of main problems encountered in each of the disease subgroups.

[Liver Transplantation as Treatment for Rare Diseases in Adults]. / Lebertransplantation als Therapie von seltenen Erkrankungen beim Erwachsenen.

In addition to the main indications pertaining to 95 % of all patients receiving liver transplantation in Germany, there are numerous other diseases that may become clinically evident in the adult age and may lead to the decision for liver transplantation. These may be metabolic diseases with their main defect located in the liver, malformations of liver cells, hepatic vascular diseases and rare tumours of the liver. Standard exceptions for the listing are in place only for a limited number of diseases. Exact diagnostics and the point in time for transplantation are crucial for the prognosis.

Evaluation of Mannose-Binding Lectin is a Useful Approach to Predict the Risk of Infectious Complications Following Autologous Hematopoietic Stem Cell Transplantation.

Hematopoietic stem cell transplantation (HSCT) associated immunocompromised state carries high risk of infectious complications. Mannose-binding lectin (MBL) is an acute phase protein involved in innate immune response. Serum MBL level is genetically determined and quite stable. According to literature, significant association was shown between low MBL concentrations and serious infections. The association between serum MBL level and frequency and severity of infections was studied in 186 patients following autologous HSCT. Double-monoclonal antibody sandwich enzyme-linked immunosorbent assay was used to determine MBL antigen level in sera. MBL levels were measured around 100 days following transplantation, in a period without active infection. Twenty-one patients (11%) were MBL deficient. The median time of first infection and number of infections during the first year post-transplantation were not significantly different between patients with MBL deficiency and those without MBL deficiency. The occurrence and number of infections after HSCT correlated with the MBL/C-reactive protein ratio. The number of severe infections was not higher among those with MBL deficiency. The occurrence of infections after the pre-engraftment period during the first year post-transplantation was significantly different in patient groups separated by MBL cut-off level. The MBL/C-reactive protein ratio might be a useful marker of infectious complications. MBL measurement may be helpful in antibiotic treatment. In case of MBL deficiency, earlier and more intensive treatment may be indicated.

Exchange of Partial Liver Transplantation Between Children with Different Non-Cirrhotic Metabolic Liver Diseases: How Do We Arrive There?

Hepatic-based metabolic disorders are characterized by an enzyme deficiency expressed solely or mainly in the liver. They are divided into cirrhotic or non-cirrhotic metabolic liver diseases (NCMLDs), and most of them can be treated by liver transplantation. Because the livers with NCMLDs are usually structurally and functionally normal, the primary aim of the liver graft is to support the deficient enzymes rather than maintaining liver functions. Hence, we hypothesize that the exchange of partial liver grafts by the technique of auxiliary partial orthotopic liver transplantation (APOLT) between patients with 2 different NCMLDs may be feasible to replace the deficient enzymes in each patient. This hypothesis is based on the following conditions: (i) the patients have no chance of undergoing timely liver transplantation, (ii) the symptoms of each NCMLD may be alleviated after exchanging partial liver grafts, and (iii) each graft is anatomically appropriate for APOLT. In addition, we evaluate it with a focus on selection of cases, designing of graft sizes, and surgical techniques for reciprocal APOLT.

Living donor liver transplantation for inborn errors of metabolism - An underutilized resource in the United States.

Inborn metabolic diseases of the liver can be life-threatening disorders that cause debilitating and permanent neurological damage. Symptoms may manifest as early as the neonatal period. Liver transplant replaces the enzymatically deficient liver, allowing for metabolism of toxic metabolites. LDLT for metabolic disorders is rarely performed in the United States as compared to countries such as Japan, where they report >2000 cases performed within the past two decades. Patient and graft survival is comparable to that of the United States, where most of the studies are based on deceased donors. No living donor complications were observed, suggesting that LDLT is as safe and effective as deceased donor transplants performed in the USA. Increased utilization of living donors in the USA will allow for early transplantation to prevent permanent neurological damage in those with severe disease. Pediatric transplant centers should consider utilizing living donors when feasible for children with metabolic disorders of the liver.

Liver transplantation for pediatric inherited metabolic disorders: Considerations for indications, complications, and perioperative management.

LT is an effective therapeutic option for a variety of IEM. This approach can significantly improve the quality of life of patients who suffer from severe disease manifestations and/or life-threatening metabolic decompensations despite medical/dietary management. Due to the significant risks for systemic complications from surgical stressors, careful perioperative management is vital. Even after LT, some disorders require long-term dietary restriction, medical management, and monitoring of metabolites. Successful liver transplant for these complex disorders can be achieved with disease- and patient-specific strategies using a multidisciplinary approach. In this article, we review indications, complications, perioperative management, and long-term follow-up recommendations for IEM that are treatable with LT.

Concise Review: Updated Advances and Current Challenges in Cell Therapy for Inborn Liver Metabolic Defects.

UNLABELLED: : The development of liver cell transplantation (LCT), considered a major biotechnological breakthrough, was intended to provide more accessible treatments for liver disease patients. By preserving the native recipient liver and decreasing hospitalization time, this innovative approach has progressively gained interest among clinicians. LCT initially targets inborn errors of liver metabolism, enabling the compensation of deficient metabolic functions for up to 18 months post-transplantation, supporting its use at least as a bridge to transplantation. The rigorous clinical development and widespread use of LCT depends strongly on controlled and consistent clinical trial data, which may help improve several critical factors, including the standardization of raw biological material and immunosuppression regimens. Substantial effort has also been made in defining and optimizing the most efficient cell population to be transplanted in the liver setting. Although isolated hepatocytes remain the best cell type, showing positive clinical results, their widespread use is hampered by their poor resistance to both cryopreservation and in vitro culture, as well as ever-more-significant donor shortages. Hence, there is considerable interest in developing more standardized and widely accessible cell medicinal products to improve engraftment permanency and post-cell transplantation metabolic effects. SIGNIFICANCE: In this therapeutic approach to liver disease, new solutions are being designed and evaluated to bypass the documented limitations and move forward toward wide clinical use. Future developments also require a deep knowledge of regulatory framework to launch specific clinical trials that will allow clear assessment of cell therapy and help patients with significant unmet medical needs.

Hepatocyte transplantation program: Lessons learned and future strategies.

This review aims to share the lessons we learned over time during the setting of the hepatocyte transplantation (HT) program at the Hepatic Cell Therapy Unit at Hospital La Fe in Valencia. New sources of liver tissue for hepatocyte isolation have been explored. The hepatocyte isolation and cryopreservation procedures have been optimized and quality criteria for assessment of functionality of hepatocyte preparations and suitability for HT have been established. The results indicate that: (1) Only highly viable and functional hepatocytes allow to recover those functions lacking in the native liver; (2) Organs with steatosis (≥ 40%) and from elderly donors are declined since low hepatocyte yields, viability and cell survival after cryopreservation, are obtained; (3) Neonatal hepatocytes are cryopreserved without significant loss of viability or function representing high-quality cells to improve human HT; (4) Cryopreservation has the advantage of providing hepatocytes constantly available and of allowing the quality evaluation and suitability for transplantation; and (5) Our results from 5 adults with acute liver failure and 4 from children with inborn metabolic diseases, indicate that HT could be a very useful and safe cell therapy, as long as viable and metabolically functional human hepatocytes are used.

[Kidney Transplantation and inborn errors of metabolism]. / Trapianto renale nelle malattie da errori congeniti del metabolismo.

Inherited kidney diseases constitute at least 150 different disorders and they have an overall prevalence of about 6080 cases per 100,000 in Europe and in USA. At least 10% of adults and nearly all children who progress to renal-replacement therapy have an inherited kidney disease, representing the fifth most common cause of end-stage renal disease after diabetes, hypertension, glomerulonephritis, and pyelonephritis. These conditions include both structural and functional disorders, among which are counted diseases resulting from inborn errors of metabolism (IEM). Some inborn errors of metabolism primarily affect kidney and because of progress in renal replacement therapy, patients with inherited kidney disorders rarely die when their disease progresses and can live for many years. However, these patients often have compromised health with a poor quality of life. Renal transplantation offers a viable treatment option for those inborn errors of metabolism characterized by primary renal damage caused by dysfunction of a mutated protein, as in cystinuria. In this case, the indication to renal transplantation makes it possible to overcome the specific enzyme defect. However this option remains valid even when the genetic defect is expressed systemically and renal involvement is just one of the clinical manifestations of the disease, as in Anderson-Fabry disease, cystinosis, hereditary amyloidosis and primary hyperoxaluria. In these conditions, renal transplantation is combined with the liver (primary hyperoxaluria) or cardiac transplant (familial amyloidosis) improving the quality and life expectancy of patients.