Conference Proceedings
Liver transplantation for pediatric metabolic disease

https://doi.org/10.1016/j.ymgme.2014.01.006Get rights and content

Highlights

  • Overall outcomes for metabolic liver transplant have improved in the past 3 decades.

  • LTx can lead to a better quality of life even if not all symptoms of the primary disorder are eliminated.

  • Risk-benefit ratio of LTx must be carefully evaluated.

  • Hepatocyte transplantation may be a viable alternative to whole organ replacement in some disorders.

Abstract

Liver transplantation (LTx) was initially developed as a therapy for liver diseases known to be associated with a high risk of near-term mortality but is based upon a different set of paradigms for inborn metabolic diseases. As overall outcomes for the procedure have improved, LTx has evolved into an attractive approach for a growing number of metabolic diseases in a variety of clinical situations. No longer simply life-saving, the procedure can lead to a better quality of life even if not all symptoms of the primary disorder are eliminated. Juggling the risk-benefit ratio thus has become more complicated as the list of potential disorders amenable to treatment with LTx has increased. This review summarizes presentations from a recent conference on metabolic liver transplantation held at the Children's Hospital of Pittsburgh of UPMC on the role of liver or hepatocyte transplantation in the treatment of metabolic liver disease.

Introduction

Liver transplantation (LTx) was initially developed as a therapy for liver diseases known to be associated with a high risk of near-term mortality. In pediatrics, a classical example is biliary atresia [1], [2], [3]. The natural history of this disorder is quite well characterized — it is one of progressive liver disease if surgical treatment by portoenterostomy is unsuccessful, where survival beyond 36 months of life is rare [3]. LTx affords long term survival in over 80% of biliary atresia patients. Therefore, risk/benefit decisions are relatively easy in this circumstance — near-universal mortality with the existing disease versus substantially less risk with transplantation. Thus, LTx is clearly an excellent therapeutic approach for biliary atresia when portoenterostomy has failed.

LTx for inborn metabolic diseases is based upon a different set of paradigms [4]. It is of potential use for disorders in which toxic intermediary metabolites from multiple organ systems can freely interchange with other organs through the systemic circulation. In this setting, a genetically normal liver can correct metabolic balance in other organs. Initially, LTx was reserved for those disorders with essentially lethal outcomes (for example, the neonatal form of the urea cycle defect ornithine transcarbamylase deficiency) [5]. However, as risks of the procedure have decreased and post-operative outcomes have improved, LTx has evolved into an attractive approach for a growing number of metabolic diseases with considerably more complicated issues and a very distinct risk benefit profile [1], [6], [7], [8], [9], [10], [11], [12]. As the collective experience with LTx has grown, the view of the procedure as life-saving vs. life-improving is evolving, blurring the line between standard medical management and a more aggressive surgical therapy [13]. The risks and benefits of LTx must be placed in the context of current and potential medical advances [4]. Genotypic and phenotypic diversity in nearly every metabolic disease complicate the ability to predict long-term outcome and response to therapy [14], [15]. Ultimately, it is critical to have a relatively complete understanding of the biology of the disease to predict the potential impact of LTx on the body, especially when the enzyme in question is not hepatocyte-specific and when living donor transplantation is contemplated from an obligate heterozygote parent with reduced enzyme activity.

Children's Hospital of Pittsburgh of UPMC (CHP) organized a conference, “Challenging the Paradigms: Liver Transplantation in Metabolic Disease” (May 4, 2012, Pittsburgh, PA), that addressed the role of liver or hepatocyte transplantation in the treatment of metabolic liver disease. This manuscript reviews the information presented at that conference, including CHP's three decades of outcome data regarding pediatric LTx for a broad range of metabolic diseases.

Section snippets

Maple syrup urine disease

Maple syrup urine disease (MSUD) is caused by mutations in six gene loci responsible for encoding the branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex, resulting in the body's transcarbamylaseinability to fully break down the essential amino acids valine, leucine, and isoleucine. Accumulating metabolites are excreted in the urine, sweat, and ear cerumen, the latter two leading to a sweet odor resembling maple syrup. The most common treatment for MSUD is a diet restricted in the

Mitochondrial disease

Mitochondrial hepatopathies are an increasingly recognized group of diseases leading to acute liver failure, fatty liver, cirrhosis, or intermittent liver dysfunction [27], [28]. Primary mitochondrial hepatopathies include disorders caused by mitochondrial DNA (mtDNA) deletions or mutations or, more commonly, by mutations in nuclear genes that encode specific respiratory chain subunits, or transcription, assembly, or translational machinery for mitochondria. Secondary mitochondrial

Glycogen storage diseases

Glycogen storage disease (GSD) types I, III, IV, VI, and IX are congenital disorders of glycogen metabolism often associated with severe liver disease [48], [49], [50]. Current interventions for the liver GSDs include dietary modifications and medical interventions such as pharmacotherapy for issues not corrected by diet. For GSD type I, nocturnal continuous enteral drip feeding to avoid fasting hypoglycemia and frequent oral uncooked corn starch intake for prolonged glucose release have

Hepatocyte transplantation

The use of solid organ LTx to treat liver-based metabolic disorders is limited by a severe shortage of donor organs, the risks associated with major surgery, and the low, but real, long-term risk of graft loss from rejection. Hepatocyte transplantation holds promise as an alternative to organ transplantation, and numerous animal studies indicate that transplants of isolated liver cells can correct metabolic deficiencies of the liver. Clinically, the procedure involves isolation of cells from

Current indications and outcomes

Inborn errors of metabolism represent approximately 15–25% of disease indications for LTx in children and have been reported to have comparable or better outcomes than transplant of patients with decompensated cirrhosis or other forms of chronic liver disease in both single and multi-center studies (Table 3) [8], [13], [83]. Three issues fundamentally affect decision making regarding a possible LTx. First, is there structural liver disease which carries “standard indications for

Organ allocation issues

The shortage of available livers for transplantation is an important issue to consider with the use of LTx for metabolic disorders, as increasing the number of LTx performed for these conditions will further tax the pool of donor organs. While the use of living donors expands the liver pool, a potential complicating issue is that parents of children with metabolic disorders are likely carriers for the conditions, and there is a 2/3 chance that their siblings are carriers. Typically, carriers'

Summary

LTx has been revolutionary and life-saving for disorders such as severe UCDs and MSUD. Initially viewed as a rescue procedure for such conditions, the risk of death or disability due to these inborn errors of metabolism now far outweigh the morbidity or mortality of transplant or long term sequelae related to immunosuppression. What factors play into this dramatic reversal? Of course, it is not hard to argue that increased experience with the technique over time has led to a broader pool of

Acknowledgments

The authors thank Christine Heiner (Scientific Writer, University of Pittsburgh Department of Surgery) for her help in the preparation of this manuscript.

References (112)

  • T.H. Vu et al.

    Navajo neurohepatopathy: a mitochondrial DNA depletion syndrome?

    Hepatology

    (2001)
  • W.S. Lee et al.

    Mitochondrial hepatopathies: advances in genetics, therapeutic approaches, and outcomes

    J. Pediatr.

    (2013)
  • J.D. Weisfeld-Adams et al.

    Newborn screening and early biochemical follow-up in combined methylmalonic aciduria and homocystinuria, cblC type, and utility of methionine as a secondary screening analyte

    Mol. Genet. Metab.

    (2010)
  • M. Nagao et al.

    Improved neurologic prognosis for a patient with propionic acidemia who received early living donor liver transplantation

    Mol. Genet. Metab.

    (2013)
  • A.M. de Mattos et al.

    Nephrotoxicity of immunosuppressive drugs: long-term consequences and challenges for the future

    Am. J. Kidney Dis.

    (2000)
  • P.S. Kishnani et al.

    Glycogen storage disease type III diagnosis and management guidelines

    Genet. Med.

    (2010)
  • F. Baertling et al.

    Liver cirrhosis in glycogen storage disease Ib

    Mol. Genet. Metab.

    (2013)
  • T.M. Manzia et al.

    Glycogen storage disease type Ia and VI associated with hepatocellular carcinoma: two case report

    Transplant. Proc.

    (2011)
  • A. Marega et al.

    Preemptive liver–kidney transplantation in von Gierke disease: a case report

    Transplant. Proc.

    (2011)
  • M. Muraca et al.

    Hepatocyte transplantation as a treatment for glycogen storage disease type 1a

    Lancet

    (2002)
  • S.E. Waisbren et al.

    Phenylalanine blood levels and clinical outcomes in phenylketonuria: a systematic literature review and meta-analysis

    Mol. Genet. Metab.

    (2007)
  • S.E. Christ et al.

    Executive function in early-treated phenylketonuria: profile and underlying mechanisms

    Mol. Genet. Metab.

    (2010)
  • A. Macdonald et al.

    Nutrition in phenylketonuria

    Mol. Genet. Metab.

    (2011)
  • F. Trefz et al.

    Adult phenylketonuria outcome and management

    Mol. Genet. Metab.

    (2011)
  • B.K. Burton et al.

    Tetrahydrobiopterin therapy for phenylketonuria in infants and young children

    J. Pediatr.

    (2011)
  • J. Meyburg et al.

    Liver, liver cell and stem cell transplantation for the treatment of urea cycle defects

    Mol. Genet. Metab.

    (2010)
  • K.A. Soltys et al.

    Late graft loss or death in pediatric liver transplantation: an analysis of the SPLIT database

    Am. J. Transplant.

    (2007)
  • K.A. Soltys et al.

    Barriers to the successful treatment of liver disease by hepatocyte transplantation

    J. Hepatol.

    (2010)
  • D. Morioka et al.

    Living donor liver transplantation for pediatric patients with inheritable metabolic disorders

    Am. J. Transplant.

    (2005)
  • T. Yorifuji et al.

    Living-related liver transplantation for neonatal-onset propionic acidemia

    J. Pediatr.

    (2000)
  • S. Romano et al.

    Cardiomyopathies in propionic aciduria are reversible after liver transplantation

    J. Pediatr.

    (2010)
  • V. Fouquet et al.

    Long-term outcome of pediatric liver transplantation for biliary atresia: a 10-year follow-up in a single center

    Liver Transpl.

    (2005)
  • H.V. Diem et al.

    Pediatric liver transplantation for biliary atresia: results of primary grafts in 328 recipients

    Transplantation

    (2003)
  • B.L. Shneider et al.

    Trading places: liver transplantation as a treatment, not a cure, for metabolic liver disease

    Liver Transplant.

    (2011)
  • D. Morioka et al.

    Current role of liver transplantation for the treatment of urea cycle disorders: a review of the worldwide English literature and 13 cases at Kyoto University

    Liver Transpl.

    (2005)
  • K. Hansen et al.

    Metabolic liver disease in children

    Liver Transpl.

    (2008)
  • K. Hansen et al.

    Metabolic liver disease in children

    Liver Transpl.

    (2008)
  • L.K. Kayler et al.

    Long-term survival after liver transplantation in children with metabolic disorders

    Pediatr. Transplant.

    (2002)
  • V.L. Ng et al.

    Outcomes of 5-year survivors of pediatric liver transplantation: report on 461 children from a North American multicenter registry

    Pediatrics

    (2008)
  • T. Stevenson et al.

    Long-term outcome following pediatric liver transplantation for metabolic disorders

    Pediatr. Transplant.

    (2010)
  • R. Arnon et al.

    Liver transplantation in children with metabolic diseases: the studies of pediatric liver transplantation experience

    Pediatr. Transplant.

    (2010)
  • J. Vockley

    Metabolism as a complex genetic trait, a systems biology approach: implications for inborn errors of metabolism and clinical diseases

    J. Inherit. Metab. Dis.

    (2008)
  • D.H. Morton et al.

    Diagnosis and treatment of maple syrup disease: a study of 36 patients

    Pediatrics

    (2002)
  • G.V. Mazariegos et al.

    Liver transplantation for classical maple syrup urine disease: long-term follow-up in 37 patients and comparative united network for organ sharing experience

    J. Pediatr.

    (2012)
  • D.A. Shellmer et al.

    Cognitive and adaptive functioning after liver transplantation for maple syrup urine disease: a case series

    Pediatr. Transplant.

    (2011)
  • B.A. Barshop et al.

    Domino hepatic transplantation in maple syrup urine disease

    N. Engl. J. Med.

    (2005)
  • A. Khanna et al.

    Domino liver transplantation in maple syrup urine disease

    Liver Transpl.

    (2006)
  • J. Haberle et al.

    Suggested guidelines for the diagnosis and management of urea cycle disorders

    Orphanet. J. Rare. Dis.

    (2012)
  • N. Ah Mew et al.

    Urea Cycle Disorders Consortium of the Rare Diseases Clinical Research, clinical outcomes of neonatal onset proximal versus distal urea cycle disorders do not differ

    J. Pediatr.

    (2013)
  • W.S. Lee et al.

    Mitochondrial hepatopathies: advances in genetics and pathogenesis

    Hepatology

    (2007)
  • Cited by (85)

    • The Multidisciplinary Pediatric Liver Transplant

      2023, Current Problems in Surgery
    • Natural history of propionic acidemia in the Amish population

      2022, Molecular Genetics and Metabolism Reports
      Citation Excerpt :

      The exact mechanism is not known but could be due to decreased accumulation of toxic metabolites in the heart. In addition, successful liver transplant appears to achieve metabolic stabilization, resulting in fewer hospitalizations, less dietary restriction, and improved linear growth [28,29]. There have, however, been reports of new or recurrent cardiomyopathy following liver transplantation for PA [30,31], though it is unclear if cardiomyopathy is secondary to the presence of a second genetic condition in these individuals or if it is a result of immunosuppressant medications.

    • Pediatric Liver Transplantation

      2022, Clinics in Liver Disease
      Citation Excerpt :

      In some metabolic diseases, such as maple syrup urine disease, LT only corrects the enzyme deficiency in the liver that is sufficient to improve QoL and decrease extrahepatic complications. There are some diseases in which an LT is needed to prevent progression of extrahepatic disease, such as primary hyperoxaluria type 1 and organic acidemias.6 In certain circumstances, a combined liver kidney transplant (hyperoxaluria, methyl malonic acidemia) or combined liver lung transplant (cystic fibrosis) is required.

    View all citing articles on Scopus

    Funding: BKB has received research funding, consulting fees and honoraria from Genzyme, Shire, Biomarin and Synageva and research funding from Ultragenyx. JV has received funding from the NIH, FDA, Biomarin Pharmaceuticals, Ultragenyx Pharmaceuticals, Alexion Pharmaceuticals, and Hyperion Therapeutics. RS was supported in part by NIH grant U01 DK 62453.

    View full text