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Metabolic Conditions
An inherited metabolic disorder is an increasingly common indication for liver transplantation (LT), accounting for more than 15% of pediatric cases worldwide and up to 30% in some specialist centers. Urea cycle disorders are now the most common indication in the United States, followed by alpha-1 antitrypsin deficiency.
In an individual child and family, the therapeutic decision has to incorporate the transplant center’s results and experience, the impact of the metabolic defect on the child and family, the natural history of the defect, and whether any new therapies are available now or in the future. The transplantation team should be supported by metabolic specialists when metabolic disease is the indication and should be able to call on other relevant organ-based specialists, as required. An individual perioperative protocol should be prepared that incorporates instructions for immediate pre-operative preparation and investigations, which individuals and teams to contact, and a summary of intraoperative and early post-transplantation management.
In considering the indications for and outcomes of LT in metabolic disease, two independent factors need to be considered: first, whether or not the metabolic defect causes significant liver disease; and second, whether or not the defect is confined to the liver. This results in four categories of disorders to consider ( Table 39.1 ).
Table 39.1
Liver disease categories
| Category | Liver Disease a | No Significant Liver Disease |
|---|---|---|
| Defect confined to liver (A) | Alpha-1 antitrypsin deficiency (PiZ) Tyrosinemia type 1 Wilson disease PFIC types 2, 3, and undefined Urea cycle disorders: ASLD (arginosuccinic aciduria) GSD types I (adenoma, HCC) and IIIb Indian childhood cirrhosis Bile acid synthesis disorders Hereditary hemochromatosis |
Crigler-Najjar syndrome type 1 Primary hyperoxaluria type 1 (preemptive) Urea cycle disorders (arginosuccinic aciduria excepted) Citrin deficiency Familial hypercholesterolemia Hemophilia Factor VII deficiency Protein C and S deficiencies Factor H deficiency Fatty acid oxidation defects Acute intermittent porphyria Familial amyloid polyneuropathy Afibrinogenemia |
| Extrahepatic defects (B) | GSD types Ib, IIIa, and IV Erythropoietic protoporphyria Lysosomal storage diseases Niemann-Pick disease Cystic fibrosis Respiratory chain disorders PFIC types 1 and 4 Cholesterol ester storage disease |
MSUD Methylmalonic acidemia Propionic acidemia Primary hyperoxaluria type 1 (with renal failure) S-Adenosylhomocysteine hydrolase deficiency Ethylmalonic encephalopathy Mitochondrial neurogastrointestinal encephalomyopathy |
ASLD, Argininosuccinate lyase deficiency; GSD, glycogen storage disease; HCC, hepatocellular carcinoma; MSUD, maple syrup urine disease; PFIC, progressive familial intrahepatic cholestasis.
Category 1: Intrinsic Liver Disease With Defect Confined to the Liver
In this group, the indications for transplantation depend on the severity of the liver disease rather than that of the intrinsic metabolic defect. If the defect causes a significantly higher risk of developing hepatocellular carcinoma (HCC), such as in tyrosinemia type 1 (HT1), transplantation maybe indicated at an earlier stage than if it were based on the severity of liver disease alone.
For this category, the outcome of LT will reflect the success of the transplantation program, the clinical status of the child at transplantation, and possibly the age at transplantation. LT for acute liver failure (ALF) is less successful than elective transplantation. The effect of age at transplantation is more unpredictable. LT in early infancy is less successful, but considering that these are very ill children with ALF, and that waiting times are usually longer for this age group, this is hardly unexpected. Beyond 6 months old, age at transplantation has little impact on outcome. Children with established liver disease usually have some degree of portal hypertension, tend to develop collateral circulation, and hence tolerate the effect of intraoperative portal vein clamping relatively well.
Post-transplantation, there is lifelong correction of the metabolic defect, with the possible exception of progressive familial intrahepatic cholestasis type 2 (PFIC2), in which functional recurrence is possible, and the long-term prognosis is similar to that of contemporary LT for other indications.
Progressive Familial Intrahepatic Cholestasis Type 2
PFIC2 is caused by deficiency of the canalicular bile salt export pump (BSEP) as a result of mutations in ABCB11 . Mutations that result in some expression of BSEP have a less severe phenotype than those resulting in no expression of BSEP. The most common clinical presentation of the severe phenotype is neonatal jaundice and subsequent pruritus. Biochemical tests show normal or low serum gamma-glutamyltransferase (GGT) activity, and liver histology typically demonstrates a severe giant cell hepatitis.
Treatment consists of supportive nutritional and medical care, with timely partial external biliary diversion in those with preserved BSEP expression. Unfortunately, progression to cirrhosis is common and, when this is established, or biliary diversion fails, LT is the only lifesaving option.
Overall, LT has been very successful and, in most cases, provides functional correction of the defect. However, as many as 8% to 10% develop recurrence of cholestasis between 3 months and 10 years post-transplantation. This has been shown to be the result of de novo anti-BSEP antibodies, which inhibit bile acid transport. This phenomenon is confined to those with severe mutations in which there is little or no BSEP expression. In this setting, BSEP protein escapes normal immune autotolerance and becomes an immune target when expressed in the allograft.
Treatment options include manipulating immunosuppression, plasmapheresis, rituximab, and, in intractable cases, bone marrow transplantation. When repeat LT has been required, the incidence of recurrent disease is very high.
Tyrosinemia Type 1
HT1 is caused by a deficiency of the enzyme fumaryl-acetoacetase (FAA), resulting in the formation of toxic intermediate metabolites, including succinyl-acetone (SA), which is pathognomonic. HT1 most commonly presents with liver failure in the first 6 months of life, but may present later with chronic liver disease, rickets, and failure to thrive. Survivors have a high risk of developing HCC. HT1 is diagnosed by the detection of urinary SA and confirmed by detection of two pathogenic mutations. Increasingly, HT1 is being diagnosed preemptively by universal newborn screening initiated in some countries.
The natural history of the disease has been transformed by the use of nitisinone, which, in combination with phenylalanine and a tyrosine-restricted diet, corrects liver failure in more than 90% of cases, abolishes porphyria-like crises, and improves renal and liver function. Treatment following early diagnosis at newborn screening results in normal liver function and structure until at least adolescence. The earlier the treatment is commenced, the lower is the risk of developing HCC, which has not been reported in those treated preemptively.
Current indications for LT include the following : ALF not responding to nitisinone (no improvement of coagulopathy or progressive jaundice after 1 week of treatment) or proven or suspected HCC 2 .
LT results in a lifelong functional cure, allowing a normal diet with improved quality of life. Renal production of SA persists following LT (see Figure 39.1 ), but this does not appear to have pathological consequences. SA production is not correlated with renal or liver function, and porphyria-like neurological crises have not been reported post-transplantation. Continued nitisinone treatment post-LT will abolish renal SA production, but at the cost of increased tyrosine levels, raising the issue of whether reintroduction of dietary restriction would be necessary. Thus this cannot be routinely recommended.
Category 2: Intrinsic Liver Disease With an Extrahepatic Defect
The indication for transplantation in this category will usually be as in category 1—that is, primarily based on the severity of the liver disease. However, in some disorders, the timing of transplantation may be affected by the extrahepatic defect, for which there may be a relatively short time window in which transplantation is feasible (e.g., in cystic fibrosis). The metabolic correction of the defect will be immediate and lifelong, but the ultimate outcome will reflect not just the outcome of transplantation but also the nature and progression of the extrahepatic disease. When counseling families, the fact that LT will not be “curative” should be highlighted. In this group of diseases, preemptive transplantation may not be appropriate, depending on the nature of the extrahepatic defect. A careful, individualized, multidisciplinary transplantation assessment process should be undertaken, and the outcome of transplantation in this group of disorders should be continuously audited.
Cystic Fibrosis–Related Liver Disease
Approximately 5% to 10% of young people with cystic fibrosis develop cirrhosis and portal hypertension, and some of them develop end-stage liver disease. LT has been shown to be very successful in selected cases, with excellent medium-term survival. Transplantation results in an initial stabilization of lung function and some slowing of the natural rate of deterioration in the first 4 years. In the longer term, respiratory deterioration continues to be the most common cause of death.
In cystic fibrosis, LT needs to be undertaken while there is sufficient pulmonary reserve to support the operation. Ideally, the FEV1 (forced expiratory volume over 1 second) should be greater than 50% predicted and certainly more than 40% predicted. Occasionally, preemptive LT, before the development of end-stage liver disease, may be appropriate if pulmonary function is deteriorating, as there is a risk of missing the window of opportunity. However, if LT is undertaken too early, end-stage liver disease may never have developed before the eventual onset of pulmonary insufficiency. In this situation, LT may not result in improved survival. However, the improved quality of life following successful LT also needs to be considered in the setting of this complex equation.
Mitochondrial Liver Diseases
Mitochondrial liver diseases may be the result of inherited disorders of respiratory chain proteins or because of abnormalities of mitochondrial DNA assembly. Unfortunately, these disorders are usually multisystemic, and when the presentation is with ALF, the outlook is very poor. LT for ALF resulting from a multisystemic defect does not prevent, and may even hasten, neurological deterioration. This is not just an individual tragedy but, in an era of organ shortage, results in the denial or delay of transplantation to someone else. The challenge is to exclude untreatable disorders as quickly and accurately as possible without denying lifesaving LT to those who may benefit.
Rapid and accurate characterization of the underlying defect is increasingly feasible, and more is known about the natural history of this group of disorders. LT is contraindicated when liver failure is because of valproate-induced ALF, in children who have pathogenic mutations in polymerase γ, Twinkle, or deoxyguanine kinase enzymes with neurological involvement. On the other hand, children presenting with chronic liver disease because of an isolated respiratory chain defect may have an excellent outcome following LT. Similarly, occasional children with mitochondrial DNA depletion owing to mutations in MPV-17 have good-quality, long-term survival, albeit often complicated by peripheral neuropathy. When the underlying defect in mitochondrial DNA cannot be defined, a systematic multidisciplinary assessment, including evaluation of extrahepatic involvement ( Fig. 39.2 ), is important so that individualized advice can be given to affected families. In general, the benefit of any genuine doubt should be given to the child.
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