Abstract
Inborn errors of metabolism are a recognizable cause of acute or chronic liver disease, as either fulminant hepatic failure, cirrhosis, or hepatocellular carcinoma. Improved survival rates following whole-organ orthotopic liver transplantation (OLT) have now made liver replacement a possible cure for several metabolic liver diseases and is therefore accepted as the definitive therapy for liver-based metabolic disease.
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In a recent analysis of 5,180 liver transplants performed in the United States, 5.3% were carried out for metabolic disease.
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Liver transplantation not only replaces the damaged organ but can also potentially correct the abnormal phenotype.
Hepatic-based metabolic diseases for which liver transplantation is appropriate fall into three general categories: metabolic liver disease with structural liver damage leading to cirrhosis and end-stage liver disease; metabolic liver disease without structural liver disease that leads to the failure of a second organ; and metabolic liver disease with partial liver function defects characterized by life-threatening progression.
In the first group, the genetic defect may be limited to the liver itself, such as occurs in the familial cholestatic syndromes, but more commonly the liver is one of the end organs damaged as a result of a more widespread defect (e.g., α
1-antitrypsin deficiency). When the liver is exclusively involved and is the only site of the metabolic defect, the decision to replace the liver is easily made and liver replacement can be expected to provide a complete reversal of the metabolic defect. However, in diseases in which the liver is damaged as a consequence of a widespread enzymatic defect residing in a variety of cells other than the hepatocyte, the determination regarding liver replacement is complex. Essential to this decision is a precise knowledge of the genetic defect itself, in which somatic cells the cellular defect is expressed, the extent of organ involvement outside the liver, and whether liver replacement alone will be sufficient to either prevent further deterioration or improve dysfunction in extrahepatic organs.
Auxillary partial liver transplantation, in which the enzymatically defective but structurally normal recipient liver is left in-situ, with a partial liver graft being placed in either a heterotopically or orthotopic position, has been used successfully to treat the urea cycle defect disease ornithine transcarbamylase deficiency.
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The auxiliary liver graft provides the enzyme of interest while the native liver remains to perform the remainder of the liver function. This technique, in addition to requiring a technically-demanding liver transplant, also requires life-long immunosuppression and carries with it the potential complications of both.
In the future, total liver replacement may become obsolete for some categories of metabolic disease.
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Normal, allogeneic hepatocytes have been able to provide temporary metabolic support in animal models,
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including the Gunn rat model of Crigler-Najjar syndrome.
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A more attractive option uses gene therapy, which modifies the genetic program of living cells.
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Harvested hepatocytes infected in vitro with a recombinant retrovirus or adenovirus carrying the normal human gene are then able to express the normal gene's protein products. Autologous transplantation of these genetically reconstituted hepatocytes is performed. This technique has been successfully applied to animal models of familial hypercholesterolemia
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and urea cycle defects.
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Alternatively, in vivo modification of hepatocytes might be achieved by a vector containing the normal gene. These types of approaches, if technically perfected, would avoid the potential morbidity and mortality associated with whole-organ and auxiliary liver transplantation and life-long immunosuppression.
The following sections systemically describe metabolic defects for liver transplantation is indicated in the adult patient. A description is provided for each disease entity and its biochemical effects, genetic predisposition, manifestations of liver disease, indications for liver transplantation, and impact of liver transplantation on the course of the disease. Liver transplantation for the child with metabolic liver disease will be discussed in the article by Dr. Kelly and Dr. McKiernan in this issue.