Model for end-stage liver disease (MELD) exception for unusual metabolic liver diseases
Metabolic liver disease is the underlying diagnosis in only a small proportion of patients who undergo liver transplantation (LT), but for these patients, LT is life-saving. Patients with metabolic liver disease often do not present with typical findings of end-stage liver disease and require special consideration and scrutiny concerning the appropriateness and timing of LT. Liver-based metabolic disease is classified into 3 types: (1) disease that causes structural liver damage with liver failure or cirrhosis, (2) metabolic disease without structural liver damage that affects other organs (especially the central nervous system), and (3) metabolic disease with systemic deficiencies that are partially represented in the liver. There may be overlap in presentation, with some disease forms presenting either with or without structural liver disease.
General considerations that affect review board decisions may include the relative contraindication of the use of living-related donor organs and the unpredictable metabolic course that may cause severe central nervous system complications in several of these disease states. Also, although many of these diseases present mostly in children, adolescents and adults previously managed medically are increasingly presenting for LT consideration when medical management becomes more difficult or complex as they mature.
METABOLIC DISEASES THAT LEAD TO LIVER FAILURE
This disease classification includes Wilson's disease, hemochromatosis, alpha-1-antitrypsin deficiency, tyrosinemia, biliary transport defects, and glycogen storage diseases. Wilson's disease and hemochromatosis are covered by the appropriate Model for End-Stage Liver Disease (MELD)/Pediatric End-Stage Liver Disease (PELD) score or status 1 listing.
Tyrosinemia type 1 (fumarylacetoacetate hydrolase deficiency) is a rare condition that results in fulminant liver disease, liver cancer, and progressive liver failure. Standard treatment is now with NTBC [2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexenedione] and a low-tyrosine diet. Potential indications for LT include fulminant disease in infants, progression of liver disease on NTBC, presence or suspicion of hepatocellular carcinoma (HCC), and possibly contraindications to the use of NTBC. Orthotopic LT corrects the metabolic liver disease and removes the risk for HCC. Renal dysfunction in later childhood or adulthood may develop. In most circumstances, MELD/PELD scoring exceptions can be applied for. Each case should be individually reviewed with advice from a physician who is experienced in the care of patients with tyrosinemia.1–5
Glycogen storage disease has at least 14 variants and subclassifications. Type 1 (1a glucose-6-phosphatase deficiency and 1b glucose-6-phosphate translocase deficiency) may result in metabolic instability, adenoma, or HCC and is cured by LT. Type 3 debrancher enzyme deficiency can lead to cirrhosis in adult patients, and there is an increased risk for adenoma and HCC. LT is an effective therapy for the liver disease. Currently, there are no data on which to base exception scores. Type 4 brancher enzyme deficiency can also result in cirrhosis in young children; PELD scores currently probably reflect severity of liver disease, and there are no data or supporting evidence to grant additional PELD points for these patients. If HCC or adenoma with malignant potential develop in these patients, standard HCC listing criteria can apply or an appeal to the Regional Review Board can be made.6–14
MELD/PELD is appropriate for patients with end-stage liver disease due to alpha-1-antitrypsin deficiency. For alpha-1-antitrypsin deficiency without evidence of chronic liver disease, there is no indication for LT.
Only one patient with COACH (cerebellar vermis hypoplasia, oligophrenia, congenital ataxia, ocular coloboma, hepatic fibrosis) syndrome has undergone LT. These patients can have severe cholestasis in addition to hepatic fibrosis, but prognosis is mostly determined by other features of the syndrome. There are no data on which to advise Regional Review Boards to grant additional PELD points.15
Biliary transport defects include Byler's disease (progressive familial intrahepatic cholestasis type 1), bile salt export protein deficiency (progressive familial intrahepatic cholestasis type 2), and MDR3 deficiency (progressive familial intrahepatic cholestasis type 3). These conditions have associated liver disease, and PELD scores are probably valid. Exceptions will be sought for the profound pruritus associated with these diseases, which can impair development and schooling. Each case should be considered with the aid of a metabolic expert and the input of the Regional Review Board.16–19
METABOLIC DISEASES WITHOUT STRUCTURAL LIVER DAMAGE LEADING TO SECONDARY ORGAN FAILURE OR CENTRAL NERVOUS SYSTEM COMPLICATIONS
These diseases include amyloidosis, primary hyperoxaluria, urea cycle defects, familial hypercholesterolemia, Crigler-Najjar type 1, and certain hematologic disorders. Amyloidosis and primary hyperoxaluria have been discussed elsewhere in this supplement. Urea cycle defects include ornithine transcarbamylase deficiency, carbamoyl phosphate synthetase deficiency, citrullinemia, and arginase deficiency. Prioritization for urea cycle defects causing hyperammonemia is addressed in current United Network for Organ Sharing policy. Arginase deficiency is a urea cycle disorder that does not produce hyperammonemia. This disease is correctable with LT, but it is most often managed medically. There are no data on this disease as an indication for LT.20
There is proven effectiveness of LT for Crigler-Najjar type 1 disease. Because there is no coagulopathy, growth failure, or hypoalbuminemia, and because the patient's unconjugated bilirubin is reduced by phototherapy, the PELD score is not able to be calculated; thus, exception scores for LT will be required. The death rate is not high (probably a negligible 90-day death rate), but serious potential for brain injury is the major indication for LT. Currently there are no data to determine what additional MELD/PELD points to assign, and the Regional Review Boards should discuss each case on an individual basis.21–24
The hemophilias are genetic diseases associated with specific factor deficiencies, including factor VIII deficiency (hemophilia A), factor IX deficiency (hemophilia B), and factor VII deficiency. LT is an effective therapy, but in general, it is reserved for other indications such as viral hepatitis with the development of end-stage liver disease secondary to hepatitis C virus infection. These diseases alone are not considered indications for LT.3, 25–27 Protein C and/or S deficiency are genetic deficiencies of coagulation factors. LT corrects the hypercoagulable state, but it is usually undertaken for other indications.28–31
Homozygous familial hypercholesterolemia leads to childhood coronary artery disease and myocardial infarction. There is no structural liver disease; thus, no PELD points are available for clinical decisions. There are no data upon which to determine priority PELD scores for these patients, and each case should be individually evaluated by the Regional Review Board.32
METABOLIC DISEASE WITH SYSTEMIC DEFICIENCY PARTIALLY REPRESENTED IN THE LIVER
These challenging diseases include methylmalonic aciduria, propionic academia, and maple syrup urine disease (MSUD). Other diseases such as phenylketonuria, although not currently considered indications for LT, also fit into this classification.
Methylmalonic academia greatly affects renal and neurologic function. LT corrects episodes of systemic metabolic decompensation, complicating this disease, but unfortunately, renal and neurological complications of methylmalonic acidemia have occurred late, even after successful LT. These patients must fulfill criteria for metabolic conditions associated with hyperammonemia to be listed at status 1b, and thus, no additional points should be assigned through the review board.33–37
Proprionic acidemia results in a variety of metabolic problems in infants and children. LT corrects episodes of systemic metabolic decompensation associated with this disease. These patients must fulfill criteria for metabolic conditions associated with hyperammonemia so they can be listed at status 1b; thus, no additional points should be assigned through the Regional Review Board.38
MSUD results in multiorgan injury. Classification is generally based on the severity of the BCKD (branched chain alpha-ketoacid dehydrogenase) enzyme deficiency; in the severe or classical form, patients are at most risk for early or late metabolic or central nervous system decompensation. Even in medically managed patients, progressive neurologic deterioration occurs and may be considered in the decision for transplantation. LT corrects episodes of systemic metabolic decompensation associated with this metabolic disease.39 This condition is not associated with hyperammonemia as a rule, and there is no liver dysfunction; therefore, one cannot calculate a PELD score. Each case should be reviewed with the help of a metabolic expert by the Regional Review Board, and additional points should be applied depending on the severity of the disease.39–42 Domino LT, although most commonly associated with amyloidosis,43 has also been successfully performed in a patient with MSUD.44 Recipients of domino transplants from patients with MSUD would not be expected to develop clinical MSUD at any time point.
OTHER METABOLIC DISEASES
Mitochondrial defects confined to the liver include a number of conditions;45–49 each case should be individually assessed with the aid of a metabolic expert and the Regional Review Board.
Neonatal hemochromatosis, which almost always fulfills criteria for fulminant hepatic failure.50–52
Erythropoietic protoporphyria. LT is typically undertaken for acute liver failure or rapidly progressing chronic liver failure; it is important to note that liver disease can recur in the allograft, and no data on priority of listing are available.53–55
Niemann-Pick type C, which in a minority of patients can present with severe neonatal hepatitis. LT cures the liver disease, but does nothing for late childhood dementia. The usual age at onset is 10-15 years, but timing of presentation is variable. The calculated PELD score probably reflects severity of liver disease, and no additional MELD or PELD priority is advised.38, 56, 57
Disorders of fatty acid metabolism, which are mostly managed medically. Each case should be discussed individually with the Regional Review Board.28
Neonatal adrenal leukodystrophy, which is a peroxisomal biogenesis defect and as such is associated with significant neurodevelomental concerns. There are no data to support this as an indication for LT, and no extra priority is advised for this condition.38
Cholesterol ester storage disease results in cirrhosis and end-stage liver disease; thus, the calculated MELD or PELD score will suffice.38