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Living-Related Liver Transplantation in Inherited Metabolic Liver Disease: Feasibility and Cautions

Braegger, Christian M.D.; Florman, Sandy M.D.; Shneider, Benjamin M.D.

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Journal of Pediatric Gastroenterology and Nutrition: October 2001 - Volume 33 - Issue 4 - p 520-521
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Living-Related Liver Transplantation for Type II Citrullinemia Using A Graft From Heterozygote Donor. Kasahara M, Ohwada S, Takeichi T, Kaneko H, Tomohasa T, Morikawa A, Yonemura K, Asonuma K, Tanaka K, Kobayashi K, Saheki T, Takeyoshi I, Morishita Y.Transplantation 2001;71(1):157–9.


This article describes a 16-year-old boy with type II citrullinemia successfully treated with liver transplantation using a left lobe graft from his father, who was genetically proven to be heterozygous for the same disease. Immediate postoperative hyperammonemia was seen in the recipient and may have been related to the small size of the graft, relative to the recipient. The donor's postoperative course was unremarkable, and serum citrulline and arginine concentrations of the donor and the recipient were normal 20 days after transplantation.

Department of Surgery

Department of Pediatrics

Recanati/Miller Transplantation Institute

Mount Sinai School of Medicine

New York, New York, U.S.A.

A Pediatric Patient With Classic Citrullinemia Who Underwent Living-Related Partial Liver Transplantation. Ban K, Sugiyama N, Sugiyama K, Wada Y, Suzuki T, Hashimoto T, Kobayashi K.Transplantation 2001;71(10):1495–7.


This article describes a 6-year-old girl with classic citrullinemia successfully treated with liver transplantation using a left lateral segment graft from her mother, who was genetically proven to be heterozygous for the same disease. Argininosuccinate synthetase levels in the donor liver were 20% of normal. Eighteen months after surgery, the recipient's plasma and urinary citrulline levels were 10 and 50 times the normal levels, respectively


The advent of live liver donation in 1989 has permitted many children to undergo liver transplantation in a more timely fashion, before having irreversible complications of their diseases. The use of living (usually related) donors for pediatric patients with end-stage liver failure has been widely accepted and successful. In the setting of metabolic disease, however, unique and important questions must be raised when contemplating the donor candidacy of a parent, who may be a heterozygous carrier of the genetic defect. First, will the heterozygous liver correct the underlying metabolic disorder? Second, what are the immediate risks to the donor that are related to dedifferentiation of his or her own liver as it undergoes regeneration? Third, what are the long-term risks to both the donor and the recipient who each have a heterozygous liver? The answers to these questions are not obvious. However, recent clinical experiences, including these two reports from Transplantation, shed light on possible answers.

The initial assumption is that a heterozygous liver should improve the manifestations of metabolic disorders. This assumption is based on the presumption that the heterozygous liver has approximately 50% of the native enzyme activity and that this will be sufficient for normal metabolic activity. The fact that the heterozygous carrier is unaffected by the metabolic disorder is used as the basis for this presumption. It is of great interest that in the second case report of classic citrullinemia (Transplantation 2001;71:1495), argininocuccinate synthetase activity in the genetically proven heterozygote was only 20% of normal levels. Fortunately, this level of activity was adequate in the short-term for the recipient, even though posttransplantation plasma and urinary citrulline levels remained 10 and 50 times the normal, respectively. The clinical significance of the mild elevation of plasma citrulline in the recipient is unclear.

Many of the enzymes affected in metabolic diseases are expressed not just in liver, but also in other tissues. For example, fumaryl acetoacetate hydrolase is expressed in both the liver and the kidney, whereas ornithine transcarbamylase (OTC) is expressed in the liver and the intestine. Therefore, liver replacement may not restore total body enzyme activity even to 50% of normal. This failure to restore 50% of normal total body activity through liver transplantation has potential adverse clinical implications. For instance, injury of the donated liver during acute rejection episodes may lead to further enzymatic insufficiency and possible recurrence of the primary metabolic disease in the recipient. We have had the opportunity to observe a child who underwent living-related (mother) transplantation for tyrosinemia. Comprehensive metabolic studies in this patient posttransplantation have not revealed evidence of deficiency in fumaryl acetoacetate hydrolase activity. In contrast, in a recently reported case, the recipient of a liver from a cadaver donor with a strong family history of OTC deficiency, died of hyperammonemic coma 6 days after undergoing transplantation (N Engl J Med 1999;341:921). The question rose after this transplant whether the donor was a heterozygote for OTC deficiency. Another recent case report, however, notes the successful living-donor transplantation from an asymptomatic carrier of OTC (J Pediatr 2001;138:432).

Citrullinemia is an autosomal recessive disorder resulting in deficiency of the urea cycle enzyme, argininosuccinate synthetase, which is mainly found in the liver. Classic disease is the result of a defect in argininosuccinate synthetase, whereas type II disease is related to a defect in a putative mitochondrial carrier protein. Liver transplantation is curative and related living donors have been used; but, in previous reports, the donor carrier status has not been documented (Intern Med 2000;39:553;Rinsho Shinkeigaku 1999;39:1049). The lack of acceptance of cadaver donation in Japan has limited liver transplantation to living donors. In the current two articles from Japan, donor-and recipient-related issues both have been carefully evaluated. In particular, donor heterozygosity was assessed at both a molecular and an enzymatic level. In addition, donor and recipient biochemistries were carefully assessed postoperatively.

Special considerations must be taken into account when considering living-related donor transplantation for certain genetic disorders. Alagille syndrome, which involves a paucity of bile ducts, is an excellent example. In our own center, a transplant procedure was aborted during surgery when the left lateral segment of the donor liver was divided and it was found that there were no reconstructible bile ducts as a result of subclinical Alagille syndrome in an otherwise healthy and asymptomatic heterozygotic donor (Transplantation 1999;67:416). Clearly, certain genetic disorders may be subclinical despite significant underlying abnormalities. α1-Antitrypsin deficiency is another example in which special considerations are in order. Controversy remains as to whether protease inhibitor MZ individuals are at increased risk for liver disease (Hepatology 1998;28:1058). As such, it has been our policy to perform percutaneous liver biopsy as part of routine assessment of known MZ donors. To date, we have not observed any significant liver injury in these individuals.

An even more important issue in the use of heterozygous living donors is the potential risk to the donor. In living-donor liver transplantation, donor safety must remain paramount. It is well known that the liver regenerates after partial resection. The mechanism of regeneration involves hepatocyte replication. This process requires dedifferentiation of the hepatocytes, with a potential loss of tertiary hepatocyte functions (Gastroenterology 1999;117:1408). Hyperbilirubinemia and coagulopathy associated with small graft size or as observed after right lobectomy are presumed to be manifestations of this process (J Am Coll Surg 2001:192:510). Therefore, heterozygous liver donors are potentially at risk for transient enzymatic insufficiency. In the case of classic citrullinemia described in the second case report, a left lateral segment was used. Because this represented less than 25% of the donor's total liver mass, it is not surprising that there was no evidence of transient clinical citrullinemia despite the donor's low enzyme activity. In the case of type II citrullinemia, a left lobe was used, but the baseline enzymatic activity of the donor was closer to normal. It is unknown whether PiMZ liver donors will be at increased risk for the development of liver disease. It is of note that late symptomatic OTC deficiency has been described in long-term carriers of this disease (Clin Genet 2001;59:111).

In summary, living-donor liver transplantation using heterozygous donors in the setting of metabolic disease is an incompletely tested therapy. Although technically feasible, caution is imperative. Short-term results may be encouraging, but enthusiasm must be guarded, because long-term effects, in both the donor and the recipient, are not clearly known. There may be heavy penalties to pay 10, 15, or 20 years down the road for both donor and recipient. We must ensure that potential donors understand these issues and accept these risks. Additionally, each case must be approached individually with a thorough understanding of the particular genetic and metabolic defect.

© 2001 Lippincott Williams & Wilkins, Inc.