Domino transplantation using livers from patients with familial amyloidotic polyneuropathy: Should we halt?

Abstract

Familial amyloidotic polyneuropathy (FAP) is a neurodegenerative genetic disorder characterized by extracellular deposition of transthyretin (TTR) amyloid fibrils, particularly in the peripheral nervous system. The first attempt to treat the disease by liver transplantation was performed by us in 1990. It was noted that the variant TTR, needed for the formation of amyloid fibrils was reduced to very low levels in serum after liver transplantation. Moreover, clinical progression of the disease was halted in most patients. Many different mutations of the TTR gene can result in FAP. Val30Met is the most commonmutation leading to transplantation, frequently seen in Portugal, Sweden, and Japan. The clinical presentation and progression of the disease may vary in relation to which mutation caused the FAP. All patients who inherited the genetic disorder show increased levels of the variant TTR in serum, but many do not develop any disease symptoms during their lifetime. The penetrance for the gene in the Swedish population of Val30Met carriers is approximately 5%, indicating that disease symptoms will not occur in 95% of persons with a liver that produces variant TTR. Apart from the genetic disorder, a presently unknown factor is needed to form amyloid deposits from the variant TTR and thereby give rise to clinical symptoms. Therefore, patients with the genetic disorder but without clinical symptoms should not undergo liver transplantation because the person may never develop the disease. Except for the production of the variant TTR, the FAP liver is functionally and morphologically normal. Although inborn, the disease never presents before the age of 15 to 20. After onset of disease, the patients live for approximately 10 years. In some endemic areas of FAP disease, this new indication for liver transplantation added a significant number of patients to the waiting lists, and the possibility of performing transplantation on patients with less favorable outcomes such as hepatic malignancies was reduced. The introduction of split liver transplantation, living related liver transplantation, as well as an increasing use of marginal donors have partly compensated for the growing number of patients presently in need of a liver transplant. During the first international workshop in liver transplantation for FAP held in Stockholm in 1993, it was decided that attempts should be made to use the explanted FAP liver for another patient. This so-called domino liver transplantation was thereby also introduced as a tool to relieve organ shortage. The first such domino transplantation was performed in 1995 in Portugal, the country with the highest proportion of FAP patients on the waiting list for liver transplantation. The early estimations of the risk for disease transfer were based on the natural course of the FAP-disease as described above. This meant that a delay of up to 15 years was expected to take place before disease symptoms would start to develop. Furthermore, only a small proportion of the domino recipients were expected to develop disease symptoms during their lifetime, as is the situation with FAP. However the peritransplantation situation is complex. Several episodes of inflammation and infection caused by rejection episodes and reactivation of latent viral diseases usually occur. Moreover, the trauma of surgery itself could very well be a surrogate for the