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

2007; Lippincott Williams & Wilkins; Volume: 13; Issue: 2 Linguagem: Inglês

10.1002/lt.21073

1527-6473

Bo‐Göran Ericzon,

Hepatitis C virus research

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.1 Moreover, clinical progression of the disease was halted in most patients.2, 3 FAP, familial amyloidotic polyneuropathy; TTR, transthyretin; FAPWTR, FAP World Transplant Registry. Many different mutations of the TTR gene can result in FAP. Val30Met is the most common mutation 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.4 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.5 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 unknown factor needed to initiate amyloid formation from the variant TTR produced by the domino liver, possibly resulting in an early appearance of disease after liver transplantation. However, the early experience did not indicate a rapid progression of amyloid deposits with fibril formation and FAP symptoms in recipients of FAP domino grafts. Instead, there are no reports of clinical symptomatic FAP up to 5 years after domino transplantation, according to the FAP World Transplant Registry and Domino Liver Transplant Registry (www.fapwtr.org). This was in sharp contrast to the situation when domino liver grafts from patients with another metabolic liver disorder with preserved liver morphology and function, namely hyperoxaluria type 1, were used. Symptoms of hyperoxaluria were seen early after transplantation in spite of medical preventions using hyperhydration and treatment with diuretics in order to avoid calculus formation in the kidneys of liver transplant recipients.6, 7 In this issue of Liver Transplantation, Takei and co-workers report on 5 domino liver transplant recipients in whom biopsies of the gastroduodenal mucosa were carried out to detect TTR-derived amyloid deposits. Patients were biopsied 30 to 70 months after transplantation. In 2 patients 4 years after transplantation, 1 of 5 biopsies were found positive for congo red staining, which indicates presence of amyloid. TTR was confirmed using immunohistochemical staining. It should be noted that none of the patients had FAP symptoms. Similar findings were previously reported by Sousa et al.8 It is now evident that de novo amyloidosis occurs in skin, nerves, and gastrointestinal mucosa of recipients of FAP livers after domino liver transplantation. However, the amount of the positive TTR in the majority of the reported cases has been very scarce. Nonfibrillar amyloid deposits in asymptomatic FAP patients may exist for decades without resulting in the disease.8 Fibrillar deposits in symptomatic FAP patients usually indicate progress of the disease within years. Stangou et al. reported in 2005 the first domino liver recipient who demonstrated FAP symptoms in the lower extremities 8 years after liver transplantation.9 After the patient underwent retransplantation, the symptoms disappeared. More recently, a second patient was reported by Goto et al. to have decreased temperature sensation and pain in fingertips and toes 7 years after domino transplantation.10 Most of the domino liver transplants performed worldwide are reported to the FAP World Transplant Registry and Domino Liver Transplant Registry. As of June 2006, 525 domino transplantations have been performed. According to the registry, 32 patients are now 7 or more years after domino liver transplantation. FAP symptoms have occurred in 2 of these patients. FAP is a disease of adulthood. The delay of onset of FAP of 15 to 20 years may not be relevant in a domino situation, because all domino livers are transplanted into an adult population. Recent data, as in the report by Takey, that indicate amyloid deposits without symptoms 3 years or later after domino transplantation and clinical presentation of FAP symptoms in a small proportion of the recipients after more than 7 years support such an assumption. Although the clinical presentation of FAP disease after domino liver transplantation seems to occur earlier than previously predicted, such a liver can still be an excellent graft in a selected group of recipients. Many patients on our waiting lists today do not have 10 to 20 years expected patient or graft survival after successful liver transplantation. In most regions in the world, the FAP patient will be a rare candidate on the waiting list, and it should be relatively easy to find a recipient for whom the benefit from domino transplantation far outweighs the risk of the procedure. In some regions with a high number of FAP patients, such as in Portugal, and thereby frequent occasions for domino transplantation a more restricted attitude toward domino transplantation may necessitate extensive international organ exchange. It is clear that domino recipients need lifelong screening for the development of FAP disease symptoms in order to take necessary actions should the disease appear. Clinical assessments of neuropathy are most important. Biopsies from skin or other tissues as well as nerve conduction studies may indicate changes before clinical symptoms become apparent. With careful selection of candidates for liver transplantation, most domino recipients of a FAP liver will never experience any disease symptoms. Nevertheless, screening to identify candidates for retransplantation as well as to give us correct information on the true risk is mandatory and will require at least another 5 to 10 years of observation. At present, a large number of domino recipients are less than 7 years past transplantation, but they will soon reach the time when symptoms have started to appear in a small proportion of them. The data by Takei et al. given in this issue of Liver Transplantation is not alarming nor unexpected. Further observation on the clinical presentation of FAP symptoms after long-term follow-up in recipients of domino liver grafts are needed. Meanwhile, the procedure should continue.