M. Larsson

Liver Transplantation for Familial Amyloidotic Polyneuropathy (FAP): A Single‐Center Experience Over 16 Years

Orthotopic liver transplantation (LTx) is currently the only available treatment that has been proven to halt the progress of familial amyloidotic polyneuropathy (FAP). The aim of this study was to assess mortality and symptomatic response to LTx for FAP. All 86 FAP patients transplanted at our hospital between April 1990 and November 2005 were included in the study. Five patients underwent retransplantation. The 1‐, 3‐ and 5‐year patient survival rates in patients transplanted during 1996–2005 were 94.6%, 92.3% and 92.3%, respectively, a significant difference from the rates of 76.7%, 66.7% and 66.7%, respectively, during 1990–1995 (p = 0.0003). Multivariate analysis revealed that the age at the time of LTx (≥40 years), duration of the disease (≥7 years) and modified body mass index (mBMI) (<600) were independent prognostic factors for patient survival. A halt in the progress of symptoms was noted in most patients, but only a minority experienced an improvement after LTx. To optimize the posttransplant prognosis, LTx should be performed in the early stages of the disease, and close post‐LTx monitoring of heart function by echocardiography and of heart arrhythmia by Holter ECG is mandatory.

Long-term data from the Familial Amyloidotic Polyneuropathy World Transplant Registry (FAPWTR)

Familial amyloidotic polyneuropathy (FAP) is a fatal systemic disease, caused by an amyloidogenic transthyretin (TTR) variant. Orthotopic liver transplantation (OLT) eliminates the main source of the TTR variant. Herein we present updated data from the Familial Amyloidotic Polyneuropathy World Transplant Registry (FAPWTR). By June 30, 2009, 1516 patients from 70 Centres in 18 countries were reported. Approximately 110-120 OLTs/year is performed worldwide. The Val30Met mutation is reported in 85% of the FAP patients. About 50 other mutations are reported as well. Ninety-eight percent of the Val30Met patients underwent OLT only, while in the non-Val30Met group 11% of the patients also received a heart transplant. OLT remains so far the only established treatment demonstrating excellent patient survival that compares well with OLT performed for other chronic liver disorders. The FAPWTR has, since its foundation in 1995, played a pivotal role in elucidating the role of liver transplantation in this field. Introduction: Familial amyloid polyneuropathy (FAP) is a rather rare autosomal dominant disease associated with a large number of different point mutations in the gene for transthyretin (TTR). More than 95% of circulating TTR is produced in the liver [1,2]. Removing the liver abolishes the hepatic source of amyloidogenic TTR variants and thus orthotopic liver transplantation (OLT) is potentially curative of the disease. The procedure was first performed in FAP in 1990 [3,4] and is now a recognized treatment for patients with TTR systemic amyloidosis disorders. Attractive outcomes have been reported, including improvement in autonomic and to a lesser extent peripheral nerve function coupled with regression of visceral amyloid deposits. The OLT results are influenced by many factors, e.g. the particular TTR variant, nutritional status, age, severity of the neuropathy, and cardiac amyloid involvement. Disturbingly, in some patients there have been reports of paradoxical acceleration of amyloid in certain organs seemingly caused by ongoing TTR amyloid deposition on pre-existing amyloid ‘prototypes’, like the heart and vitreous body but perhaps also in nerves [5–8]. Remaining ongoing production of variant TTR in the choroid plexus and retina may also be the cause of disease progress posttransplantation or for new ocular and central nervous manifestations appearing after OLT [9]. Data on these patients are collected in the Familial Amyloidotic Polyneuropathy World Transplant Registry (FAPWTR). Herein, we briefly present an update from the FAPWTR on the outcome following OLT for FAP. Results and discussion: By 30 June 2009, 1516 patients from 70 centers in 18 countries were reported. The Val30Met TTR mutation was reported in 85% of the FAP patients. About 50 other mutations are reported as well, including non-TTR mutations such as Glu526Val Fibrinogen alfa-chain and ApoA1 Gly26Arg. Ser77Tyr is the commonest non-Val30Met variant reported (n1⁄4 29). The main initial symptom in Val30Met patients was loss of sensory function (67%), cardiovascular dysfunction (1%), and extraneurological dysfunction (1%). NonVal30Met patients suffered more gastrointestinal dysfunction (20%) as well as having more cardiovascular and extraneurological manifestations (9% and 8%, respectively). Ninety-eight percent of the Val30Met patients were subjected to OLT only, while in the non-Val30Met group 11% of the patients also received a heart transplant (2% underwent heart transplantation before OLT and 9% were subjected to simultaneous liver–heart transplantation). Val30Met patients in different countries differ with regard to age at onset and initial symptoms. Brazil presents the youngest age at onset patients while the highest age at onset is found in Sweden. Sensory neuropathy is the most frequent initial symptom in Portuguese patients and least common in Japan. Gastrointestinal dysfunction is most often seen in Japan and Spain and less often met in Sweden while pain as initial symptom is most commonly encountered in Sweden and least in Spain. The 5-year patient survival in the Val30Met group was significantly better than for other TTR variants (82% and 59%, respectively, p5 0.0001). Val30Met patients with a modified body mass index (mBMI) 600 at time of transplantation have a shorter disease duration than those with mBMI 5600 (3.8+ 2.6 years and 5.7+ 3.6 years, respectively, p5 0.001). The mean age at the time of transplantation was the same in the two groups (39.0+ 10.4 years and 39.7+ 9.0 years, respectively). When analyzing Val30Met patients with regard to early ( 50 years) or late onset of the disease, female patients in the early onset group were significantly older than male patients at the time of transplantation (38.8+ 6.6 years and 34.5+ 7.1, respectively, p5 0.001). No difference in survival between female and male patients was found. In the late onset group, females were younger than male patients when transplanted (59.1+ 4.3 and 62.1+ 4.1 years, respectively, p5 0.001). Females 193

Domino liver transplantation: risks and benefits.

Domino liver transplantation, wherein a patient who himself undergoes liver transplantation in turn donates his liver to another recipient, has been performed since the mid-1990 s. Although livers from a handful of metabolic disorders cured by liver transplantation have been used for domino transplantation, familial amyloidotic polyneuropathy (FAP) livers are by far the most common source. FAP is an inherited disorder never presenting its clinical manifestation before the age of 15. In many carriers, the genetic disorder never manifests during lifetime. Thus, only a proportion of patients with FAP develop disease symptoms, which has been the rationale for using such livers for other patients on the waiting list for liver transplantation. According to the Familial Amyloidotic Polyneuropathy World Transplant Registry (FAPWTR), only 2 out of more than 500 patients so far have developed symptoms after domino liver transplantation using an FAP liver. Domino recipients with nonmalignant indications for liver transplantation show excellent long-term survivals. With careful selection of recipients, the procedure helps to reduce the organ shortage and the time on the waiting list for patients with malignant disorders.

Long-term consequences of domino liver transplantation using familial amyloidotic polyneuropathy grafts

Domino liver transplantation (DLT) using grafts from patients with familial amyloidotic polyneuropathy (FAP) is an established procedure at many transplantation centers. However, data evaluating the long‐term outcome of DLT are limited. The aim of the present study was to analyze the risk of de novo polyneuropathy, possibly because of amyloidosis, and the patient survival after DLT. At our department, 28 DLT using FAP grafts were conducted between January 1997 and December 2005. One patient was twice subjected to DLT. Postoperative neurological monitoring of peripheral nerve function was performed with electroneurography (ENeG) in 20 cases. An ENeG index based on 12 parameters was calculated and correlated to age and/or height. Three patients developed ENeG signs of polyneuropathy 2–5u2003years after the DLT, but with no clinical symptoms. The 1‐, 3‐ and 5‐year actuarial patient survival in hepatocellular carcinoma (HCC) patients (nu2003=u200312) and non‐HCC patients (nu2003=u200315) was 67%, 15%, 15% and 93%, 93%, 80%, respectively (Pu2003=u20030.001). Development of impaired nerve conduction in a proportion of patients may indicate that de novo amyloidosis occurs earlier than previously expected. Survival after DLT was excellent except in patients with advanced HCC.

Domino liver transplantation

Orthotopic liver transplantation is today an established treatment for end stage liver diseases. However, the ongoing shortage of suitable livers together with progressively longer waiting lists prevents many patients from being transplanted, and many patients die while being on the waiting list. Using livers from living donors is one way to increase the supply of liver grafts. Another group of potential living liver donors are some selected liver recipients, whose native explanted liver in turn can be considered for transplantation into another patient. This unorthodox procedure have been named domino liver transplantation (DLT). The domino approach can be considered in patients with some genetic or biochemical disorders that today are treated by liver transplantation. The underlying rationale is that such livers ultimately cause severe systemic disease but are otherwise normal. In this review we present the current world status of DLT as well as updated results from the Domino Liver World Transplant Register (DLTR) and our own experience at the Karolinska University Hospital Huddinge with the DLT procedure.

The second report of the Nordic Pediatric Renal Transplantation Registry 1997-2012: More infant recipients and improved graft survivals

The NPRTSG has collected data on pediatric KTx since 1994. The registry archives information from all centers that perform pediatric KTx in Denmark, Finland, Norway, and Sweden and has 100% coverage. The first NPRTSG report was published in 1998 and was based on data collected in the 1982─1996 period. The present report provides data on 602 pediatric KTx in the Nordic countries from 1997 to 2012. Comparison of the patient demographics and one‐ and three‐yr graft survivals between the two time cohorts revealed no significant change in the recipient and donor demographics. The number of transplantations increased by approximately 30%, doubling the recipients below the age of two yr. The use of Tac and mycophenolate as primary immunosuppression increased from practically 0% to 50% and 40%, respectively. The one‐ and three‐yr graft survivals improved significantly (p < 0.001), especially among the youngest recipients with transplant from DD. In these patients, the one‐yr survival improved from 70% to 94.6% and the three‐yr graft survival from 60% to 94.6%, respectively. The improved graft survival may be at least partly due to changes in immunosuppression strategies, but also greater experience may also be of importance.

LIVER TRANSPLANTATION FOR TRANSTHYRETIN SYSTEMIC AMYLOIDOSIS DISORDERS: AN UPDATED REVIEW FROM THE FAMILIAL AMYLOIDOTIC POLYNEUROPATHY WORLD TRANSPLANT REGISTER (FAPWTR): 1930

Introduction/Methods: Several hereditary amyloidosis disorders can be treated with liver transplantation (Ltx). The FAPWTR exists since 1993 and gets data on these patients from centres all over the world. Results: By Dec 2009, a total of 70 centres from 18 different countries reported patients to the FAPWTR. A total of 1536 patients underwent 1660 liver transplantations. 37 patients received a combined liver/kidney graft and 25 patients a combined liverand heart transplantation. 81 LTx:s were done with grafts from living related donors. Patients with more than 45 different variants of TTR mutations have been transplanted, the most common being Val30Met (83%) followed by Ser77Tyr, Thr60Ala and Tyr114Cys (1-2% each, respectively). 1274 of the FAP patients had the Val30Met TTR mutation, 196 patients had a nonVal30Met variant, 11 were non-TTR variants and in 55 patients information was missing or unknown. Most transplantations have been done in Portugal (n=650), France (n=207), Sweden (n=130), USA (n=79), UK (n=78), Brazil (n=71) and Spain (n=72).