Transthyretin-derived amyloid deposition on the gastric mucosa in domino recipients of familial amyloid polyneuropathy liver.

Familial amyloid polyneuropathy (FAP) is a form of hereditary generalized amyloidosis. Liver tissue explanted from FAP patients has normal structure and function, except for the production of amyloidogenic variant transthyretin (TTR), and domino liver transplantation (DLT) using grafts from FAP patients was first performed in 1995. FAP symptoms usually develop in genetically determined individuals after the age of 20, but it is difficult to estimate when FAP symptoms will appear in domino recipients. Concerning this problem, histological findings showing amyloid deposition have recently been obtained in a few domino recipients of FAP livers. This study investigated the presence of de novo amyloid deposition in the gastroduodenal mucosa of domino recipients transplanted at our institution. Biopsy of gastroduodenal mucosa was carried out in 5 recipients of FAP livers and TTR-derived amyloid deposits were detected in 2 patients, both of whom had undergone DLT 47 months previously. In FAP liver recipients, de novo systemic amyloid deposition may begin much sooner than previously supposed. Therefore, careful follow-up of domino recipients of FAP livers is required.     

Domino liver transplantation: how far can we push the paradigm?

Domino liver transplantation (DLT) has emerged as a strategy for increasing the number of liver grafts available: morphologically normal livers from donors with metabolic diseases can be used for select recipients with hepatocellular carcinoma (usually outside the Milan criteria). Familial amyloidotic polyneuropathy (FAP) is the most common indication for DLT. When FAP patients are involved in DLT, the indications and outcomes are clear and good, although de novo FAP development within various periods of time has been described in DLT recipients of FAP livers. With the increasing need for organs, livers explanted from patients with rare metabolic diseases, such as primary hyperoxaluria (PH), acute intermittent porphyria (AIP), maple syrup urine disease (MSUD), and homozygous familial hypercholesterolemia (HFHC), are being used for DLT. However, insufficient data about the use of livers from patients with these rare metabolic diseases are available. In this review, we focus on the latter disorders. PH is not a good indication for DLT because recipients of PH livers develop hyperoxaluria and early acute renal failure. AIP also seems to be a debatable indication for DLT because of the rapid development of neurotoxicity in AIP liver recipients. However, the outcomes of DLT with HFHC and MSUD liver grafts (which include the risk of the de novo development of these genetic diseases) are promising. For rare metabolic liver diseases to be established as indications for DLT, more reports and studies are needed.     

Domino liver transplant: influence on the number of donors and transplant coordination

The shortage of organs forces coordinators to seek new forms of generating organs for transplantation of the increasing numbers of patients on waiting lists. A recent technique called sequential transplant or domino liver transplant (DLT) allows the transplantation of a patient with chronic liver disease by implantation of a full-size liver derived from a patient with familial amyloidosis polyneuropathy (FAP) who receives a cadaveric graft. Therefore, it is possible to transplant two patients with only one cadaveric liver. The present report illustrates the use of this technique for the first time in our country, thereby increasing the number of hepatic transplants by 25%.     

Domino liver transplantation in living donors

Domino liver transplantation (DLT) has been developed as a method to expand the donor pool. In living donors DLT, the prime concern is to avoid any disadvantage to the donor and the first recipient. Seven DLTs were performed among 211 patients who underwent living donor liver transplantation. The domino recipients included six with hepatocellular carcinoma and one with citrullinemia. The domino grafts were obtained from patients with familial amyloid polyneuropathy (FAP) including the left liver in three cases and the right liver in four. Among the seven domino recipients, a 64-year-old woman with advanced hepatocellular carcinoma died of lung metastasis. The other six domino recipients are alive without FAP symptoms. In living donor liver transplantation, because the vessels of the graft from the first donor are not long enough for anastomosis, the hepatic vessels must be left as long as possible when removing the liver from the FAP patients in order to ensure sufficient safety for vascular reconstruction. With careful decision making during the procedure, such as where to divide the vessels in the FAP patients, DLT may help address the shortage of liver grafts.     

Outcomes of Domino Liver Transplantation: A Single Institution's Experience

Aims

Domino liver transplantation (DLT) is a strategy to increase the donor pool. Explanted liver from patients with familial amyloidotic polyneuropathy (FAP) are often used as domino grafts, because the liver is normal apart from the production of the mutated transthyretin variant. We present the outcomes for both donors and recipients of DLT.

Materials and Methods

Retrospective analysis of initial DLT for 16 consecutive adult patients performed between July 2004 and July 2009. All cases of FAP donor to grafts were removed preserving the cava vein with reconstruction of the hepatic veins, except the first and seventh cases, where in we removed the retrohepatic vena cava with the liver without venovenous bypass. The postoperative follow-up period for surviving DLT recipients at the end of September 2009 was 2-62 months (mean, 26).

Results

Two patients out of 8 FAP donors died due to pulmonary thromboembolism on the 31st postransplant day, or sepsis at 35 days namely, an overall survival of 75%. One patient out of 8 recipients died namely, an early portal thrombosis on the 22nd postransplant day) with a crude survival of 87.5% in the recipient group (P = no significant [NS]). Four grafts from 8 FAP donors were lost—2 deaths and 2 retransplants due to thrombotic events on the first and second postransplant day—with a crude survival of 50%. Two of 8 recipients lost their grafts: 1 death and 1 retransplantation for an acute Budd-Chiari syndrome on the first postransplant day with a crude survival of 75% in the recipient group (P = not significant [NS]).

Conclusion

We believe that the FAP liver graft is an excellent option for selected patients. Special care must be taken with thrombotic events.     

Manifestations of transthyretin-related familial amyloidotic polyneuropathy: Long-term follow-up of Japanese patients after liver transplantation

Purpose

To observe which symptoms of transthyretinrelated familial amyloidotic polyneuropathy (FAP) progressed in the long term after liver transplantation (LT), focusing on cardiac, kidney, and ocular symptoms.

Methods

We reviewed the medical records of 34 Japanese patients with FAP, who underwent LT between 1994 and 2006. The mean follow-up period (±SD) after LT was 9.6 ± 3.4 years. Of the 34 patients, 30 had FAP amyloidogenic transthyretin (ATTR) Val30Met, 1 had FAP ATTR Ser50Ile, and 3 had FAP ATTR Tyr114Cys.

Results

The 10-year survival rates from the onset of FAP and from the time of LT were 100% and 91.4%, respectively. Progression of ocular amyloidosis was seen in 17 (50%) patients, 13 of whom had de novo amyloid deposits in the vitreous body; progression of cardiac amyloidosis was seen in 10 (29%) patients, 4 of whom had newly granular sparkling echo on echocardiography, and 9 of whom had newly implanted pacemakers or implantable cardioverter-defibrillators. Although the mean serum creatinine levels did not increase significantly after LT in any of the patients, the estimated glomerular filtration rate had decreased significantly by 7 years after LT.

Conclusion

Although LT is life-saving for patients with FAP, we observed progression of the ocular and cardiac symptoms of FAP in a significant number of these patients over the long term after LT.     

A different amyloid formation mechanism: de novo oculoleptomeningeal amyloid deposits after liver transplantation

BACKGROUND: Liver transplantation has served as a treatment for patients with familial amyloidotic polyneuropathy (FAP) because variant transthyretin (TTR), the pathogenic protein of FAP, is predominantly produced by the liver. However, the effect on amyloid formation of TTR that is synthesised by the retina and the choroid plexus remains to be elucidated in FAP patients with liver transplants. OBJECTIVE: To investigate changes in ocular tissues and the central nervous system (CNS) of FAP patients after liver transplantation. DESIGN: Clinical study. SETTING: Graduate School of Medical Sciences, Kumamoto University, Japan. INTERVENTION: Transplantation of livers from cadaveric or living donors. MEASUREMENTS: Preoperative measures and postoperative (16-108 months) follow-up of clinical data, including routine ophthalmologic, neurologic, and laboratory evaluations. RESULTS: In 22 patients with FAP related to the amyloidogenic TTR (ATTR) Val30Met and 3 patients with FAP ATTR Tyr114Cys, after liver transplantation, 3 patients began to show evidence of de novo glaucoma, and 1 had vitreous opacity that was caused by the variant TTR. Another three patients showed new amyloid deposits in the pupillary margin, which could lead to glaucoma and vitreous opacity. As for changes in the CNS and levels of total protein and TTR in cerebrospinal fluid (CSF), after liver transplantation, two FAP ATTR Tyr114Cys patients exhibited de novo amyloid deposition in the leptomeninges, and total protein and TTR levels in CSF were significantly increased. CONCLUSIONS: Oculoleptomeningeal involvement in FAP was not prevented by liver transplantation because variant TTR produced by the retina and the choroid plexus forms amyloid fibrils in situ.     

Liver transplantation for familial amyloidotic polyneuropathy in Australia

Familial amyloidotic polyneuropathy type 1 (FAP-1) is a type of systemic amyloidosis caused by mutant transthyretin (mTTR) that is mainly produced in the liver. Most patients have progressive peripheral and autonomic neuropathy. Ten patients with FAP underwent orthotopic liver transplantation (OLT) at the Queensland Liver Transplant Service (Princess Alexandra Hospital, Brisbane, Australia). Nine patients are still alive, and one patient died of cardiac failure 10 days after OLT. Some symptoms of FAP were alleviated in some of the patients. OLT seems to be a worthwhile treatment for FAP, because it halts the progression of symptoms and achieves improvement in some patients. Received for publication on July 15, 1999; accepted on April 14, 2000     

Transthyretin amyloidosis with cardiomyopathy after domino liver transplantation: Results of a cross-sectional study

Domino liver transplantation (DLT) has been used widely in patients with hereditary amyloid transthyretin (ATTR) amyloidosis. New-onset polyneuropathy in recipients of DLT has been reported, but there are few cases of cardiac involvement reported. We aimed to perform a cross-sectional study for ATTR amyloidosis with cardiomyopathy (ATTR-CM) in DLT recipients. We evaluated 23 living DLT recipients a median of 9 years since DLT at 2 referral centers with a systematic cardiac evaluation, including bone scintigraphy. Median age was 72 years, 91% had hypertension, 35% had diabetes mellitus, 67% had chronic renal failure, and 8 patients (35%) developed new-onset polyneuropathy. Only 13% had a normal electrocardiogram and a normal echocardiography, and most of them showed some conduction disturbance or increase in left ventricular wall thickness, but only 1 patient with a Glu89Lys mutation developed ATTR-CM diagnosed by bone scintigraphy and endomyocardial biopsy. None of the recipients of a DLT with Val30Met mutation showed cardiac involvement by bone scintigraphy. In conclusion, DLT from Val30Met donors seems to be safe regarding the development of ATTR-CM. Evaluation of cardiomyopathy in DLT recipients is challenging due to concomitant comorbidities and in this context, bone scintigraphy can be helpful to evaluate ATTR-CM.     

Whole-Liver Graft Without the Retrohepatic Inferior Vena Cava for Sequential (Domino) Living Donor Liver Transplantation

Grafts used in Domino liver transplantation (LT) obtained from living donor liver transplantation (LDLT) for familial amyloid polyneuropathy (FAP) patients have been mainly used as reduced grafts. Because of small-for-size problems seen in LDLT, using whole liver grafts could improve post-LT outcome. Eight consecutive Domino LDLT using whole livers without retrohepatic inferior vena cava (IVC) from FAP patients were retrospectively analyzed. The graft weight/recipient's body weight ratio (GWRW) in the domino recipients ranged from 1.28% to 2.4% (mean: 1.52). Multiple vascular reconstructions in the whole-liver domino LT resulted in longer than usual warm ischemia time (mean: 64 min); however immediate post-operative recovery of hepatic function was uneventful. At 8-40 months after the transplant, all the FAP patients are well and all of the domino recipients are alive. Domino LT using a whole FAP liver from a LDLT for a FAP patient presents satisfactory results, even though the transplant procedure is technically complicated.     

Carpal Tunnel Syndrome Due to Iatrogenic Amyloidosis After Domino Liver Transplantation From Hereditary Transthyretin Amyloidosis: A Case Report

BackgroundCarpal tunnel syndrome is the most common compression syndrome of the peripheral nerve. Transthyretin amyloidosis and dialysis-related β2-microglobulin amyloidosis are known causes of carpal tunnel syndrome.Case ReportA Japanese woman showed carpal tunnel syndrome 16 years after a domino liver transplantation (DLT) from the donor with hereditary transthyretin amyloidosis. DLT indication was congenital extrahepatic portosystemic shunt, and the patient had been put on maintenance hemodialysis because of chronic kidney disease 6 years before DLT. Moreover, the amyloid precursor protein of the patient was histologically confirmed not to be β2-microglobulin, but transthyretin.ConclusionsThe existence of amyloid was speculated when the patient who underwent DLT from hereditary transthyretin amyloidosis showed carpal tunnel syndrome. Additionally, elucidating the amyloid precursor protein when the patient has another cause of amyloidosis is necessary.     

No ocular involvement in familial amyloidotic polyneuropathy ATTR V30M domino liver recipients

In many transplantation centers domino liver transplantation is an established procedure, increasing the number of available liver grafts. Increasingly, grafts from familial amyloidotic polyneuropathy (FAP) patients are used. Ocular involvement is a well known manifestation of FAP, and can be vision-threatening. The aim of this study was to evaluate the risk of development of familial amyloidotic polyneuropathy ocular manifestations in domino liver recipients. Forty-four cirrhotic patients submitted to liver transplantation were studied, with an average of 6 years of follow up after the procedure. Twenty two patients had received a liver from a FAP donor (Group 1) and 22 had received a liver from a non-FAP cadaveric donor (Group 2). Both groups were similar for mean age and gender. Routine ophthalmological examinations with particular attention to amyloid deposition in the anterior segment and vitreous, peripheral retina state, lacrimal functions tests (Schirmer and tear break-up time) and pupillometry (dynamic and static) were performed. No statistically significant differences were observed in all studied ophthalmic parameters between the two groups. No FAP related ophthalmic manifestations were detected after 6 years of domino liver transplantation, but further prospective regular ophthalmological examinations are necessary to detect the eventual development of late ocular manifestations.     

Outcome of kidney transplantation for renal amyloidosis:a single-center experience

The aim of this retrospective study was to investigate the results of kidney transplantation in patients with renal amyloidosis. We analyzed the results of renal transplantation in 13 amyloidotic transplant recipients compared with those in a control group of 13 nonamyloidotic patients. While the etiology of amyloidosis was rheumatoid arthritis in one patient, in all of the others it was secondary to familial Mediterranean fever. Acute rejection episodes developed once in six and twice in one patient. The renal function in these patients was improved by antirejection treatment. Chronic rejection did not develop in any patient. However six patients (46%) died due to various complications despite functional grafts. The others are still being followed with well-functioning grafts. Among the control group, acute and chronic rejection were diagnosed in three and two patients, respectively: one patient returned to hemodialysis after 26 months of transplantation, while the others are still alive with functional grafts. There was no death in the control group. The 5- and 10-year actuarial patient survival rates of the amyloidosis and control groups were 52.2%, 26.6%, and 100%, 100%, respectively (P = .002). However, the graft survivals of the amyloidosis versus control groups were 100%, 100%, versus 87.5%, 87.5, respectively (P = .47). In conclusion, we observed a high rate of early mortality among recipients with amyloidosis associated with infectious complications. Moreover, patient survivals were lower among amyloidotic renal recipients.     

Operative Risks of Domino Liver Transplantation for the Familial Amyloid Polyneuropathy Liver Donor and Recipient: A Double Analysis

Although domino liver transplantation (LT) is an established procedure, data about the operative risks are limited. This study aimed at evaluating the operative risks of domino LT. Two retrospective analyses were conducted (comparison of familial amyloid polyneuropathy [FAP] liver donors [61 patients] vs. FAP nondonors [39 patients] and FAP liver recipients [61 patients] vs. deceased donor liver recipients [61 patients]). First analysis showed a 60‐day mortality of 6.6% for FAP donors and 7.7% for FAP nondonors (p = 1.0). No patient developed primary graft nonfunction. Acute rejection was higher in FAP nondonors compared to FAP donors (38.5% vs. 13.1%). Both groups had similar vascular and biliary complication rates. ICU stay was similar, whereas total hospitalization was longer for FAP nondonors. Both groups had similar 1‐ and 5‐year patient and graft survival rates (83.4% vs. 87.2%, and 79.8% vs. 71.8%, p = 0.7) and (83.3% vs. 87.2%, and 79.1% vs.71.8%, p = 0.7). The second analysis showed a 1.6% mortality for FAP liver recipients vs. 3.2% of the control group (p = 1). Both groups had similar morbidity and technical complication rates (18.0% vs. 13.1%, p = 0.45) and (0.18 vs. 0.15, p = 0.65). The domino procedure does not add any risk to FAP donor or recipient. It increases the organ pool allowing transplantation of marginal recipients who otherwise are denied deceased donor liver transplantation.     

Characterization of end-stage renal disease after liver transplantation in transthyretin amyloidosis (ATTR V30M)

Transthyretin (TTR) amyloidosis, an autosomal-dominant disease, is characterized by peripheral and autonomic neuropathy—familial amyloidotic polyneuropathy (FAP). End-stage renal disease (ESRD) occurs at 10 years after the onset of neuropathy. Orthotopic liver transplantation (OLT) is the usual treatment of choice. We evaluated FAP patients, ATTR V30M, before and after OLT who started dialysis within 3 months after surgery. The 11 patients had an age at the onset of neuropathy of 31.9 ± 6.3 years with a mean evolution of disease to OLT of 4.54 ± 2.5 years. The glomerular filtration rate was <60 mL/min in 2 patients, 2 displayed nephrotic range proteinuria, and 3 had microalbuminuria. Elective pacemaker implantation was necessary in 8 subjects. Post-OLT 3 patients developed proteinuria, 2 of whom showed increasing nephrotic syndrome. Dysautonomia worsened leading to bladder catheterization in 6. In patients with previous normal renal function and proteinuria <3 g/d, the evolution of neuropathy to the first dialysis was 14.6 ± 4.2 years versus 7.5 ± 1.1 among the other subjects. Overall, dialysis was implemented at 7.4 ± 4.9 years after surgery. There was no liver graft dysfunction. The heart evaluation post-OLT showed the following: 3 patients with de novo dysrhythmias requiring pacemaker implantation and 3 with N-terminal pro-natriuretic peptide levels >10,000 pg/mL. Death occurred in 4 subjects at an average of 26 months after initiation of dialysis. Concerning ESRD, there was no clear benefit of transplantation in the early stages. Patients with normal renal function and lower levels of proteinuria showed slower progression to ESRD, irrespective of their duration of neuropathy.     

Effects of a Domino Liver Transplantation Program on Patient Survival and Waiting List Time: A Single-Center Retrospective Study

Explanted livers from patients with familial amyloid polyneuropathy have often been used for domino liver transplantation (DLT). This has expanded the organ pool for liver transplantation. We evaluated the effects of a single-center DLT program on waiting list duration and patient survival. Liver transplants conducted from 2007 to 2017 were analyzed. Selected patients, all liver transplant candidates above the age of 60 years and patients with hepatocellular carcinoma, were offered DLT. Survival, time on waiting list, and operative factors were evaluated. The study group included 485 patients transplanted with grafts from deceased donors (conventional liver transplantation) and 149 patients who were offered and accepted a potential DLT, of whom 34 underwent DLT and 115 did not; these patients received a deceased donor graft (non-DLT). Five-year and overall estimated survival rates respectively were 79% and 54.4% for DLT and 67.6% and 46.7% for non-DLT (P = .67, log rank test). No differences were noted in survival (P = .816) or waiting times (P = 1.0) between DLT and non-DLT groups. As expected, survival time in the conventional liver transplantation group was longer (84.7% and 60.6%, P < .001). Donor age and ischemia time were significantly different between DLT and non-DLT (P < .001). DLT has enabled 6% additional transplantations without affecting waiting time or survival (34/600).     

Indications and Management of Everolimus After Liver Transplantation

Objective

Our aim was to assess our experience with the use and management of everolimus after orthotopic liver transplantation (OLT).

Materials and Methods

Among the 759 patients who underwent transplantation from 1988 to 2008, 25 (3.2%) received immunosuppression with everolimus. Their mean age was 55.6 years. We analyzed indications for use, time between transplantation and introduction of everolimus, as well as its efficacy, side effects, and patient survival.

Results

The indications for everolimus treatment were: extended hepatocellular carcinoma (HCC) in the explanted liver (n = 6; 24%); HCC recurrence during follow-up (n = 4; 16%); de novo tumor (n = 6; 24%); refractory rejection (n = 3; 12%); side effects of calcineurin inhibitors (CNI; n = 3; 12%); and other causes (n = 3; 12%). Mean time between OLT and everolimus treatment was 40 ± 33 months (range, 10 days-178 months). Mean follow-up after conversion was 10 ± 9 months (range, 1.5-25 months). More than half of the patients resolved the event for which the drug was indicated: 75% of patients with refractory rejection; 60% of those with renal insufficiency; and 100% of those converted for neurotoxicity or hepatotoxicity. Two patients with recurrent HCC and 1 with extended HCC died at a mean time of 10.5 months. The 6 cases of de novo tumors were operated and are healthy. Side effects were dyslipidemia in 8 and infection in 2. Five patients (20%) discontinued the drug.

Conclusions

In the early posttransplantation period, everolimus is indicated for refractory rejection or as prophylaxis for recurrence of extended tumors. In any time but especially in the late period, everolimus is indicated for patients with serious side effects due to a CNI or to a de novo tumor.     

Active Immunization to Prevent De Novo Hepatitis B Virus Infection in Pediatric Live Donor Liver Recipients

This study aims to evaluate the efficacy of HBV vaccination as an alternative preventive measure against de novo HBV infection in pediatric living donor liver transplantation (LDLT). Sixty recipients were enrolled in this study. Thirty received grafts from anti-HBc(+) donors, and another 30 received grafts from anti-HBc(-) donors. HBV vaccine was given pretransplant to every candidate. Posttransplant, lamivudine was routinely given to recipients receiving anti-HBc(+) grafts for about 2 years. Forty-seven (78%) recipients achieved high levels of anti-HBs titer (>1000 IU/L). Two (3.3%) recipients developed de novo HBV infection where one received an anti-HBc(-) graft and another received an anti-HBc(+) graft. Both recipients were in the lower anti-HBs titer group (<1000 IU/L). The incidence of de novo HBV infection was significantly higher in the lower titer group (15.4% vs. 0%, p = 0.04). The median follow-up period was 51 months in recipients with anti-HBc(-) grafts and 57 months in those with anti-HBc(+) grafts. Active immunization is an effective method to prevent de novo HBV infection. It can result in high levels of anti-HBs titer (>1000 IU/L) which may prevent de novo HBV infection in pediatric patients with efficient primary vaccination undergoing LDLT.     

Impact of the Learning Curve on the Outcome of Domino Liver Transplantation

Domino liver transplantation (DLT) is a strategy used to increase the number of available grafts. In this procedure, the transplant recipient is a living donor of her own liver. It is mandatory that the graft should be fully functional and the genetic defect should recur with sufficient latency period in the new recipient. Corino-Andrade disease, or familial amyloidotic polyneuropathy (FAP), satisfies these conditions. We retrospectively reviewed our prospective database of DLT. From July 2004 to April 2013, we performed 12 DLTs. We assessed age, sex, real Model for End-Stage Liver Disease (MELD) score, waiting list time, cold and warm ischemia times, intraoperative transfusion requirements, hospital stay, early peritransplantation morbidity (post-reperfusion syndrome, intraoperative cardiac arrest, post-transplantation thrombotic events, and biliary morbidity), acute cellular rejection, retransplantation, mortality, patient and graft survivals. With the intention to study the effect of the learning curve in the global survival results (including both donors and recipients of livers with FAP), we divided our series into 2 periods: the early period (from 2004 to 2008) and the present period (from 2009 to 2013). The crude mortality was 40% vs 0% (P = .042) in the early and present periods, respectively. The cumulative patient survival was also significantly in favor of the present period (P = .049). The graft loss prevalence was 60% vs 7.1% (P = .019) in the early and present periods, respectively. The cumulative graft survival was also significantly in favor of the present period (P = .030; Fig 2). In conclusion, we consider DLT to be a complex procedure, whose initial results are conditioned by the learning curve.     

Thirteen cases of liver-kidney transplantation

Combined kidney-liver transplantation is currently the best therapeutic option for patients with end-stage kidney and liver disease. We present our experience of kidney-liver transplantation in a series of 13 patients. The most frequent indications were familial amyloidotic polyneuropathy (FAP) and polycystosis of the liver and kidney. The 1- and 5-year survival rates of the liver grafts were 75% and 67%, respectively, with no kidney losses during follow-up.