Liver Transplantation in Transthyretin Amyloidosis: Issues and Challenges

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1 LIVER TRANSPLANTATION 21: , 2015 REVIEW Liver Transplantation in Transthyretin Amyloidosis: Issues and Challenges Andreia Carvalho, 1 * Ana Rocha, 2,3,4 * and Luısa Lobato 2,3,4 1 Faculty of Medicine, University of Porto, Porto, Portugal; 2 Department of Nephrology, Hospital de Santo Ant onio, Centro Hospitalar do Porto, Porto, Portugal, 3 Unidade Corino de Andrade, Hospital de Santo Ant onio, Centro Hospitalar do Porto, Porto, Portugal; and 4 Multidisciplinary Unit for Biomedical Research, Instituto de Ci ^encias Biom edicas Abel Salazar, University of Porto, Porto, Portugal Hereditary transthyretin amyloidosis (ATTR) is a rare worldwide autosomal dominant disease caused by the systemic deposition of an amyloidogenic variant of transthyretin (TTR), which is usually derived from a single amino acid substitution in the TTR gene. More than 100 mutations have been described, with V30M being the most prevalent. Each variant has a different involvement, although peripheral neuropathy and cardiomyopathy are the most common. Orthotopic liver transplantation (OLT) was implemented as the inaugural disease-modifying therapy because the liver produces the circulating unstable TTR. In this review, we focus on the results and long-term outcomes of OLT for ATTR after more than 2063 procedures and 23 years of experience. After successful OLT, neuropathy and organ impairment are not usually reversed, and in some cases, the disease progresses. The overall 5-year survival rate is approximately 100% for V30M patients and 59% for non- ATTR V30M patients. Cardiac-related death and septicemia are the main causes of mortality. Lower survival is related to malnutrition, a longer duration of disease, cardiomyopathy, and a later onset (particularly for males). Deposits, which are composed of a mixture of truncated and full-length TTR (type A) fibrils, have been associated with posttransplant myocardial dysfunction. A higher incidence of early hepatic artery thrombosis of the graft has also been documented for these patients. Liver-kidney/heart transplantation is an alternative for patients with advanced renal disease or heart failure. The sequential procedure, in which ATTR livers are reused in patients with liver disease, reveals that neuropathy in the recipient may appear as soon as 6 years after OLT, and ATTR deposits may appear even earlier. Long-term results of trials with amyloid protein stabilizers or disrupters, silencing RNA, and antisense oligonucleotides will highlight the value and limitations of liver transplantation. Liver Transpl 21: , VC 2015 AASLD. Received July 2, 2014; accepted November 26, Transthyretin (TTR) is a soluble carrier molecule of thyroxine and vitamin A. The protein is mainly synthesized and excreted by the liver as a native tetrameric structure that, in the presence of point mutations, is more unstable and prone to dissociation into monomers. Epithelial cells of the choroid plexus and the retinal pigment epithelium also locally express TTR. The monomers are susceptible to misfolding and self-aggregate into insoluble amyloid fibrils capable of systemic extracellular deposition. 1,2 Hereditary transthyretin amyloidosis (ATTR) is an autosomal dominant disease of adulthood and most likely reflects the influence of nongenetic factors, Abbreviations: ATTR, hereditary transthyretin amyloidosis; DLT, domino liver transplantation; FAP, familial amyloidotic polyneuropathy; FAPWTR, Familial Amyloidotic Polyneuropathy World Transplant Registry; NSAID, nonsteroidal anti-inflammatory drug; OLT, orthotopic liver transplantation; TTR, transthyretin. Potential conflict of interest: Andreia Carvalho gave an oral presentation of the review at the University of Porto. The Multidisciplinary Unit for Biomedical Research is funded by grants from the Foundation for Science and Technology (Fcomp FEDER ). *These authors contributed equally to this work. Address reprint requests to Luısa Lobato, M.D., Ph.D., Department of Nephrology, Hospital de Santo Antonio, Centro Hospitalar do Porto, Largo Professor Abel Salazar, , Porto, Portugal. Telephone: ; FAX: ; lmlobato@icbas.up.pt DOI /lt View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI /lt. Published on behalf of the American Association for the Study of Liver Diseases VC 2015 American Association for the Study of Liver Diseases.

2 LIVER TRANSPLANTATION, Vol. 21, No. 3, 2015 CARVALHO, ROCHA, AND LOBATO 283 such as those associated with the aging process. 3 To date, more than 120 mutations of the single gene encoding TTR have been described in the literature, 2,3 and approximately 13 are nonamyloidogenic. 4,5 The clinical manifestations vary according to the mutation, although a clear relationship between genotype and phenotype may be absent. 1,5 The most common mutation worldwide, TTR V30M, has its main foci in Portugal, Sweden, and Japan. 1,6 It predominantly gives rise to an autosomal dominant sensorimotor polyneuropathy previously known as familial amyloidotic polyneuropathy (FAP). 5,7 The disease usually begins with sensitive disturbances in lower extremities that present with an upward progression. The autonomic involvement also manifests early, with gastrointestinal disturbances, orthostatic hypotension, neurogenic bladder, or erectile dysfunction. Motor dysfunction commonly occurs within a few years. 1,7 TTR-FAP relentlessly progresses and becomes extremely disabling, with patients losing their walking capacity and experiencing malnutrition, life-threatening autonomic dysfunction, and finally death. 5 ATTR-related cardiomyopathy is a less common phenotype and is characterized by an infiltrative cardiomyopathy with involvement of the conduction system. 1,3 Other organs, such as the gastrointestinal tract and kidneys, can be affected, and this demonstrates the disease s systemic nature. 1,5 Outside high-penetrance areas of the disease, the diagnosis can be difficult because ATTR may manifest without a family history 1,5 and with atypical features such as ataxia or upper limb onset neuropathy. 8 Distinct geographic groups vary in penetrance, age at onset, symptoms, and survival, even for the same TTR mutation. 1,2 Figure 1 depicts several clues important to the diagnosis of ATTR and how to confirm it. Liver transplantation suppresses the production of circulating mutant TTR and theoretically stops amyloid formation and disease progression because TTR mainly have a hepatic origin. 2,5 In this review, we focus on the current knowledge of orthotopic liver transplantation (OLT). The review also addresses combined liver-heart/kidney transplantation, the controversies around sequential liver transplantation, and novel therapeutic approaches for ATTR. ORTHOTOPIC LIVER TRANSPLANTATION FOR HEREDITARY TRANSTHYRETIN AMYLOIDOSIS Historical Perspective The inaugural OLT for ATTR was performed in Previously, disease management was based only on symptomatic treatment without any improvement in overall survival. By the time of the first workshop in liver transplantation for FAP (1993), OLT became an accepted treatment because the outcomes were encouraging. 9,10 According to the Familial Amyloidotic Polyneuropathy World Transplant Registry (FAPWTR), by December 31, 2012, a total of 2063 patients with ATTR had undergone OLT, which was performed at 77 centers in 19 countries. 11 Prognostic Predictors After Orthotopic Liver Transplantation After 23 years of cumulative experience, it is agreed that the major prognostic factors are as follows. Age at Liver Transplantation Advanced age is an independent risk factor for late mortality Late-onset disease tends to be associated with lower posttransplant survival 16 and progressive cardiomyopathy, especially in males with TTR V30M. 17 This appears to be related to agedependent modifications in extracellular matrix components and the deposition of different types of amyloid fibrils. 18 Duration of Disease OLT performed for longstanding disease (7 years) is associated with inferior survival and quality of life Pretransplant Clinical Status Peripheral neuropathy does not appear to be correlated with mortality. 24,25 Its main impact is on quality of life because the pretransplant symptoms usually do not regress significantly. 5,26 However, autonomic dysfunction increases the surgical risk because of the intraoperative circulatory instability and may be associated with late sudden death, which is most likely potentiated by life-threatening arrhythmias. 27,28 In Portuguese patients, myocardial sympathetic denervation assessed by 123-iodine meta-iodobenzylguanidine imaging is an independent prognostic predictor. A late heart-tomediastinum uptake ratio < 1.60 is associated with higher neurological disability and mortality, although these patients apparently still benefit from OLT. 29 Okamoto et al. 30 proposed a possible correlation between pretransplant cardiomyopathy and posttransplant survival, with 10-year survival rates of 92% and 64% for patients without and with cardiomyopathy, respectively. Preoperative Nutritional Status Severe malnutrition is associated with higher mortality, and OLT does not improve the prognosis. 20 The modified body mass index is remarkable in predicting posttransplant morbidity and survival. It presents a strong correlation with the duration of disease and, as an objective measure, allows more accurate survival comparisons. 12 In comparison with patients not undergoing OLT, the survival is better for patients with a modified body mass index 600 kg/m 2 g/l. 16 Type of Transthyretin Mutation OLT performed in non-ttr V30M cases is associated with a lower 5-year survival rate. 31 There are also several records of amyloidosis progression in such patients. 17,28,32,33

3 284 CARVALHO, ROCHA, AND LOBATO LIVER TRANSPLANTATION, March 2015 Figure 1. Algorithm for the diagnosis of ATTR. Composition of Transthyretin Fibrils Patients with a mixture of truncated and full-length TTR (type A) appear to be more prone to posttransplant development or progression of cardiomyopathy in comparison with patients with type B fibrils (only full-length TTR). Hereafter, this histopathological criterion can assume a relevant role in patient selection. 34 Despite all of these predictive factors for OLT outcomes and their importance in optimizing patient selection, establishing the prognosis for a specific patient is still a challenge. Indications and Timing of Referral for Orthotopic Liver Transplantation Patients with symptomatic TTR-FAP are the most common candidates for OLT because asymptomatic carriers may never develop the disease. 1,27 Absolute and relative contraindications for OLT are difficult to establish because clinical practice varies between centers, and this decision is made on an individual basis. The selection of transplant candidates should be performed according to the prognostic factors mentioned 1 (Table 1). Suhr et al. 27 defined some unsuitable candidates: patients with severe neuropathy, particularly if they have hand dysfunction or a pronounced risk for circulatory instability; patients with late-onset cardiomyopathy; elderly patients (especially males); patients with type A fibrils; patients with longstanding disease; and patients with a modified body mass index < 600 kg/m 2 g/l. Moreover, OLT appears to be an inadequate treatment for patients with an oculoleptomeningeal phenotype. 35,36 To optimize posttransplant survival and quality of life, the referral for OLT should be performed immediately after the diagnosis and ideally in the initial phases of the disease, particularly stage I (walking unaided) and sometimes early stage II (walking with TABLE 1. Factors to Consider for the Selection of OLT Candidates Age < 50 years Duration of symptoms < 7 years Low polyneuropathy disability score Modified body mass index 600 kg/m 2 g/l No severe autonomic dysfunction Absence of amyloid cardiomyopathy No significant renal dysfunction

4 LIVER TRANSPLANTATION, Vol. 21, No. 3, 2015 CARVALHO, ROCHA, AND LOBATO 285 Pump-driven venovenous bypass maintains hemodynamic stability and decompresses the portal venous system; this reduces injury to other capillary beds. The piggyback technique has the advantage of preserving caval flow to the heart by conserving the full length of the recipient vena cava. 44 This is currently the most widely used technique in the world for liver transplant surgery with the benefit of a shorter warm ischemia time. OLT can successfully be performed in FAP patients with either of the techniques. 45 Figure 2. Example of severe cardiomegaly in a patient with progressive amyloid cardiomyopathy after OLT (L.L., unpublished data, 2014). assistance). 37 However, the challenge of early diagnosis, the unpredictable rate of symptomatic progression, and the prolonged waiting time on the transplant list are recognized barriers The evaluation of the heart function and the identification of high-risk patients are both of utmost importance because cardiovascular complications are a leading cause of death in the posttransplant period. In FAP patients, conduction disorders are the predominant manifestation of cardiovascular disease, although myocardial infiltration is also frequently present and initially manifests more as a diastolic dysfunction than a systolic dysfunction. 38 In contrast to the clear symptoms of cardiac impairment leading to the decision for heart transplantation, a definitive position on the survival impact of prophylactic pacemaker implantation awaits a prospective randomized trial. 39 Limited experience confounds the analysis. A retrospective, single-center experience involving 104 ATTR V30M patients documented 26 pacemaker insertions, with 7 placed preoperatively and 19 inserted a median of 5 years after OLT; there was no survival improvement. 40 A second center reported no difference in 5-year survival rates among ATTR patients undergoing OLT with (n 5 9) or without a pacemaker (n 5 7). 41 Therefore, the benefit of pacemaker implantation is questionable. The recipient surgery includes a conventional hepatectomy with the removal of both the vena cava and the liver as well as the replacement of the inferior vena cava as part of the recipient hepatectomy. Hemodynamic changes caused by inferior vena cava and portal vein clamping are not well tolerated by FAP patients. 42 Besides the cardiac involvement, these patients have no portosystemic collaterals to shunt part of the stagnant venous blood from the splanchnic organs back to the heart, as in patients with cirrhosis. Vascular exclusion of the liver results in a limited vasoconstrictive response with decreases in the cardiac index and systolic blood pressure. 42,43 To avoid hemodynamic disturbances, a standard procedure with venovenous bypass or inferior vena cava preservation is contemplated. Outcomes of Orthotopic Liver Transplantation Overall Patient Survival Rate The natural average life expectancy is 9 to 13 years after the symptomatic presentation, and death usually results from cardiac involvement or cachexia. 5 The value of OLT in prolonging survival has been demonstrated, 14,46 with an estimated 10-year survival probability of 100% versus 56.1% for nontransplant patients. 46 These results most likely reflect current better patient selection and management. 18,21 However, these statistics are mostly related to patients with ATTR V30M. According to FAPWTR, the 5-year survival rate is 59% for non- ATTR V30M patients. 31 Clinicopathological Outcomes Early experience suggested symptomatic improvement as the rule, 16,19 but currently, the consensus is that the pretransplant symptoms will still be present after OLT, and this reinforces the need for early intervention. 12,15,33 After OLT, mutant TTR is rapidly cleared from circulation because it has a brief plasma half-life, and there is no consistent evidence that extrahepatic sources of TTR contribute to its plasmatic pool. 2,9 Figure 3. Congo red stained material showing amyloid deposits in the arteriole of the liver in a sequential liver receptor from a donor with ATTR V30M amyloidosis (3400): amyloid spared the bile ducts (L.L., unpublished data, 2014).

5 286 CARVALHO, ROCHA, AND LOBATO LIVER TRANSPLANTATION, March 2015 TABLE 2. Clinicopathological Outcomes Peripheral neuropathy Autonomic neuropathy Cardiac amyloidosis Renal amyloidosis Ocular amyloidosis Leptomeningeal amyloidosis Clinical Outcomes Neurologic dysfunction rarely progresses. 10,15,25 Sensory disturbances and early stages of disease are more likely to improve. 5,15,33 Recovery of peripheral nerve function is rare. 15,48 There are several reports of autonomic disturbances regression, particularly in ATTR V30M. 10,28 There can be improvement of orthostatic hypotension. 25 There can be decreases in gastrointestinal symptoms and improvements in nutritional status. 15,19 The few reports about bladder dysfunction have indicated variable outcomes. 10 There are several reports of cardiomyopathy progression after successful OLT, predominantly but not exclusively for non-attr V30M. 15,18,32,50 Aging also appears to be a risk factor for progression. 51 It does not prevent life-threatening arrhythmias, which appear more prevalent in ATTR V30M. 41,51 Stabilization of kidney function after initial deterioration is controversial. 33,51 There can be regression, intensification, or onset of proteinuria. 53 Other factors can contribute to renal impairment: nephrotoxicity of immunosuppressants, kidney damage secondary to neurogenic bladder, and diabetes mellitus. 5,33 There is progression independent of the type of TTR mutation, with aging being the major determinant. 51 There is 1 report of unsuccessful OLT in 2 siblings with ATTR Leu12Pro manifested as grand mal seizures. 41 Histopathological Outcomes Regression of amyloid deposits in peripheral nerves is still uncertain. 48 Contradictory histological evidence favors the posttransplant persistence of denervation. 49 Autopsy findings indicate a predominance of wild-type TTR in posttransplant cardiac amyloid deposits. 52 The rare histopathological reports suggest that OLT can prevent further progression of kidney amyloidosis. 54 A biochemical analysis of amyloid kidney deposits supports de novo amyloidogenesis. 52 There remain questions about the reduction or disappearance of visceral amyloid deposits. Currently, the most acceptable posttransplant outcome is no reduction, 1,47 with some reports of continuous deposition, essentially for cardiac tissue (Fig. 2) and for cases of non-attr V30M. 17,22,28 Some patients may manifest clinical deterioration (most likely those presenting with poor prognostic factors). 15,27 Results vary according to the specific symptoms evaluated (Table 2). As indicated by senile systemic amyloidosis, an agerelated TTR amyloidosis predominantly manifests via cardiomyopathy, and wild-type TTR has an intrinsic amyloidogenic capacity. 5,33 Thus, amyloidogenesis can persist even in the absence of mutant TTR, apparently by the deposition of wild-type TTR onto a substrate of preexisting amyloid fibrils, 2,5 especially with type A fibrils. 34 ATTR patients are more susceptible to early posttransplant thrombotic complications, particularly hepatic artery thrombosis, which correlates with high morbidity. 55 In the absence of a disturbed liver architecture, a surgical cause for the highly increased incidence of thrombosis is unlikely. 56 Moreover, patients with FAP have a fully competent synthetic capacity of the liver, there being unexpected alterations in the hemostatic system. 56 A recent work investigated the biological effects of TTR proteins in the vasculature and recognized that genes involved in angiogenesis regulation are significantly modulated by TTR V30M; this suggests an underlying mechanism for the increased incidence of hepatic artery thrombosis. 57

6 LIVER TRANSPLANTATION, Vol. 21, No. 3, 2015 CARVALHO, ROCHA, AND LOBATO 287 Quality of Life As a progressively disabling disease, the goal of OLT goes beyond mortality reduction. However, this has fallen short of expectations in comparison with OLT performed for end-stage liver diseases, partially because of less recognizable posttransplant improvement. 58 Thus, ATTR patients must be advised that the aim of this major surgery is preventing additional deterioration and new complications and that the surgery does not guarantee symptom regression. 5,15 Causes of Death In the OLT era, death from cardiac disease has increased with respect to historical causes such as cachexia. 7 Currently, 45% of posttransplant deaths occur because of cardiac causes or septicemia. 11 To prevent this outcome, the posttransplant follow-up of all ATTR cases, especially aging patients with their greater risk for cardiomyopathy progression, must include periodic echocardiograms, Holter electrocardiograms, 15,33 and an evaluation of serum B type natriuretic peptides. 50 Sequential Liver Transplantation Sequential liver transplantation, also known as domino liver transplantation (DLT), consists of transplanting the explanted ATTR liver into a selected non-attr patient. This is feasible because ATTR livers have the essential conditions: a liver anatomically and functionally normal despite being the major source of mutant TTR and displaying scarce amyloid deposits circumscribed to portal vessels and hilar nerves (Fig. 3) 59 and a long latency time before clinical onset. 60 Furthermore, this living graft displays less probability of graft dysfunction because the ischemic time is very short. 61 DLT was first performed in 1995 in Portugal 60 as a strategy for addressing the disproportionate supply of deceased organ donors and the rising waiting list for OLT. The safety and successful short-term results for both DLT donors and recipients have facilitated worldwide acceptance. 60 The last update of the DLT registry displayed a total of 1085 DLT procedures performed, with ATTR patients being the main donors. 11 However, the main pitfall is the risk of the DLT recipient developing ATTR amyloidosis because circulating mutant TTR is readily detected. Thus, the need for close follow-up was recognized early. 59,60 Despite the hope that ATTR in a DLT recipient would take at least 30 years to develop on the basis of its natural history, 60 the first report of symptomatic ATTR amyloidosis occurred after 8 years of followup. 62 However, subclinical skin and nerve amyloid deposits were found 3 and 6 years after DLT, respectively. 63 Electrophysiological signs of progressive peripheral polyneuropathy were also detected 2 to 5 years after DLT, without clinical symptoms or histological evidence. 64 Recently, cases of sensory neuropathy of the lower limbs without autonomic involvement, occurring as early as 6 to 7 years after transplantation, have been published Possible explanations for this accelerated amyloidogenesis are related to aging because the clinical onset in these cases varied from 55 to 75 years. However, there is a report of ATTR amyloidosis in a 45-year-old man with primary sclerosing cholangitis who underwent DLT 10 years before. 70 Other potential reasons are surgical trauma, immunosuppression, and inflammatory reactions related to graft rejection or reactivation of latent viruses. 71 This complication has been considered an indication for retransplantation with a non-attr liver. 62,64 Its efficacy in halting disease progression is now starting to be reported, with 1 case of partial symptomatic recovery. 72 Pharmacologic treatment may be an alternative approach. 72 Even though every transplant center has a unique set of guidelines for selecting potential domino liver recipients, typically they are older and more marginal transplant candidates because of the risks of novo disease. 73 For the transplants registered by the DLT registry, the mean domino recipient age was years, with 40.6% of the domino grafts being used in recipients with a primary hepatic malignancy. 11 Another relatively common indication for DLT is the need for hepatic retransplantation due to graft failure. 73 It is advocated that DLT should continue when the future recipient provides truly informed consent because the ATTR liver can still be an excellent graft if a case-by-case risk-benefit assessment is performed and a regular monitoring program is instituted A scheme for neurologic follow-up of these patients was recently proposed. 69 It is based on a periodic assessment of specific scores of peripheral neuropathy, quantitative sensory testing, nerve conduction studies, and sural nerve biopsy performed only in patients with 2 alterations in the previous tests. On the basis of these findings and the possibility of neuropathy from other etiologies, a relative probability of de novo ATTR amyloidosis is calculated. Multiple Organ Transplantation Among the 2063 transplants reported to FAPWTR, there were 46 combined heart-liver transplants and 47 combined liver-kidney transplants. Only 4 were simultaneous heart-liver-kidney transplants. 11 The first worldwide combined heart-liver transplant for ATTR dates back before 1993, 54 and the following reports reveal that most of them were performed in non-ttr V30M cases. 41,74,75 This can be explained by the higher and earlier predisposition to cardiomyopathy, which can progress even after successful OLT. 28 The paradoxical progression of cardiac amyloid is associated with wild-type TTR deposition. 74 Outcomes have been adversely influenced by the preoperative clinical status; however, they appear to be encouraging

7 288 CARVALHO, ROCHA, AND LOBATO LIVER TRANSPLANTATION, March 2015 TABLE 3. Potential Therapeutic Strategies for ATTR According to the Model of TTR Amyloidogenesis Mechanism Potential Treatments Considerations Substitution of mutant TTR gene for normal TTR gene Suppression of TTR messenger RNA expression Decrease in plasmatic levels of mutant TTR Stabilization of TTR tetramer Prevention of amyloid formation Liver transplantation* Gene therapy (conversion): Single-stranded oligonucleotides Injection of a large amount of normal TTR Gene therapy (silencing): Small interfering RNA: ALN-TTR01 and ALN-TTR02 Antisense oligonucleotides: ISIS- TTR Plasma exchange Affinity column chromatography TTR absorption column chromatography Thyroxine-based therapeutic drugs: Tafamidis meglumine* NSAIDs: diflunisal, diclofenac, and flufenamic acid Trivalent chromium (Cr 31 ) TTR T119M monomers Free-radical scavenger therapy (300 mg of N-acetylcysteine, 300 mg of a-tocopherol, and 500 mg of vitamin C) Immunization with unstable TTR (TTR Y78F) Cyclodextrin Gene therapy to repair the mutant TTR gene still has a long path before it can be applied clinically. There is a significant (but not sufficient) reduction in mutant TTR plasmatic levels. Clinical utility is precluded by the rapid turnover of TTR. There is synthesis inhibition of mutant and wild-type TTR (both with amyloidogenic capacity). It induces a dose-dependent and more durable response. There are phase 3 clinical trials. Treatments are ineffective in inducing a sufficient decrease in serum TTR. They are infeasible because of the short TTR half-life; this implies continuous treatment. These are the most promising agents for halting the relentless progression of ATTR. This can potentiate the effects of NSAIDs because of its noncompetitive action. These nonamyloidogenic monomers are incorporated into tetramers, and this makes them less amyloidogenic. There are in vitro studies. There is no effect in nontransplant patients; there is a slight improvement in the nutritional status of transplant patients. Clinical application is limited by immunization-related inflammation. This reduces the conformational change of TTR. It is in preclinical studies. Carvedilol This decreases amyloid deposits because of an antioxidant effect. It is in preclinical studies. Dissolution of amyloid aggregates 4 0 -Iodo-4 0 -deoxydoxorubicin There is a lack of in vivo studies. It is nephrotoxic. Doxycycline and tauroursodeoxycholic acid Anti serum amyloid P component monoclonal antibodies Epigallocatechin-3-gallate This appears to stabilize the disease at least for 1 year. There are tolerable adverse effects. There is a phase 1 study in patients with AA amyloidosis. This is in preclinical trials. NOTE: This is table is based on the work of Ando et al., 1,26 Araki and Ando, 6 Hund, 79 Lobato and Rocha, 77 and Adams et al. 8 *Therapies currently available for clinical use. Therapies with promising future outcomes.

8 LIVER TRANSPLANTATION, Vol. 21, No. 3, 2015 CARVALHO, ROCHA, AND LOBATO 289 because histological and imaging evidence of cardiac amyloid deposits has not yet been found. 41,74 Combined liver-kidney transplantation is indicated in patients with end-stage renal disease. Renal replacement therapy correlates with poor survival, and isolated OLT in patients with a preoperative glomerular filtration rate < 30 ml/minute/1.73 m 2 is associated with a significant postoperative deterioration of kidney function. 76,77 A series of 13 patients with different indications for combined liver-kidney transplantation, including 3 patients with FAP, reinforced the idea that the liver graft may have a protective immunologic effect on the kidney graft. 78 After 84 months of follow-up of 6 patients with ATTR V30M subjected to combined liver-kidney transplantation, a group reported the absence of proteinuria and a mean serum creatinine level within the upper limit of the reference range. 76 These results suggest that combined liver-kidney transplantation prevents the recurrence of nephropathy, although this has not been histologically proven. NOVEL THERAPEUTIC APPROACHES The persistent searching for an ideal therapy for ATTR began many years ago, and it still continues today with a preference toward less invasive options. The partial understanding of TTR amyloidogenesis has allowed the development of several potential new treatments acting in different phases of the process (Table 3). Further progress in this area is expected because of recent success in the generation of ATTRspecific induced pluripotent stem cells. 80 Currently, the most promising drugs appear to be TTRstabilizing agents. They prevent amyloidogenesis by inhibiting TTR tetramer dissociation and include the first medical treatment specifically approved for TTR- FAP in Europe in 2011: tafamidis meglumine. This drug has demonstrated the capacity to slow the progression of early stages of peripheral neuropathy and, therefore, is formally indicated for patients with the neuropathic form of ATTR in stage I, regardless of the type of mutation. 1,79 Nevertheless, there is evidence that suggests less efficacy in halting neurological dysfunction in non-ttr V30M mutations. Moreover, patients with late-onset ATTR V30M involved in a nonrandomized controlled trial displayed disability progression in 55% of cases and increased neuropathy impairment scores in most cases. 8 Nonsteroidal anti-inflammatory drugs (NSAIDs) are capable of stabilizing the TTR tetramer because their structure resembles that of thyroxine, which is mainly responsible for tetramer stabilization. Diflunisal is already in clinical trials, with the actual concerns being the therapeutic serum concentrations, the adverse effect profile requiring regular renal and hematological monitoring, and its efficacy for other phenotypes of ATTR. 1,79 An open-label uncontrolled trial was conducted with 13 patients presenting with symptomatic and biopsy-proven ATTR cardiomyopathy. They were treated with diflunisal (250 mg twice daily) for a mean of 10.8 months, during which no significant changes in cardiac structure, function, or biomarkers were observed. Diflunisal appears to have the potential to slow disease progression, although these results require confirmation in a randomized placebo-controlled trial. 81 Several agents are presently under investigation, with some still restricted to preclinical studies. A recent article about the clinical management of ATTR patients expresses the idea that as new effective drugs become available, they should be offered to patients meeting their clinical indications, regardless of liver transplant plans. 1 CONCLUSIONS It is well known that in many patients, the preexisting symptoms will remain unchanged after OLT, and not all are suitable candidates. The shortage of liver donors is another important restriction that is partially relieved by DLT, which has recently demonstrated some unexpected and unfavorable long-term outcomes. Current therapeutic options for ATTR have recently expanded with another disease-modifying therapy: tafamidis. The approval of this drug in Europe has raised several unanswered questions, such as its efficacy in the treatment of amyloid cardiomyopathy or stage 0 or advanced stages of disease, for which there is still a gap in therapeutic options. The future may validate a combined approach of OLT plus drug treatment. 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10 LIVER TRANSPLANTATION, Vol. 21, No. 3, 2015 CARVALHO, ROCHA, AND LOBATO Okamoto S, H ornsten R, Obayashi K, Wijayatunga P, Suhr OB. Continuous development of arrhythmia is observed in Swedish transplant patients with familial amyloidotic polyneuropathy (amyloidogenic transthyretin Val30Met variant). Liver Transpl 2011;17: Barreiros AP, Post F, Hoppe-Lotichius M, Linke RP, Vahl CF, Sch afers HJ, et al. Liver transplantation and combined liver-heart transplantation in patients with familial amyloid polyneuropathy: a single-center experience. Liver Transpl 2010;16: Acosta F, Sansano T, Rodriguez MA, Contreras RF, Reche M, Beltran R, et al. Need for venovenous bypass in patients with familial amyloidotic polyneuropathy treated with liver transplantation. Transplant Proc 1999;31: Parrilla P, Ramirez P, Bueno FS, Robles R, Acosta F, Miras M, et al. Clinical improvement after liver transplantation for type I familial amyloid polyneuropathy. 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11 292 CARVALHO, ROCHA, AND LOBATO LIVER TRANSPLANTATION, March Pilato E, Dell Amore A, Botta L, Arpesella G. Combined heart and liver transplantation for familial amyloidotic neuropathy. Eur J Cardiothorac Surg 2007;32: Arpesella G, Chiappini B, Marinelli G, Mikus PM, Dozza F, Pierangeli A, et al. Combined heart and liver transplantation for familial amyloidotic polyneuropathy. J Thorac Cardiovasc Surg 2003;125: Lobato L, Beir~ao I, Seca R, Pessegueiro H, Rocha MJ, Queiroz J, et al. Combined liver-kidney transplantation in familial amyloidotic polyneuropathy TTR V30M: nephrological assessment. Amyloid 2011;18(suppl 1): Lobato L, Rocha A. Transthyretin amyloidosis and the kidney. Clin J Am Soc Nephrol 2012;7: Gonzalez MR, Ramırez P, Cascales P, Domingo J, Lopez MD, Rios A, et al. Thirteen cases of liver-kidney transplantation. Transplant Proc 2010;42: Hund E. Familial amyloidotic polyneuropathy: current and emerging treatment options for transthyretin-mediated amyloidosis. Appl Clin Genet 2012;5: Isono K, Jono H, Ohya Y, Shiraki N, Yamazoe T, Sugasaki A, et al. Generation of familial amyloidotic polyneuropathy-specific induced pluripotent stem cells. Stem Cell Res 2014;12: Casta~no A, Helmke S, Alvarez J, Delisle S, Maurer MS. Diflunisal for ATTR cardiac amyloidosis. Congest Heart Fail 2012;18: