Familial amyloid polyneuropathy and liver transplantation

Abstract

Familial amyloid polyneuropathy (FAP) is an autosomal dominant multisystemic fatal disorder: the Portuguese type was first observed in 1939 by Corino de Andrade, a Portuguese neurologist and his findings were later published in 1951 [1Andrade C. A peculiar form of peripheral neuropathy.Acta Psych et Neurol Scand. 1951; 26: 251-257Crossref PubMed Scopus (16) Google Scholar, 2Andrade C. Note preliminaire sur une forme particuliere de neuropathie peripherique.Rev Neurol. 1951; 85: 302-306PubMed Google Scholar]. FAP is characterised by a progressive peripheral and autonomic neuropathy with neural and systemic amyloid deposits [3Andrade C. Clinique de la paramyloidose du type portugais.Acta Neuropathol (Berl). 1963; Suppl II: 3-11Google Scholar, 4Becker P.E. Antunes L. Rosario M.R. Barros F. Paramyloidose der peripheren nerven in Portugal.Z menschl vereb-ukonstitutionslehre. 1964; 37: 329-364PubMed Google Scholar]. The disease is caused by a mutant gene in chromosome pair 18. The amyloid protein in type 1 FAP of portuguese, swedish and japanese origin, is the variant transthyretin [[5]Costa P.P. Figueira A.S. Bravo F. Amyloid fibril protein related to prealbumin in familial amyloidotic polyneuropathy.Proc Natl Acad Sci USA. 1978; 75: 4499-4503Crossref PubMed Scopus (337) Google Scholar] in which methionine is a substitute for valine at position 30 (transthyretin-methionine 30, TTR Met 30). This type 1 FAP seems to be the most common variety. More than 90% of TTR Met 30 is produced by the liver: the rest is produced by the choroid plexus. Amyloid fibres may be formed through different mechanisms [[6]Glenner G.G. Amyloid deposits and amyloidosis. The B-fibrilloses.N Engl J Med. 1980; 302: 1283-1292Crossref PubMed Scopus (1296) Google Scholar]. There was evidence that amyloid fibres were related to the prealbumin transthyretin [[5]Costa P.P. Figueira A.S. Bravo F. Amyloid fibril protein related to prealbumin in familial amyloidotic polyneuropathy.Proc Natl Acad Sci USA. 1978; 75: 4499-4503Crossref PubMed Scopus (337) Google Scholar]. Saraiva et al. [[7]Saraiva M.J.M. Birken S. Costa P.P. Goodman D.S. Amyloid fibril protein in familial amyloidotic polyneuropathy Portuguese type. Definition of molecular abnormality in transthyretin (pre-albumin).J Clin Invest. 1984; 74: 104-119Crossref PubMed Google Scholar], demonstrated that the amyloid deposits correspond to the abnormal transthyretin. Furthermore, it was demonstrated that TTR Met 30 was present in the serum of all affected patients and that its presence is a reliable (100%) biochemical marker for the defect [8Saraiva M.J.M. Birken S. Costa P.P. Goodman D.S. Family studies of the genetic abnormality in transthyretin (pre-albumin) in Portuguese patients with familial amyloidotic polyneuropathy.Ann NY Acad Sci. 1984; 435: 86-100Crossref PubMed Scopus (47) Google Scholar, 9Saraiva M.J.M. Costa P.P. Goodman D.S. Biochemical marker in familial amyloidotic polyneuropathy, Portuguese type. Family studies on the transthyretin (pre-albumin)-methionine-30 variant.J Clin Invest. 1985; 76: 2171-2177Crossref PubMed Scopus (100) Google Scholar]. Although cases of FAP type 1 may be found all over the world, the most important clusters are in Portugal and Sweden. The original cases occurred in the area of Povoa do Varzim (North of Portugal), a small fishing village, and fishermen were probably responsible for the worldwide spread of the disease, mainly to Sweden and Japan [[10]Monteiro E. Perdigoto R. Furtado A.L. Liver transplantation for familial amyloid polyneuropathy.Hepato-Gastroenterology. 1998; 45: 1375-1380PubMed Google Scholar]. At present in Portugal more than 600 families are under follow-up with more than 2000 symptomatic cases. Approximately 50 new cases arise every year. Symptoms appear between 20 and 35 years of age and patients usually die within 10–12 years. The Portuguese type of the disease is particularly severe. In a few cases there is a rapid progression within 2 years with multiorgan involvement mainly peripheral nerves, kidney, heart, and upper GI tract (stomach and small intestine). This multisystemic involvement largely justified the previous denomination of disseminated amyloidosis or paramiloidosis [[11]Andrade C. A peculiar form of peripheral neuropathy. Familial atypical generalized amyloidosis with special involvement of the peripheral nerves.Brain. 1952; 75: 408-427Crossref PubMed Scopus (836) Google Scholar] However, the majority of cases begin with peripheral polyneuropathy: pain, sensory loss and motor disability. Frequently the polyneuropathy is shortly followed by some autonomic nervous signs. Erectile dysfunction is one of the first disturbances. Gastrointestinal dysfunction develops, either severe constipation or diarrhoea and sometimes faecal incontinence. Difficulty in gastric emptying with nausea and vomiting are also frequent. Bladder dysfunction with either urine retention or incontinence is present in advanced stages. Cardiovascular symptoms range from orthostatic hypotension to different arrhythmias and first and second degree atrioventricular block. Proteinuria is frequently the expression of kidney involvement with reduction of the glomerular filtration rate and decreased creatinine clearance. Frequently the disease is present either in the father or mother and there are also other family members affected, although the manifestation of the disease seems dependent on individual enzymatic and/or hormonal variations [[10]Monteiro E. Perdigoto R. Furtado A.L. Liver transplantation for familial amyloid polyneuropathy.Hepato-Gastroenterology. 1998; 45: 1375-1380PubMed Google Scholar]. Although early onset cases are not uncommon in swedish patients [[12]Suhr O.B. Ericzon B.-G. Friman S. Longterm follow-up of survival of liver transplant recipients with familial amyloid polyneuropathy (Portuguese type).Liver Transpl Surg. 2002; : 787-794Crossref Scopus (81) Google Scholar], the majority of patients have a later onset after the age of 50. The initial symptom is usually related to the peripheral neuropathy, with frequent gastrointestinal and cardiovascular symptoms and malnutrition, which have a substantial impact on morbidity and mortality [13Steen L. Ek B. Familial amyloidosis with polyneuropathy. A long-term follow-up of 21 patients with special reference to gastrointestinal symptoms.Acta Med Scand. 1983; 214: 387-397Crossref PubMed Scopus (65) Google Scholar, 14Suhr O. Danielsson A. Holmgren G. Steen L. Malnutrition and gastrointestinal dysfunction as prognostic factors for survival in familial amyloidotic polyneuropathy.J Intern Med. 1994; 235: 479-485Crossref PubMed Google Scholar]. The survival of Swedish patients is variable, but the average survival period is reported to be between 9 and 13 years with a mean of 10.8 years after onset [14Suhr O. Danielsson A. Holmgren G. Steen L. Malnutrition and gastrointestinal dysfunction as prognostic factors for survival in familial amyloidotic polyneuropathy.J Intern Med. 1994; 235: 479-485Crossref PubMed Google Scholar, 15Anderrson R. Familial amyloidosis with polyneuropathy: a clinical study based on patients living in northern Sweden.Acta Med Scand. 1976; 198: 1-64Google Scholar]. Since more than 90% of TTR Met 30 is produced within the liver, it is expected that liver transplantation will stop disease progression and that TTR Met 30 will clear from the serum. Two different therapeutic approaches have been used to reduce the high blood levels of TTR Met 30 in order to prevent further deposits or to reduce already existing deposits: plasmapheresis and immunoadsorption. Both techniques [16Sales Luis M.L. Galvão M. Carvalho M. Sousa G. Alves M.M. Serrão R. Treatment of familial amyloidotic polyneuropathy (Portuguese type) by plasma exchange.Muscle Nerve. 1991; : 377-378PubMed Google Scholar, 17Lobato L, Costa PMP, Castro R, Beirão I, Estacio A, Costa PP. In vivo immunoadsorption of transthyretin in familial amyloidotic polyneuropathy TTR-Met 30: preliminary clinical experience. Proceedings of the 3rd International Symposium on Familial Amyloidotic Polyneuropathy and other Transthyretin Related Disorders. Lisboa, Portugal; 1995.Google Scholar] have been the subject of several reports. Plasmapheresis needs to be repeated several times a month, which is not practical and leads to impaired quality of life. Immunoadsorption has met with serious doubts concerning its efficacy, cost and predictability. The failure of these previous therapeutic tools led Holmgren [[18]Holmgren G. Steen L. Ekstedt J. Groth C.G. Ericzon B.-G. Eriksson S. et al.Biochemical effect of liver transplantation in two Swedish patients with familial amyloidotic polyneuropathy (FAP-Met30).Clin Genet. 1991; 40: 242-246Crossref PubMed Scopus (346) Google Scholar] to perform the first orthotopic liver transplantation for FAP patients, Portuguese type in 1990. Soon afterwards [[19]Holmgren G. Ericzon B.-G. Groth C.G. Steen L. Suhr Andersen O. Wallin B.G. et al.Clinical improvement and amyloid regression after liver transplantation in hereditary transthyretin amyloidosis.Lancet. 1993; 341: 1113-1116Abstract PubMed Scopus (507) Google Scholar] it was confirmed that the replacement of a liver abnormally producing TTR Met 30 by a normal organ fulfilled the expectations of a quick and drastic decrease in the high blood levels of the abnormal protein. As previously stated, the first liver transplant in a FAP patient was performed in 1990 by Holmgren [[18]Holmgren G. Steen L. Ekstedt J. Groth C.G. Ericzon B.-G. Eriksson S. et al.Biochemical effect of liver transplantation in two Swedish patients with familial amyloidotic polyneuropathy (FAP-Met30).Clin Genet. 1991; 40: 242-246Crossref PubMed Scopus (346) Google Scholar]. Since then, several other liver transplants in FAP patients have taken place all over the world, with a considerable number performed in Portugal. The number of liver transplantations for FAP patients in the three portuguese liver transplant centres totalled about 460 up to the end of 2003. Fig. 1 shows the actuarial survival curve at 10 years in our centre at Curry Cabral Hospital (102 patients transplanted). A total of 539 patients have undergone liver transplantations world-wide for FAP, according to the FAPWTR (Familial Amyloidotic Polyneuropathy world transplant registry) report from 1990 to the end of 2000 [[20]Herlenius G. Wilezek H.E. Larsson M. Ericzon B.-G. Ten years of International experience with liver transplantation for familial amyloidotic polineuropathy: results from the familial amyloidotic polyneuropathy World Transplant Registry.Transplantation. 2004; 77: 64-71Crossref PubMed Scopus (220) Google Scholar]. However, the number is probably much higher, since the Portuguese centres have transplanted 315 in the last 3 years, increasing from 145 by the end of 2000 to 460 cases by the end of 2003. In the 10 years analysed by FAPWTR, 20 different TTR mutations were reported. The TTR Val 30 Met mutation is present in 83% of cases. At the time of transplantation the main clinical manifestation in the cases reported by FAPWTR was peripheral polyneuropathy (75%) followed by manifestations of autonomic neuropathy (24%). Only 1% had extraneurological amiloidosis, namely eye complaints, as initial manifestation [[20]Herlenius G. Wilezek H.E. Larsson M. Ericzon B.-G. Ten years of International experience with liver transplantation for familial amyloidotic polineuropathy: results from the familial amyloidotic polyneuropathy World Transplant Registry.Transplantation. 2004; 77: 64-71Crossref PubMed Scopus (220) Google Scholar]. It is proved that TTR-Met 30 clears from the patient's serum soon after liver transplantation. Several papers have been published after liver transplantation in FAP patients. TTR Met 30 cleared in all patients’ serum [[18]Holmgren G. Steen L. Ekstedt J. Groth C.G. Ericzon B.-G. Eriksson S. et al.Biochemical effect of liver transplantation in two Swedish patients with familial amyloidotic polyneuropathy (FAP-Met30).Clin Genet. 1991; 40: 242-246Crossref PubMed Scopus (346) Google Scholar]. The first portuguese publications concerning transplanted FAP patients [10Monteiro E. Perdigoto R. Furtado A.L. Liver transplantation for familial amyloid polyneuropathy.Hepato-Gastroenterology. 1998; 45: 1375-1380PubMed Google Scholar, 21Monteiro E. Perdigoto R. Morbey A. Mota O. Ribeiro T. Freire A. et al.Portuguese national experience in familial amyloid polyneuropathy (FAP) treated by orthotopic liver transplant.Hepatology. 1995; 22: 149ACrossref Google Scholar] reported 12 deaths. Interestingly all the deaths occurred in patients with a history of the disease of over 6 years. Our findings have been confirmed by swedish researchers [22Suhr O. Holmgren G. Steen L. Wikstrom L. Norden G. Friman S. et al.Liver transplantation in familial amyloidotic polyneuropathy. Follow-up of the first 20 Swedish patients.Transplantation. 1995; 60: 933-938Crossref PubMed Google Scholar, 23Suhr O.B. Hernelius G. Friman S. Ericzon B.-G. Liver transplantation for hereditary transthyretin amyloidosis.Liver Transpl. 2000; 6: 263-276Crossref PubMed Scopus (112) Google Scholar]. The disease duration before liver transplantation seems to have an important impact on the follow-up. Survival significantly decreased in patients with symptomatic disease for longer than 7 years. In Japan the results of partial transplantation using living donors were consistent with these conclusions [[24]Ikeda S. Takai Y. Yanagisawa N. Matsunami H. Hashikura Y. Ikegami T. et al.Partial liver transplantation from living donors in familial amyloid polyneuropathy.Amyloid. 1997; 4: 18-23Crossref Scopus (22) Google Scholar]. In the United States of America it also seems likely that patients with longstanding disease were among fatalities [25Skinner M. Lewis W. Jons L. Kasirsky J. Kane K. Ju S.-T. et al.Liver transplantation as a treatment for familial amyloidotic polyneuropathy.Ann Int Med. 1994; 120: 133-134Crossref PubMed Scopus (83) Google Scholar, 26Lewis W. Skinner M. Jenkins R. Report on 24 patients with liver transplantation for FAP in the United States (abstract).Neuromuscul Disord. 1996; 6: 77AAbstract Full Text PDF Google Scholar]. However, Parrilla et al. [[27]Parilla P. Ramirez P. Bueno F. Robles R. Acosta F. Miras M. et al.Clinical improvement after liver transplantation for type 1 familial amyloid polyneuropathy.Br J Surg. 1995; 82: 825-828Crossref PubMed Scopus (39) Google Scholar] found no correlation between longstanding disease and mortality. Adams et al. [[28]Adams D. Samuel D. Goulon-Goeau C. Costa P. Nakazzato M. Costa P.M.P. et al.The course and prognostic factors of familial amyloid polyneuropathy after liver transplantation.Brain. 2000; 123: 1495-1504Crossref PubMed Scopus (211) Google Scholar] do not establish a statistically significant straight correlation between longstanding disease and poor outcome. Nevertheless they emphasize the fact that severely affected patients mainly with urinary incontinence and/or severe sensory-motor neuropathy should be excluded from liver transplant lists on account of the high mortality rate. The presence of cardiac involvement before liver transplantation also seems to be associated with a poorer outcome. In Adams’ series, every patient at inclusion had symptomatic autonomic dysfunction and sensory-motor neuropathy was only present in 73% of the cases. Gastrointestinal impairment with malabsorption and malnutrition were present in almost all portuguese patients who died. In Sweden these factors seem to have had a pronounced impact on survival after transplantation [[29]Suhr O. Danielsson A. Rydh A. Nyhlin N. Hietale S.O. Steen L. Impact of gastrointestinal dysfunction on survival after liver transplantation for familial amyloidotic polyneuropathy.Dig Dis Sci. 1996; 10: 1909-1914Crossref Scopus (45) Google Scholar]. Suhr et al. [[30]Suhr O. Danielsson A. Holmgren G. Steen L. Malnutrition and gastrointestinal dysfunction as prognostic factors for survival in familial amyloidotic polyneuropathy.J Intern Med. 1994; 235: 479-485Crossref PubMed Scopus (161) Google Scholar] developed a modified body mass index (m BMI) in which BMI (weight in kilograms/height2 in meters) is multiplied by serum albumin (in grams per litre). This index has proved valuable in patient selection, excluding patients with m BMI less than 600. Cardiac problems are frequent and decreased orthostatic blood pressure with paradoxal response to catecholamines has been interpreted as autonomic polyneuropathy [[31]Hagerman I. Berglund L. Ericzon B.-G. Eleborg L. Total pharmacologic autonomic blockade (TAB) reveals severe autonomic imbalance of heart rate variability (HRV) in familial amyloidotic polyneuropathy (abstract).Proc Int Workshop Liver Transpl FAP. 1999; 10: 22Google Scholar]. Also cardiac arrhythmias with atrioventricular conduction disturbances are well known complications of FAP and in some centres a pre or perioperative pacemaker insertion has been used in the majority of patients. In Portugal the majority of transplant centres place a pacemaker prior to the liver transplant. Bladder dysfunction is frequently present in FAP patients. Urinary retention can also contribute to renal insufficiency, so intermittent catheterisation, to improve bladder emptying, should be recommended [[23]Suhr O.B. Hernelius G. Friman S. Ericzon B.-G. Liver transplantation for hereditary transthyretin amyloidosis.Liver Transpl. 2000; 6: 263-276Crossref PubMed Scopus (112) Google Scholar]. Kidney failure is also a very important problem in these patients after transplantation. Several patients have impaired renal function before transplantation and immunosuppression using calcineurin inhibitors (CycA or Tac) may aggravate kidney function. Three of the first series of patients transplanted in Portugal required subsequent kidney transplantation [[10]Monteiro E. Perdigoto R. Furtado A.L. Liver transplantation for familial amyloid polyneuropathy.Hepato-Gastroenterology. 1998; 45: 1375-1380PubMed Google Scholar]. According to FAPWTR [[20]Herlenius G. Wilezek H.E. Larsson M. Ericzon B.-G. Ten years of International experience with liver transplantation for familial amyloidotic polineuropathy: results from the familial amyloidotic polyneuropathy World Transplant Registry.Transplantation. 2004; 77: 64-71Crossref PubMed Scopus (220) Google Scholar], kidney and heart comorbidities led to 17 combined liver–kidney transplantations and, in one case, to a triple transplant: liver, kidney and heart. Of the 17 patients who underwent liver–kidney double transplant, 7 died. Two out of the 6 liver–heart transplants also died. Malnutrition was a common finding among those patients who died [[20]Herlenius G. Wilezek H.E. Larsson M. Ericzon B.-G. Ten years of International experience with liver transplantation for familial amyloidotic polineuropathy: results from the familial amyloidotic polyneuropathy World Transplant Registry.Transplantation. 2004; 77: 64-71Crossref PubMed Scopus (220) Google Scholar]. A recent publication [[32]Grazi G.L. Cescon M. Salvi F. Ercolani G. Ravaioli M. Arpesella G. et al.Combined heart and liver transplantation for familial amyloidotic neuropathy: considerations from the hepatic point of view.Liver Transpl. 2003; 9: 986-992Crossref PubMed Scopus (40) Google Scholar] defends the feasibility of combined heart–liver transplantation (CHLT), which in the case of dysfunction of both organs provides good results. The authors present their 3 cases and a review of 13 cases with only 3 deaths. Cardiac instability seems to be more likely among non-TTR-Met 30 mutations. After liver transplantation the main problems raised were the benefit concerning both the evolution and the regression of the disease. Moreover, guidelines are needed to determine the type of patient and the exact timing for transplant. The report of the first 40 FAP patients transplanted in Portugal was published in 1995 [[21]Monteiro E. Perdigoto R. Morbey A. Mota O. Ribeiro T. Freire A. et al.Portuguese national experience in familial amyloid polyneuropathy (FAP) treated by orthotopic liver transplant.Hepatology. 1995; 22: 149ACrossref Google Scholar]. Polyneuropathy improved subjectively in 16 patients but only 4 were confirmed by electromiography. Gastrointestinal symptoms and erectile dysfunction improved at 6 and 12 months in 60 and 30% of patients, respectively. Weight gain was evident in a few patients but only after 1 year. Seven patients died: 3 from multiple organ failure (MOF), 2 from stroke, 1 from cardiac arrest and 1 from sepsis [[21]Monteiro E. Perdigoto R. Morbey A. Mota O. Ribeiro T. Freire A. et al.Portuguese national experience in familial amyloid polyneuropathy (FAP) treated by orthotopic liver transplant.Hepatology. 1995; 22: 149ACrossref Google Scholar]. A later publication [[10]Monteiro E. Perdigoto R. Furtado A.L. Liver transplantation for familial amyloid polyneuropathy.Hepato-Gastroenterology. 1998; 45: 1375-1380PubMed Google Scholar] showed a superimposed 5 deaths—2 of sepsis, 1 of cardiac arrest and 2 from hepatic artery thrombosis. The most important issue is to evaluate if there is true halt in the progression of the disease, any regression of the symptoms or the contrary, i.e. if there is either progression or new complaints. The majority of published work agrees that liver transplantation halts the progression of the disease [10Monteiro E. Perdigoto R. Furtado A.L. Liver transplantation for familial amyloid polyneuropathy.Hepato-Gastroenterology. 1998; 45: 1375-1380PubMed Google Scholar, 12Suhr O.B. Ericzon B.-G. Friman S. Longterm follow-up of survival of liver transplant recipients with familial amyloid polyneuropathy (Portuguese type).Liver Transpl Surg. 2002; : 787-794Crossref Scopus (81) Google Scholar, 21Monteiro E. Perdigoto R. Morbey A. Mota O. Ribeiro T. Freire A. et al.Portuguese national experience in familial amyloid polyneuropathy (FAP) treated by orthotopic liver transplant.Hepatology. 1995; 22: 149ACrossref Google Scholar, 22Suhr O. Holmgren G. Steen L. Wikstrom L. Norden G. Friman S. et al.Liver transplantation in familial amyloidotic polyneuropathy. Follow-up of the first 20 Swedish patients.Transplantation. 1995; 60: 933-938Crossref PubMed Google Scholar, 23Suhr O.B. Hernelius G. Friman S. Ericzon B.-G. Liver transplantation for hereditary transthyretin amyloidosis.Liver Transpl. 2000; 6: 263-276Crossref PubMed Scopus (112) Google Scholar, 24Ikeda S. Takai Y. Yanagisawa N. Matsunami H. Hashikura Y. Ikegami T. et al.Partial liver transplantation from living donors in familial amyloid polyneuropathy.Amyloid. 1997; 4: 18-23Crossref Scopus (22) Google Scholar]. However, there are a few reports which contest this statement [33Kobayashi S. Movita H. Asawa T. Takei Y.I. Hashimoto T. Ikegami T. et al.Peripheral nerve function in patients with familial amyloid polyneuropathy after liver transplantation.Amyloid. 2003; 10: 17-24Crossref PubMed Scopus (16) Google Scholar, 34Dubrey S.W. Davidoff R. Kinnar M. Bergethon P. Lewis D. Falk R.H. Progression of ventricular wall thickening after liver transplantation for familial amyloidosis.Transplantation. 1997; 64: 74-80Crossref PubMed Scopus (148) Google Scholar]. According to the FAPWTR ten-year report, [[20]Herlenius G. Wilezek H.E. Larsson M. Ericzon B.-G. Ten years of International experience with liver transplantation for familial amyloidotic polineuropathy: results from the familial amyloidotic polyneuropathy World Transplant Registry.Transplantation. 2004; 77: 64-71Crossref PubMed Scopus (220) Google Scholar] two thirds of the first complaints of the disease are related to peripheral neuropathy and only 1/3 start with autonomic neuropathy symptoms. The results presented sustain that liver transplant in FAP patients seems to improve sensory neuropathy in 41.6%, while motor and muscular manifestations only improve in 37.4%. Although some authors [[33]Kobayashi S. Movita H. Asawa T. Takei Y.I. Hashimoto T. Ikegami T. et al.Peripheral nerve function in patients with familial amyloid polyneuropathy after liver transplantation.Amyloid. 2003; 10: 17-24Crossref PubMed Scopus (16) Google Scholar] find some improvement in skin temperature of foot and hand soon after surgery, the recovery of peripheral nerve function in patients submitted to liver transplant seems to be slow and limited. Tashimo et al. [[35]Tashimo K. Ando Y. Terazaki H. Yoshimatsu S. Suhr O.B. Obayashi K. et al.Outcome of liver transplantation for transthyretin amyloidosis; Follow-up of Japanese familial amyloidotic polyneuropathy patients.J. Neurol Sci. 1999; 171: 19-23Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar] developed a scoring system for FAP Met 30 that takes into account a variety of clinical symptoms of the disease. Improvement of sensory and autonomic disturbances was observed during the first year after transplantation. No improvement of motor function and visceral organ damage was seen. They conclude that liver transplantation in these patients halts the progress of the disease and several patients show minor improvements. Adams et al. [[28]Adams D. Samuel D. Goulon-Goeau C. Costa P. Nakazzato M. Costa P.M.P. et al.The course and prognostic factors of familial amyloid polyneuropathy after liver transplantation.Brain. 2000; 123: 1495-1504Crossref PubMed Scopus (211) Google Scholar] noted that 2 years after transplant, the rate of myelinated axon loss in nerve biopsy specimens was markedly lower in seven transplanted patients. Improvement of gastrointestinal manifestations was observed in about 50% of patients and malnutrition improved in 40% of the patients. With regard to cardiovascular symptoms, only 20% showed any improvement [[20]Herlenius G. Wilezek H.E. Larsson M. Ericzon B.-G. Ten years of International experience with liver transplantation for familial amyloidotic polineuropathy: results from the familial amyloidotic polyneuropathy World Transplant Registry.Transplantation. 2004; 77: 64-71Crossref PubMed Scopus (220) Google Scholar]. Adverse outcomes are mainly related with the presence of malnutrition, longstanding disease before liver transplantation or non-Met 30 (NMet 30) mutations [23Suhr O.B. Hernelius G. Friman S. Ericzon B.-G. Liver transplantation for hereditary transthyretin amyloidosis.Liver Transpl. 2000; 6: 263-276Crossref PubMed Scopus (112) Google Scholar, 34Dubrey S.W. Davidoff R. Kinnar M. Bergethon P. Lewis D. Falk R.H. Progression of ventricular wall thickening after liver transplantation for familial amyloidosis.Transplantation. 1997; 64: 74-80Crossref PubMed Scopus (148) Google Scholar]. A recent paper from the United States of America showed poor outcome in their 15 patients transplanted for FAP, with the disease even worsening. Although only five patients were TTR Met 30 type I, both Met 30 and NMet 30 were similar with regard to neuropathy, diarrhoea and orthostatic hypotension [[36]Sharma P. Perri R.E. Sirven J.E. Zeldenrust S. Brand hagen D.J. Rosen C.B. et al.Outcome of liver transplantation for familial amyloidotic polyneuropathy.Liver Transpl. 2003; 12: 1273-1280Crossref Scopus (50) Google Scholar]. However, this cohort included both older patients and patients with later referrals in the course of the disease. For NMet 30 mutations, increased cardiac miopathy has been reported after liver transplantation [[37]Stangou A.J. Hawkins P.N. Heaton N.D. Rela M. Monaghan M. Nihoyannopoulos P. et al.Progressive cardiac amyloidosis following liver transplantation for familial amyloid polyneuropathy: implications for amyloid fibrillogenesis.Transplantation. 1998; 66: 229-233Crossref PubMed Scopus (179) Google Scholar]. Also a progression of ventricular wall thickening after liver transplantation seems to take place [[34]Dubrey S.W. Davidoff R. Kinnar M. Bergethon P. Lewis D. Falk R.H. Progression of ventricular wall thickening after liver transplantation for familial amyloidosis.Transplantation. 1997; 64: 74-80Crossref PubMed Scopus (148) Google Scholar]. Although Promfret et al. [[38]Pomfret E.A. Lewis W.D. Jenkins R.L. Bergelhon P. Dubrey S.W. Reisinger J. et al.Effect of orthotopic liver transplantation on the progression of familial amyloidotic polyneuropathy.Transplantation. 1998; 65: 918-925Crossref PubMed Scopus (112) Google Scholar] state that liver transplantation offers the only cure for the genetic defect causing FAP, resulting in subjective and objective improvement in neurological dysfunction, they also claim that patients with pre-existing cardiovascular abnormalities progress despite transplantation: therefore, consideration for CHLT may be warranted in this subset of patients. So, it seems reasonable that a CHLT should be considered whenever there is cardiac involvement. To establish the optimal timing for this combined surgery seems to be crucial in order to ensure a positive outcome [[32]Grazi G.L. Cescon M. Salvi F. Ercolani G. Ravaioli M. Arpesella G. et al.Combined heart and liver transplantation for familial amyloidotic neuropathy: considerations from the hepatic point of view.Liver Transpl. 2003; 9: 986-992Crossref PubMed Scopus (40) Google Scholar]. Suhr [[39]Suhr O. Impact of liver transplantation on familial amyloidotic polyneuropathy (FAP) patients symptoms and complications.Amyloid. 2003; 10: 77-83Crossref PubMed Scopus (28) Google Scholar] draws attention to the deposition of TTR within the eye, since TTR production by choroid plexus does not cease with the liver transplant. It is important to remember that TTR is not only synthesized by the liver but is also produced by the choroid plexus and the retina and the role of TTR synthesized by these tissues in FAP patients remains to be elucidated. Moreover ocular manifestations are common in patients with FAP TTR Met 30 and may become a serious problem after liver transplantation [[40]Ando Y. Terazaki H. Nakamura M. Ando E. Haraok K. Yamashila T. et al.A different amyloid formation mechanism: de novo oculo leptomeningeal amyloid deposits after liver transplantation.Transplantation. 2004; 77: 345-349Crossref PubMed Scopus (84) Google Scholar]. Studies conducted by these authors [[40]Ando Y. Terazaki H. Nakamura M. Ando E. Haraok K. Yamashila T. et al.A different amyloid formation mechanism: de novo oculo leptomeningeal amyloid deposits after liver transplantation.Transplantation. 2004; 77: 345-349Crossref PubMed Scopus (84) Google Scholar] in 22 patients with FAP undergoing liver transplant showed evidence of de novo glaucoma in 3 patients, and 1 with vitreous opacity. Moreover new amyloid deposits in the pupillary margin of another 3 patients were described. The experience of these authors shows an increasing yearly occurrence of ocular complaints in FAP patients who have received a liver transplantation, and this problem is even more common among types of FAP other than TTR Met 30. Also, their study showed that liver transplantation could not prevent posttransplantation leptomeningeal amyloid deposition, in the same way that cardiac amyloid deposits progress even after liver transplantation [[38]Pomfret E.A. Lewis W.D. Jenkins R.L. Bergelhon P. Dubrey S.W. Reisinger J. et al.Effect of orthotopic liver transplantation on the progression of familial amyloidotic polyneuropathy.Transplantation. 1998; 65: 918-925Crossref PubMed Scopus (112) Google Scholar]. Liver transplantation continues to be considered a promising therapy to prevent the deterioration of neurological complications in FAP patients, although we must be aware of the novo oculo meningeal amyloid deposits [[40]Ando Y. Terazaki H. Nakamura M. Ando E. Haraok K. Yamashila T. et al.A different amyloid formation mechanism: de novo oculo leptomeningeal amyloid deposits after liver transplantation.Transplantation. 2004; 77: 345-349Crossref PubMed Scopus (84) Google Scholar]. It was the portuguese surgeon Linhares Furtado who, in 1995 [41Furtado AJL. Sequential liver transplantation. Proceedings of the: second International Workshop on Liver Transplantation in Familial Amyloidotic Polyneuropathy. Lisbon; 1995.Google Scholar, 42Furtado A. Tomé L. Oliveira F.J. Furtado E. Viana J. Perdigoto R. Sequential liver transplantation.Transpl Proc. 1997; 29: 467-468Abstract Full Text PDF PubMed Scopus (98) Google Scholar] for the first time performed a sequential liver transplantation using the morphologically normal liver of a FAP patient as a donor to a patient suffering from liver metastasis. The FAP patient received the cadaveric liver and supplied his liver to the patient with metastasis. Within 2 years the procedure was quickly accepted [43Hesse U. Troisi R. Mortier E. Decruyenaere J. de Hemptinne B. Sequencial orthotopic liver transplantation: domino transplantation.Chirurg. 1997; 68: 1011-1013Crossref PubMed Scopus (8) Google Scholar, 44Hemming A.W. Catral M.S. Shari R.S. Greyg P.D. Lilly L.B. Ashby P. et al.Domino liver transplantation for familial amyloid polyneuropathy.Liver Transpl Surg. 1998; 4: 236-238Crossref PubMed Scopus (32) Google Scholar, 45Schmidt H.H.-J. Nashan B. Propsting M.J. Nakazato M. Flemming P. Kubicka S. et al.Familial amyloidotic polyneuropathy: domino liver transplantation.J Hepatol. 1999; 30: 293-298Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 46Azoulay D. Samuel D. Castaing D. Adam R. Adams D. Said G. et al.Domino liver transplants for metabolic disorders: experience with familial amyloidotic polyneuropathy.J Am Coll Surg. 1999; 189: 584-593Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar], since the FAP liver is a functionally and morphologically normal liver (Fig. 2, Fig. 3) albeit a carrier of a defect in amyloid protein production. Since the clinical onset of the disease takes between 25 and 30 years, if the patient is more than 50 years old, and suffering from a neoplastic disease, this technique is very useful, not only shortening the waiting list time of patients with neoplastic diseases, but also increasing the graft supply, which is a considerable problem within transplant centres nowadays.Fig. 3(A) Amyloid (pre-albumin) vascular deposits in the hilum of a otherwise normal liver of a FAP patient. (B) Nerve deposits in the same patient.View Large Image Figure ViewerDownload Hi-res image Download (PPT) As this procedure might involve an ethical problem it is important that the domino recipient gives his informed consent and that he is aware of the theoretical possibility of developing a FAP disease 25 or 30 years later. Nowadays, ethical committees have accepted the use of these FAP livers in patients with diseases other than tumours or metastasis. The indication has been extended to Hepatitis B and C or alcoholic patients over 50 years old [[42]Furtado A. Tomé L. Oliveira F.J. Furtado E. Viana J. Perdigoto R. Sequential liver transplantation.Transpl Proc. 1997; 29: 467-468Abstract Full Text PDF PubMed Scopus (98) Google Scholar]. In 2000, 75 dominos were performed in Portugal, France, Brazil, Sweden, Belgium and Germany [[47]Furtado A.J.L. Domino liver transplantation using livers from patients with familial amyloidotic polyneuropathy.Curr Opin Org Transpl. 2000; 5: 69-73Crossref Google Scholar]. In Portugal, 151 dominos were performed up to the end of December 2003. The domino graft may be implanted in the classic fashion or as a piggy back. Pena et al. [[48]Pena J.R. Barroso E. Martins A. Andrade J.R. Pereira J.P. Sequential whole liver transplant resected as piggy-back from FAP patients (abstract).Liver Transpl. 2002; 8: C-24Google Scholar] described a new technique for domino liver transplantation that avoids some complications of inferior vena cava anastomosis, allowing the FAP hepatectomy to be performed with inferior vena cava preservation. This technique has already been successfully followed in Brazil [[49]Pacheco Moreira L.F. Oliveira M.E. Balbi E. Cerqueira da Silva A. Miecznikowski R. de Faria L.J.A. A new technical options for domino liver transplantation.Liver Transpl. 2003; 9: 632-633Crossref PubMed Scopus (24) Google Scholar]. Several other experiments with domino liver transplants [[50]Carrera M.T. Bogue E.H. Domino liver transplantation: a practical option in the face of the organ shortage.Prog Transpl. 2003; 13: 151-153PubMed Google Scholar] have been successful. The pending problem is that the recipient of the FAP liver can develop the FAP disease. Although the recipient does not have the genetic trace, it is theoretically possible to develop the disease. However, if, this happens it is likely that the development of the disease will only become clinically apparent 25 or 30 years later. What is known so far is that TTR Met 30 was found in the serum of the recipient soon after the transplant. However, some nerve and skin biopsies did not show any amyloid two and a half years after the transplant [[47]Furtado A.J.L. Domino liver transplantation using livers from patients with familial amyloidotic polyneuropathy.Curr Opin Org Transpl. 2000; 5: 69-73Crossref Google Scholar] and repeated neurological assessments showed no evidence of the neurological disease. These patients should be carefully followed since TTR Met 30 is in the serum and produced as it was in the FAP patient. Bittencourt et al. followed seven recipients of domino FAP livers 12 to 40 months after surgery and signs or symptoms of FAP did not occur in that period [[51]Bittencourt P.L. Couto C.A. No evidence of de novo amyloidosis in recipients of domino liver transplantation: 12 to 40 (mean 24) months follow-up.Amyloid. 2002; 9: 194-196Crossref PubMed Scopus (23) Google Scholar]. Scarce deposited TTR was found in a non-fibrillar form in skin biopsies 3 years after domino liver transplantation; fibrillar amyloid deposition was detected in sural nerve 7 years after domino liver transplantation in one case; however, no signs of neuropathy were evident [[52]Sousa M.M. Ferrão J. Fernandes R. Guimarães A. Geraldes J.B. Perdigoto R. et al.Deposition and passage of transthyretine through the blood-nerve barrier in recipients of familial amyloid polyneuropathy livers.Laboratory Investigation. 2004; 84: 865-873Crossref PubMed Scopus (58) Google Scholar]. From the data so far published we may say that liver transplantation for portuguese type FAP patients is an accepted treatment for the disease and the only way to halt progression of the disease until genetic therapy is available.1.Although regression of some symptoms and signs has been described, patients should be transplanted early, in the first year of symptoms, since the majority of them remain unchanged after surgery. The earlier the transplant, the better the outcome.2.Patients with longstanding disease (longer than 6 years) should be carefully and individually evaluated before a proposal for liver transplant is made.3.Patients with severe malabsorption and malnutrition should not be transplanted.4.Patients with orthostatic hypotension and cardiac arrhythmias should be fitted with a pacemaker before the liver transplantation or, even better, a combined heart-liver transplant should be proposed. This is even more consistent in a NTTR Met 30 mutation.5.A complete screening of renal function should be carried out and a combined liver and kidney transplantation should be considered if the EDTA clearance is less than 30 ml/min/1.73 m2.6.Recent findings of amyloid production by the retina and choroid plexus with superimposed de novo glaucoma, vitreous opacity and leptomeningeal amyloid deposition, after liver transplant, must be considered and carefully evaluated.7.Domino transplant seems to be a new and safe way to increase donor offer and so far there is no evidence of FAP de novo in the recipient.8.The presence of TTR Met 30 in the serum of the recipients of FAP livers soon after the transplant and the finding of amyloid deposits in the sural nerve of these recipients 5 years later means that these patients should be closely followed up.