- Email: [email protected]
Liver Retransplantation in Patients With Acquired Familial Amyloid Polyneuropathy: A Portuguese Center Experience
Liver Retransplantation in Patients With Acquired Familial Amyloid Polyneuropathy: A Portuguese Center Experience H. Vieiraa,b,*, C. Rodriguesa, L. Pereiraa,b, J. Jesusa, C. Bentoa,b, C. Secoa,b, F. Pintoa,b, A. Eufrásioa,b, S. Calretasb, N. Silvab, J. Ferrãob, L. Toméb, A. Barrosb, D. Diogob, and E. Furtadob a Serviço de Anestesiologia, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal; and bUnidade de Transplantação Hepática Pediátrica e de Adultos, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
ABSTRACT In 1995 Furtado et al performed the first domino transplantation using a donor liver with familial amyloid polyneuropathy (FAP), thereby increasing the pool of donors. Our experience showed that the onset of FAP symptoms occurs earlier in some patients. Patients with FAP acquired by transplantation are candidates for liver retransplantation to minimize the progression of symptoms. Liver retransplantation is considered to be a high-risk procedure and has lower survival compared with the first transplantation. We evaluated the risk of liver retransplantation in patients with acquired FAP. We did a retrospective analysis of these patients based on the records of perioperative data. From 1995 to 2004 we carried out 81 domino transplantations, of which 10 were submitted to liver retransplantation because of acquired FAP. The better outcomes in this group lead us to think that the liver retransplantation in patients with acquired FAP is not associated with the same risks of liver retransplantation in candidates with graft failure.
F
AMILIAL AMYLOID POLYNEUROPATHY (FAP) is an autosomal, dominant, debilitating, and fatal condition caused by a mutation in transthyretin (TTR). It affects the peripheral and autonomous nervous system, the heart, kidneys, and intestines. Because the liver is the main source of the circulating mutant form of TTR, orthotopic liver transplantation was introduced in 1990 as a curative treatment for FAP [1]. The disease was first described in Portugal in 1952 by Corino de Andrade. This country has the highest incidence of the disease, followed by Sweden and Japan [2]. In 1993 in Stockholm, at the first International Meeting of Liver Transplantation in FAP patients, given the scarcity of organs the need was emphasized to use the explanted livers of these patients in select liver transplant recipients (liver tumor and acute liver failure) [3]. This idea was developed because of the shortage of donors and became known as domino or domino liver transplantation. This technique has some advantages: these grafts belong to young donors, they are morphologically and structurally normal, short ischemia times, and absence of ischemic injury related to the death of cadaveric donors [4]. The early estimation of the risk for disease transfer was based on the natural course of the FAP disease: a delay of
up 20 years was expected to take place before disease symptoms would start [4]. In 1995, Furtado et al performed at Coimbra the first domino liver transplantation with FAP donor grafts [4]. Since then, according to the Familial Amyloid Polyneuropathy World Transplant Registry, 1,085 domino liver transplantations were performed worldwide, 48.6% of which in Portugal [1]. Although the appearance of substance amyloid deposits was known in the tissues of domino recipients in short time, symptoms of the disease, it was published for the 1st time only in 2005 by Stangou et al [5]. The patient developed FAP symptoms 8 years after the domino transplantation. Specimens from nerve and rectal biopsies were found to contain transthyretin amyloid deposits, as indicated by Congo red dichroism and immunohistochemical staining, and the patient had been submitted to retransplantation 1 year later [5]. The cases of acquired amyloid neuropathy continue appearing in patients submitted to domino liver transplantation
*Address correspondence to Helena Vieira, Serviço de Anestesiologia, Centro Hospitalar e Universitário de Coimbra, Praceta Prof Mota Pinto, 3000-075, Coimbra, Portugal. E-mail: [email protected]
0041-1345/15 http://dx.doi.org/10.1016/j.transproceed.2015.04.003
ª 2015 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1012
Transplantation Proceedings, 47, 1012e1015 (2015)
RETRANSPLANTATION IN PATIENTS WITH FAP
1013
Table 1. Characterization of Cases that Underwent Liver Retransplantation Patient
Date of DLTx
Primary Pathology
Onset of Symptoms (y)
ReLTx (y)
Age at ReLTx (y)
1 2 3 4 5 6 7 8 9 10 Mean
2002 2000 2000 2000 2003 2001 2000 2001 2002 2004
Alcoholic cirrhosis Bowel cancer metastases Alcoholic cirrhosis HBV cirrhosis Alcoholic cirrhosis Alcoholic cirrhosis and hepatocarcinoma Alcoholic cirrhosis Cryptogenic cirrhosis Alcoholic cirrhosis Alcoholic cirrhosis
5 9 7 7 5 6 12 7 7 7 7.2
9 11 12 13 10 12 13 12 11 9 11
52 57 69 70 57 56 68 61 62 67 61.9
Abbreviations: DLTx, domino liver transplantation; ReLTx, liver retransplantation; y, years.
[6e14]. In 2013, Antonini et al described their experience of reversibility of neurologic symptoms in a patient that was submitted to retransplantation after the domino transplant [15]. Adding to the existing literature on classic indications for retransplantation a new entity arises (acquired paramyloidosis, “de novo” or iatrogenic FAP) in an attempt to minimize the progression of the symptoms associated with the deposition of amyloid produced by graft. Retransplantation is considered to be a high-risk procedure, owing to the surgical challenges that surgeons face during dissection in a patient already transplanted as well as comorbidities: coagulopathy, renal disease, infection, age, and chronic immunosuppression [16,17]. It is also associated with a lower survival rate compared with the survival of 1st transplant. The retransplantation mortality rate in the 1st year varies from 17.4% to 40% depending on the literature. The survival rate is 80.6% vs 82.6% at the 1st year compared with 1st/primary transplant [16,17]. Our center performed 81 domino transplantations from 1995 to 2003. At the time of this study, there were 79 patient records. Thirty-nine had died and 40 remained in follow-up. Of the 40 patients in follow-up, 15 were free of symptoms compatible with amyloidosis. Of the 25 patients who had some kind of symptoms, 12 showed no indication for retransplantation, 9 have undergone retransplantation, and 3 are on the waiting list.
PATIENTS AND METHODS We reviewed the perioperative anesthetic records of all patients undergoing retransplantation for acquired amyloidosis as well as postoperative intensive care records.
RESULTS
The causes of domino transplantation are presented in Table 1 as well as times in years between the transplantation and the beginning of FAP symptoms leading to retransplantation (mean, 7.2 y), the intervals in years to the retransplantation (mean, 11 y), and the ages at retransplantation (mean, 61.9 y). Mean body mass index (25.4 kg/ m2), preoperative mean hemoglobin (13.3 g/dL), international normalized ratio (1.09), and mean creatinine value (1.38 mg/dL) are presented in Table 2. For the 10 patients who underwent retransplantation because of acquired FAP in the University Hospitals of Coimbra (January 2011 to December 2013), blood consumption, plasma, platelets, need for amines, cold ischemia time, and anesthesia time are presented in Table 3. The extubation time was an average of 18.5 hours after the arrival of the patient to the intensive care unit, with a maximum time of 48 hours and 1 patient arriving already extubated. The length of stay in intensive care ranged from 2 to 5 days, with an average of 3.65 days. From the complications recorded after surgery, we highlight 1 hemoperitoneum requiring laparotomy, 1 suture dehiscence, 2 biliary complications, 1 with a biliary draining, 3 initial poor liver function (PLF), 1 septic patient, 2 cases of acute renal failure, and 1 patient with abnormal cardiac enzymology. Table 3. Intraoperative Consumption of Blood Products and Amines, as Well as Surgical Time
Table 2. Preoperative Values Sex Age (y) Body mass index Hemoglobin (g/dL) Creatinine (mg/dL) International normalized ratio
From January 2011 to December 2013 we performed 10 retransplantations for acquired amyloidosis. We analyzed blood consumption, plasma, platelets, need for amines, cold ischemia time, and anesthesia time.
100% Male 61.9 (6.3) 25.4 (5.3) 13.3 (2.3) 1.3 (1.1e1.7) 1.1 (1.0e1.2)
Note. Values are presented as mean (SD) or median (interquartile range).
Erythrocytes (U) Plasma (U) Platelets (U) Fibrinogen (g) Amines Anesthesia time (h) Note. Values are presented as median (interquartile range).
2 0.5 0 0 2 10
(0e3) (0e4.3) (0e1) (0e4) (2e2.25) (9.3e10.8)
1014
VIEIRA, RODRIGUES, PEREIRA ET AL
Fig 1. Kaplan-Meier survival. Abbreviations: FAP, familial amyloid polyneuropathy; LReTx, liver retransplantation.
DISCUSSION
REFERENCES
The appearance of early symptoms in patients submitted to domino transplantation is poorly understood. Factors such as age, immunosuppression, inflammation, and diabetes may be implicated in the deposition of amyloid and subsequent disease [11,15,18]. Despite the association of retransplantation with higher mortality, in our center only 1 patient died at 13 months for sepsis caused by biliary complication, and the follow-ups ranged from 5 to 36 months [16,17]. In our center, the liver retransplantation survival, excluding liver retransplantation for acquired FAP (nonFAP liver retransplantation), was 84.3% after 6 months and 81.7% after 1 year (Fig 1). The surgical technique employed in both groups was similar (piggyback technique).
[1] Familial Amyloidotic Polyneuropathy World Transplant Registry and Domino Liver Transplant Registry. Available from www.fapwtr.org. [2] Munar-Qués M. Familial amyloid polyneuropathy or corino de Andrade’s disease. JANO 2005;68:1136e9. [3] Ericzon BG, Larsson M, Wilczek HE, et al. Domino liver transplantation: risks and benefits. Transplant Proc 2008;40:1130e1. [4] Furtado AJL. Domino liver transplantation using livers from patients with familial amyloidotic polyneuropathy. Curr Opin Organ Transplant 2000;5:69e73. [5] Stangou AJ, Heton ND, Hawkins PN. Transmission of systemic transthyretin amyloidosis by means of domino liver transplantation. N Engl J Med 2005;352:356. [6] Benson M. Liver Transplantation and transthyretin amyloidosis. Muscle Nerve 2013;47:157e62. [7] Bolte FJ, Schmidt HHJ, Blecker T, et al. Evaluation of domino liver transplantation in Germany. Transpl Int 2013;26:715e23. [8] Takei Y, Gono T, Masahide Y, et al. Transthyretin-derived amyoid deposition on the gastric mucosa in domino recipients of familial amyloid polyneuropathy liver. Liver Transpl 2007;13:215e8. [9] Yamamoto S, Wilczek HE, Iwata T, et al. Long-term consequences of domino liver transplantation using familial amyloidotic polyneuropathy grafts. Transpl Int 2007;20:926e33. [10] Ericzon BG. Domino transplantation using livers from patients with familial amyloidotic polyneuropathy: should we halt? Liver Transpl 2007;13:185e7. [11] Comellas CB, Garriga LL, Prous JF. Sequential liver transplantation and familial amyloidotic polyneuropathy. GH Continuada 2011;10:136e9. [12] Barreiros AP, Geber C, Birklein F, et al. Clinical symptomatic de novo systemic transthyretin amyloidosis 9 years after domino liver transplantation. Liver Transpl 2010;16:109.
CONCLUSION
Our series has the highest number of patients undergoing retransplantation for acquired amyloidosis due to a liver graft donor with FAP. Our results seem to show that the risk of FAP mortality in retransplantation for acquired FAP is less than that reported in the literature for retransplantation from other causes, despite advanced age. However, we must keep in mind that, despite being the largest series described, it is still small in absolute numbers.
RETRANSPLANTATION IN PATIENTS WITH FAP [13] Furtado AJL. Domino liver transplantation using FAP grafts. HUC experiencedhopes and realities. Amyloid 2003;10: 84e7. [14] Yoo PS, Umman V, Davalos-R MI, et al. Retransplantation of the liver: review of current literature for decision making and technical considerations. Transplant Proc 2013;45:854e9. [15] Adams D, Lacroix C, Antonini T, et al. Symptomatic and proven de novo amyloid polyneuropathy in familial amyloid polyneuropathy domino liver recipients. Amyloid 2011;18:174e7.
1015 [16] Zarrinpar A, Hong JC. What is the prognosis after retransplantation of the liver? Adv Surg 2012;16:87e100. [17] Alves C, Silva A, Pessegueiro H, et al. Domino liver transplantation (DLT) and de novo familial amyloid polyneuropathy (FAP): the Portuguese experience. Neurology 2013;80(Meeting Abstract 1):S58.004. [18] Lladó L, Babiellas C, Casasnovas C, et al. Risk of transmission of systemic transthyretin amyloidosis after domino liver transplantation. Liver Transpl 2010;16:1386e92.
ABSTRACT In 1995 Furtado et al performed the first domino transplantation using a donor liver with familial amyloid polyneuropathy (FAP), thereby increasing the pool of donors. Our experience showed that the onset of FAP symptoms occurs earlier in some patients. Patients with FAP acquired by transplantation are candidates for liver retransplantation to minimize the progression of symptoms. Liver retransplantation is considered to be a high-risk procedure and has lower survival compared with the first transplantation. We evaluated the risk of liver retransplantation in patients with acquired FAP. We did a retrospective analysis of these patients based on the records of perioperative data. From 1995 to 2004 we carried out 81 domino transplantations, of which 10 were submitted to liver retransplantation because of acquired FAP. The better outcomes in this group lead us to think that the liver retransplantation in patients with acquired FAP is not associated with the same risks of liver retransplantation in candidates with graft failure.
F
AMILIAL AMYLOID POLYNEUROPATHY (FAP) is an autosomal, dominant, debilitating, and fatal condition caused by a mutation in transthyretin (TTR). It affects the peripheral and autonomous nervous system, the heart, kidneys, and intestines. Because the liver is the main source of the circulating mutant form of TTR, orthotopic liver transplantation was introduced in 1990 as a curative treatment for FAP [1]. The disease was first described in Portugal in 1952 by Corino de Andrade. This country has the highest incidence of the disease, followed by Sweden and Japan [2]. In 1993 in Stockholm, at the first International Meeting of Liver Transplantation in FAP patients, given the scarcity of organs the need was emphasized to use the explanted livers of these patients in select liver transplant recipients (liver tumor and acute liver failure) [3]. This idea was developed because of the shortage of donors and became known as domino or domino liver transplantation. This technique has some advantages: these grafts belong to young donors, they are morphologically and structurally normal, short ischemia times, and absence of ischemic injury related to the death of cadaveric donors [4]. The early estimation of the risk for disease transfer was based on the natural course of the FAP disease: a delay of
up 20 years was expected to take place before disease symptoms would start [4]. In 1995, Furtado et al performed at Coimbra the first domino liver transplantation with FAP donor grafts [4]. Since then, according to the Familial Amyloid Polyneuropathy World Transplant Registry, 1,085 domino liver transplantations were performed worldwide, 48.6% of which in Portugal [1]. Although the appearance of substance amyloid deposits was known in the tissues of domino recipients in short time, symptoms of the disease, it was published for the 1st time only in 2005 by Stangou et al [5]. The patient developed FAP symptoms 8 years after the domino transplantation. Specimens from nerve and rectal biopsies were found to contain transthyretin amyloid deposits, as indicated by Congo red dichroism and immunohistochemical staining, and the patient had been submitted to retransplantation 1 year later [5]. The cases of acquired amyloid neuropathy continue appearing in patients submitted to domino liver transplantation
*Address correspondence to Helena Vieira, Serviço de Anestesiologia, Centro Hospitalar e Universitário de Coimbra, Praceta Prof Mota Pinto, 3000-075, Coimbra, Portugal. E-mail: [email protected]
0041-1345/15 http://dx.doi.org/10.1016/j.transproceed.2015.04.003
ª 2015 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1012
Transplantation Proceedings, 47, 1012e1015 (2015)
RETRANSPLANTATION IN PATIENTS WITH FAP
1013
Table 1. Characterization of Cases that Underwent Liver Retransplantation Patient
Date of DLTx
Primary Pathology
Onset of Symptoms (y)
ReLTx (y)
Age at ReLTx (y)
1 2 3 4 5 6 7 8 9 10 Mean
2002 2000 2000 2000 2003 2001 2000 2001 2002 2004
Alcoholic cirrhosis Bowel cancer metastases Alcoholic cirrhosis HBV cirrhosis Alcoholic cirrhosis Alcoholic cirrhosis and hepatocarcinoma Alcoholic cirrhosis Cryptogenic cirrhosis Alcoholic cirrhosis Alcoholic cirrhosis
5 9 7 7 5 6 12 7 7 7 7.2
9 11 12 13 10 12 13 12 11 9 11
52 57 69 70 57 56 68 61 62 67 61.9
Abbreviations: DLTx, domino liver transplantation; ReLTx, liver retransplantation; y, years.
[6e14]. In 2013, Antonini et al described their experience of reversibility of neurologic symptoms in a patient that was submitted to retransplantation after the domino transplant [15]. Adding to the existing literature on classic indications for retransplantation a new entity arises (acquired paramyloidosis, “de novo” or iatrogenic FAP) in an attempt to minimize the progression of the symptoms associated with the deposition of amyloid produced by graft. Retransplantation is considered to be a high-risk procedure, owing to the surgical challenges that surgeons face during dissection in a patient already transplanted as well as comorbidities: coagulopathy, renal disease, infection, age, and chronic immunosuppression [16,17]. It is also associated with a lower survival rate compared with the survival of 1st transplant. The retransplantation mortality rate in the 1st year varies from 17.4% to 40% depending on the literature. The survival rate is 80.6% vs 82.6% at the 1st year compared with 1st/primary transplant [16,17]. Our center performed 81 domino transplantations from 1995 to 2003. At the time of this study, there were 79 patient records. Thirty-nine had died and 40 remained in follow-up. Of the 40 patients in follow-up, 15 were free of symptoms compatible with amyloidosis. Of the 25 patients who had some kind of symptoms, 12 showed no indication for retransplantation, 9 have undergone retransplantation, and 3 are on the waiting list.
PATIENTS AND METHODS We reviewed the perioperative anesthetic records of all patients undergoing retransplantation for acquired amyloidosis as well as postoperative intensive care records.
RESULTS
The causes of domino transplantation are presented in Table 1 as well as times in years between the transplantation and the beginning of FAP symptoms leading to retransplantation (mean, 7.2 y), the intervals in years to the retransplantation (mean, 11 y), and the ages at retransplantation (mean, 61.9 y). Mean body mass index (25.4 kg/ m2), preoperative mean hemoglobin (13.3 g/dL), international normalized ratio (1.09), and mean creatinine value (1.38 mg/dL) are presented in Table 2. For the 10 patients who underwent retransplantation because of acquired FAP in the University Hospitals of Coimbra (January 2011 to December 2013), blood consumption, plasma, platelets, need for amines, cold ischemia time, and anesthesia time are presented in Table 3. The extubation time was an average of 18.5 hours after the arrival of the patient to the intensive care unit, with a maximum time of 48 hours and 1 patient arriving already extubated. The length of stay in intensive care ranged from 2 to 5 days, with an average of 3.65 days. From the complications recorded after surgery, we highlight 1 hemoperitoneum requiring laparotomy, 1 suture dehiscence, 2 biliary complications, 1 with a biliary draining, 3 initial poor liver function (PLF), 1 septic patient, 2 cases of acute renal failure, and 1 patient with abnormal cardiac enzymology. Table 3. Intraoperative Consumption of Blood Products and Amines, as Well as Surgical Time
Table 2. Preoperative Values Sex Age (y) Body mass index Hemoglobin (g/dL) Creatinine (mg/dL) International normalized ratio
From January 2011 to December 2013 we performed 10 retransplantations for acquired amyloidosis. We analyzed blood consumption, plasma, platelets, need for amines, cold ischemia time, and anesthesia time.
100% Male 61.9 (6.3) 25.4 (5.3) 13.3 (2.3) 1.3 (1.1e1.7) 1.1 (1.0e1.2)
Note. Values are presented as mean (SD) or median (interquartile range).
Erythrocytes (U) Plasma (U) Platelets (U) Fibrinogen (g) Amines Anesthesia time (h) Note. Values are presented as median (interquartile range).
2 0.5 0 0 2 10
(0e3) (0e4.3) (0e1) (0e4) (2e2.25) (9.3e10.8)
1014
VIEIRA, RODRIGUES, PEREIRA ET AL
Fig 1. Kaplan-Meier survival. Abbreviations: FAP, familial amyloid polyneuropathy; LReTx, liver retransplantation.
DISCUSSION
REFERENCES
The appearance of early symptoms in patients submitted to domino transplantation is poorly understood. Factors such as age, immunosuppression, inflammation, and diabetes may be implicated in the deposition of amyloid and subsequent disease [11,15,18]. Despite the association of retransplantation with higher mortality, in our center only 1 patient died at 13 months for sepsis caused by biliary complication, and the follow-ups ranged from 5 to 36 months [16,17]. In our center, the liver retransplantation survival, excluding liver retransplantation for acquired FAP (nonFAP liver retransplantation), was 84.3% after 6 months and 81.7% after 1 year (Fig 1). The surgical technique employed in both groups was similar (piggyback technique).
[1] Familial Amyloidotic Polyneuropathy World Transplant Registry and Domino Liver Transplant Registry. Available from www.fapwtr.org. [2] Munar-Qués M. Familial amyloid polyneuropathy or corino de Andrade’s disease. JANO 2005;68:1136e9. [3] Ericzon BG, Larsson M, Wilczek HE, et al. Domino liver transplantation: risks and benefits. Transplant Proc 2008;40:1130e1. [4] Furtado AJL. Domino liver transplantation using livers from patients with familial amyloidotic polyneuropathy. Curr Opin Organ Transplant 2000;5:69e73. [5] Stangou AJ, Heton ND, Hawkins PN. Transmission of systemic transthyretin amyloidosis by means of domino liver transplantation. N Engl J Med 2005;352:356. [6] Benson M. Liver Transplantation and transthyretin amyloidosis. Muscle Nerve 2013;47:157e62. [7] Bolte FJ, Schmidt HHJ, Blecker T, et al. Evaluation of domino liver transplantation in Germany. Transpl Int 2013;26:715e23. [8] Takei Y, Gono T, Masahide Y, et al. Transthyretin-derived amyoid deposition on the gastric mucosa in domino recipients of familial amyloid polyneuropathy liver. Liver Transpl 2007;13:215e8. [9] Yamamoto S, Wilczek HE, Iwata T, et al. Long-term consequences of domino liver transplantation using familial amyloidotic polyneuropathy grafts. Transpl Int 2007;20:926e33. [10] Ericzon BG. Domino transplantation using livers from patients with familial amyloidotic polyneuropathy: should we halt? Liver Transpl 2007;13:185e7. [11] Comellas CB, Garriga LL, Prous JF. Sequential liver transplantation and familial amyloidotic polyneuropathy. GH Continuada 2011;10:136e9. [12] Barreiros AP, Geber C, Birklein F, et al. Clinical symptomatic de novo systemic transthyretin amyloidosis 9 years after domino liver transplantation. Liver Transpl 2010;16:109.
CONCLUSION
Our series has the highest number of patients undergoing retransplantation for acquired amyloidosis due to a liver graft donor with FAP. Our results seem to show that the risk of FAP mortality in retransplantation for acquired FAP is less than that reported in the literature for retransplantation from other causes, despite advanced age. However, we must keep in mind that, despite being the largest series described, it is still small in absolute numbers.
RETRANSPLANTATION IN PATIENTS WITH FAP [13] Furtado AJL. Domino liver transplantation using FAP grafts. HUC experiencedhopes and realities. Amyloid 2003;10: 84e7. [14] Yoo PS, Umman V, Davalos-R MI, et al. Retransplantation of the liver: review of current literature for decision making and technical considerations. Transplant Proc 2013;45:854e9. [15] Adams D, Lacroix C, Antonini T, et al. Symptomatic and proven de novo amyloid polyneuropathy in familial amyloid polyneuropathy domino liver recipients. Amyloid 2011;18:174e7.
1015 [16] Zarrinpar A, Hong JC. What is the prognosis after retransplantation of the liver? Adv Surg 2012;16:87e100. [17] Alves C, Silva A, Pessegueiro H, et al. Domino liver transplantation (DLT) and de novo familial amyloid polyneuropathy (FAP): the Portuguese experience. Neurology 2013;80(Meeting Abstract 1):S58.004. [18] Lladó L, Babiellas C, Casasnovas C, et al. Risk of transmission of systemic transthyretin amyloidosis after domino liver transplantation. Liver Transpl 2010;16:1386e92.