Domino liver transplantation in living donors

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

Domino liver transplantation with double piggyback: is this the best technique? A case report

Sequential or domino liver transplantation is a well-established procedure for patients with familial amyloidotic polyneuropathy (FAP). Donation for domino liver transplantation imposed the resection of the inferior vena cava along with the liver, requiring complete suprarenal vena cava clamping and usually the use of venovenous bypass. We describe a successful case in which it was possible to perform the FAP hepatectomy by the piggyback technique.     

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

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

Thirteen cases of liver-kidney transplantation

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

Domino liver transplantation: risks and benefits

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

Domino liver transplants for metabolic disorders: experience with familial amyloidotic polyneuropathy

Background: Shortage of liver donors means that new methods of liver procurement must be explored. In domino transplantation, organs explanted during transplantation in one patient are transplanted into a second patient. Domino procedures can be performed with livers from patients having transplantion for hepatic metabolic disorders that cause systemic disease without affecting other liver functions. Familial amyloidotic polyneuropathy (FAP) type I is one of these.

Study Design: We reviewed the Paul Brousse experience with a domino liver transplant program for FAP, hoping to extend the approach to other metabolic disorders.

Results: Livers from 10 patients transplanted for FAP type 1 were used for domino transplants to patients with unresectable primary or metastatic liver cancers. There was no perioperative mortality. Neuropathy or cardiomyopathy did not increase the morbidity of the domino liver explant and transplant procedures. Morbidity for the domino recipients did not appear to be increased. Variant transthyretin was detected in the serum in FAP liver recipients, with no immediate clinical consequences.

Conclusions: The domino approach is feasible and requires careful planning of the surgical procedures for liver explantation, particularly for the nature and site of vascular anastomoses. Domino transplantation of metabolically dysfunctional livers creates new categories of potential donors and potential recipients. It raises new ethical, technical, and societal issues. The domino approach could be used in several genetic or biochemical disorders now treated by liver transplantation. It has the potential to increase the number of liver grafts available for transplantation.     

Liver transplantation does not prevent the development of life-threatening arrhythmia in familial amyloidotic polyneuropathy, Portuguese-type (ATTR Val30Met) patients

BACKGROUND: Orthotopic liver transplantation (OLT) is today the only available treatment to halt the progress of familial amyloidotic polyneuropathy (FAP). Because heart arrhythmia and conduction disturbances are well-known manifestations of FAP, the aim of this study was to investigate the occurrence and development of heart conduction and rhythm disturbances in Swedish FAP patients who underwent liver transplantation. METHODS: Ambulatory 24-hour electrocardiography (ECG) recordings (Holter-ECGs) were available from 30 patients, who had been investigated before and reexamined after OLT. RESULTS.: The number of patients with abnormalities on their ECG recordings increased after OLT. Four patients developed serious arrhythmia after transplantation that necessitated the insertion of a pacemaker 40 months or longer after OLT. CONCLUSIONS: The development of cardiac conduction disturbances and arrhythmias appear not to be halted by liver transplantation, indicating that the physician should be aware of the potential risk for FAP patients receiving transplants to develop fatal arrhythmia. The follow-up after liver transplantation should include Holter-ECG recordings.     

Corino-andrade disease (familial amyloidotic polineuropathy type I) in Spain: Urological and andrological disorders

In our hospital, we have followed a group of patients with familial amyloidotic polyneuropathy (FAP), type I. This disease is characterized by a progressive sensitive-motor and autonomic polyneuropathy. The amyloid fibrils of FAP I contain a mutant transthyretin (TTR) molecule. More than 90% of TTR production occurs in the liver. Thus, therapy with liver transplantation has proved useful. All our patients received this treatment. In this study we describe the urological and andrological disorders caused by FAP type I in 12 patients with low bladder pressure and bladder neck obstruction with micturition disorders. In some males, it was accompanied by impotence and retrograde ejaculation produced by autonomic neuropathy. We believe hepatic transplantation may be the best treatment for this disease.     

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

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

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

Aims

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

Materials and Methods

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

Results

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

Conclusion

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

Iatrogenic Amyloid Neuropathy in a Japanese Patient After Sequential Liver Transplantation

A 57-year-old woman in Japan, the first recipient of part of a liver from a 58-year-old man with familial amyloidotic polyneuropathy (FAP) amyloidogenic transthyretin Val30Met who had had sensorimotor polyneuropathy in the lower limbs for 3 years, started to develop sensory neuropathy 7 years after transplantation. Before the July 1998 sequential transplantation, she had been in a hepatic coma at the terminal stage of primary biliary cirrhosis and waiting for deceased donor liver transplantation. In September 2004, biopsy samples of her duodenum first showed amyloid deposition. Although biopsy materials in 2005 and 2006 showed no changes in amyloid deposition, decreased temperature sensation and pain in fingertips and toes were detected at a neurologic examination in March 2006. Thus, clinical symptoms of FAP appeared about 2 years after amyloid deposition started. Nerve conduction velocity studies revealed mild to moderate axonal sensory polyneuropathy without demyelination. Our findings confirmed iatrogenic sensory neuropathy induced by amyloid deposition 7 years after sequential liver transplantation.     

Domino liver transplantation from a living related donor

BACKGROUND: Although domino liver transplantations (OLT) from cadaveric donors have been performed in about 50 cases since 1995, only one case in the Japanese literature has been reported on a domino OLT from a living related donor. The difficulties of the later surgery lie in the small size of the graft volume and the short length of the vascular cuffs in the graft. METHODS: The left lobe graft was procured from a 43-year-old younger brother of a familial amyloidotic polyneuropathy (FAP) patient. Next, the left lobe graft (510 g, 44% of the estimated standard liver volume of the FAP patient) was implanted into the 48-year-old female FAP patient. At surgery for the FAP patient, a sufficient length of the vascular cuffs was secured by an extended left lobe resection, although the right lobe graft was able to maintain sufficient vascular cuffs. The right lobe graft (720 g, 54% of the recipient's estimated standard liver volume) was then implanted in the 43-year-old male patient with liver cirrhosis and hepatocellular carcinoma (stage IV-A). RESULTS: The two recipients were discharged from the hospital 1 month after OLT. At 7 months after OLT, they are both doing well and the domino recipient is free of any tumor recurrence. CONCLUSION: A domino OLT from the living related donor can therefore be done safely when careful attention is paid to the graft volume and the length of the vascular cuffs for anastomosis.     

Domino liver transplantation: indications, techniques, and outcomes

The long-term shortage of livers available for transplantation has spurred the development of many strategies to bolster the donor organ supply. One particularly innovative strategy is domino liver transplantation in which a select group of liver transplant recipients can donate their explanted native livers for use as liver grafts in other patients. Several hereditary metabolic diseases (such as familial amyloid polyneuropathy, maple syrup urine disease, and familial hypercholesterolemia) are caused by aberrant or deficient protein production in the liver, and these conditions can be cured with an orthotopic liver transplant. Although their native livers eventually caused severe systemic disease in these patients, these livers are otherwise structurally and functionally normal, and they have been used successfully in domino liver transplants for the past 15 years. This article will review the indications for donating or receiving a domino liver transplant, the surgical techniques necessary to perform these transplants, as well as the recently revealed long-term outcomes and risks of domino transplantation.     

Effect of tacrolimus and partial hepatectomy on transthyretin metabolism in rats

Liver transplantation, which serves as treatment of familial amyloidotic polyneuropathy (FAP), and domino liver transplantation, which utilizes resected livers from patients with FAP for treatment of liver diseases, may induce changes in transthyretin (TTR), a pathogenic FAP-related protein. To evaluate this possibility, we performed a 70% hepatectomy or administered tacrolimus to Dark Agouti (DA) rats for 7 days and then measured changes in liver TTR mRNA levels and changes in serum TTR concentrations. After hepatectomy, TTR mRNA levels decreased by 77%; at day 3, they returned to preoperative levels. Except for slightly elevated serum TTR concentrations 12 h after operation, serum TTR levels remained unchanged. Thus, partial hepatectomy did not influence serum TTR concentrations. After tacrolimus administration, TTR mRNA declined by 56% 12 h after the experiment started; however, after day 3, a rebound phenomenon occurred until day 7. Tacrolimus may facilitate serum TTR degradation, although production of TTR in the liver also increased. This finding -- that TTR, the source of FAP-inducing amyloid, did not increase after transplantation -- may help post-transplantation treatment of patients who have FAP and other liver diseases.     

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

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

Combined heart and liver transplantation in four adults with familial amyloidosis: experience of a single center

There are few reports of combined heart and liver transplantation (CHLT) for familial amyloidotic polyneuropathy (FAP). The technique for the operation remains to be defined. Four CHLTs were performed for amyloidogenic transthyretin-related (variant Glu89Gln-ATTR Glu89Gln) cardiomyopathy in our center. Patients 1 and 4 had no serious involvement of other organs, whereas patients 2 and 3 had evident peripheral neuropathy and gastrointestinal motility alterations. Patient 3 also had high-grade orthostatic hypotension. All four patients underwent cardiac and sequential hepatic transplantation with organs procured from the same donor. Venovenous bypass was used in patients 1 and 4 who experienced uncomplicated procedures. The amyloidotic liver of patient 4 was successfully utilized for a domino procedure to treat a patient with hepatocellular carcinoma on cirrhosis. The cardiac performance of patients 1 and 4 remains normal; there has been no progression of amyloidosis at 42 and 1 months after transplantation. Patient 2 had no intraoperative complications but experienced postoperative bleeding, renal failure, sepsis, and heart failure, and finally died of multiorgan failure 2 months after transplant. In patient 3, right hemicolectomy was required intraoperatively due to intestinal ischemia, without significant hemodynamic instability, while extracardiac symptoms of amyloidosis gradually worsened postoperatively. In conclusion, CHLT for ATTR Glu89Gln may be performed even in patients with advanced disease. However, the most compromised patients are more likely to display intraoperative risks, postoperative complications, and worsening of extracardiac, extrahepatic symptoms.     

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

Domino liver transplantation (DLT) using grafts from patients with familial amyloidotic polyneuropathy (FAP) is an established procedure at many transplantation centers. However, data evaluating the long-term outcome of DLT are limited. The aim of the present study was to analyze the risk of de novo polyneuropathy, possibly because of amyloidosis, and the patient survival after DLT. At our department, 28 DLT using FAP grafts were conducted between January 1997 and December 2005. One patient was twice subjected to DLT. Postoperative neurological monitoring of peripheral nerve function was performed with electroneurography (ENeG) in 20 cases. An ENeG index based on 12 parameters was calculated and correlated to age and/or height. Three patients developed ENeG signs of polyneuropathy 2-5 years after the DLT, but with no clinical symptoms. The 1-, 3- and 5-year actuarial patient survival in hepatocellular carcinoma (HCC) patients (n = 12) and non-HCC patients (n = 15) was 67%, 15%, 15% and 93%, 93%, 80%, respectively (P = 0.001). Development of impaired nerve conduction in a proportion of patients may indicate that de novo amyloidosis occurs earlier than previously expected. Survival after DLT was excellent except in patients with advanced HCC.     

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

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

Domino and split liver transplantation: technical problems

Because the shortage of donor livers has been the rate-limiting factor in the expansion of liver transplantation, several innovative techniques including reduced, split, and living donor liver transplantation have been developed to expand the relatively constant pool of organs. Domino liver transplantation, which was first reported from Portugal in 1995, has been performed worldwide and allows a donor organ to be used for a subsequent graft in a second liver recipient. Domino liver transplantation involves specific ethical and technical problems. The most important ethical problem in the procedure is the use of a diseased liver (e.g., familial amyloid polyneuropathy [FAP]) for a second recipient. Furthermore, the safety of the first recipient (FAP patient) should be the primary consideration. From the technical point of view, the management of short vascular cuffs is important, especially in domino liver transplantation from a living donor. The results of split liver transplantation have significantly improved and it is now recognized as an ideal method to expand the donor pool, especially for small children. Either the ex vivo or in vivo technique can be used with comparable results.