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.     

Domino liver transplantation

Orthotopic liver transplantation is today an established treatment for end stage liver diseases. However, the ongoing shortage of suitable livers together with progressively longer waiting lists prevents many patients from being transplanted, and many patients die while being on the waiting list. Using livers from living donors is one way to increase the supply of liver grafts. Another group of potential living liver donors are some selected liver recipients, whose native explanted liver in turn can be considered for transplantation into another patient. This unorthodox procedure have been named domino liver transplantation (DLT). The domino approach can be considered in patients with some genetic or biochemical disorders that today are treated by liver transplantation. The underlying rationale is that such livers ultimately cause severe systemic disease but are otherwise normal. In this review we present the current world status of DLT as well as updated results from the Domino Liver World Transplant Register (DLTR) and our own experience at the Karolinska University Hospital Huddinge with the DLT procedure.     

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.     

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.     

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

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

Combined heart–liver transplantation: a single‐center experience

Combined orthotopic heart and liver transplantation (CHLT) is a lifesaving procedure for patients with end‐stage heart–liver disease. We reviewed the long‐term outcome of patients who have undergone CHLT at the University of Bologna, Italy. Fifteen patients with heart and liver failure were placed on the transplant list between November 1999 and March 2012. The pretransplant cardiac diagnoses were familial amyloidosis in 14 patients and chronic heart failure due to chemotherapy with liver failure due to chronic hepatitis in one patient. CHLT was performed as a single combined procedure in 14 hemodynamically stable patients; there was no peri‐operative mortality. The survival rates for the CHLT recipients were 93%, 93%, and 82% at 1 month and 1 and 5 years, respectively. Freedom from graft rejection was 100%, 90%, and 36% at 1, 5, and 10 years, respectively, for the heart graft and 100%, 91%, and 86% for the liver graft. The livers of eight recipients were transplanted as a “domino” with mean overall 1‐year survival of 93%. Simultaneous heart and liver transplantation is feasible and was achieved in this extremely sick cohort of patients. By adopting the domino technique, we were able to enlarge the donor cohort and include high‐risk patients.     

Domino liver transplantation: a practical option in the face of the organ shortage

This case study describes a domino liver transplantation in which a patient with familial amyloid polyneuropathy received a cadaveric liver, and the explanted liver was in turn transplanted into a second recipient. Familial amyloid polyneuropathy is an autosomal dominant inherited disease associated with a mutant form of the protein transthyretin. Liver transplantation is the only definitive treatment for this disease. Transplantation removes the source of mutant transthyretin, halts the progression of this otherwise fatal disease, and significantly palliates many underlying symptoms. This case study illustrates that domino transplantation is a practical option to provide a liver transplant for a patient with this disease and a second listed patient from a single cadaveric liver organ, thus alleviating the organ donor shortage. Transplantation offers the only cure for the genetic defect that causes familial amyloid polyneuropathy, appears to result in subjective and objective improvement in neurological function, and eliminates the mortality associated with the disease. A signed informed consent was provided for publication of this case study.     

Long-term follow-up after liver transplantation in patients with hepatic iron overload.

Patients with hepatic iron overload who undergo orthotopic liver transplantation (OLT) have a worse 1-year survival than those who undergo transplantation for other indications; the long-term outcome in this population is unknown. The purpose of this study is to report long-term follow-up after OLT in a cohort of patients with hepatic iron overload. Five liver transplant centers in the United States reported follow-up data on 37 patients receiving a first liver transplant who had severe hepatic iron overload in their native livers. Kaplan-Meier 5-year survival among these patients was compared with survival data from all age-matched liver transplantations reported to the United Network for Organ Sharing (UNOS) over the same time period (1987 to 1993). The 5-year survival rate after OLT was 40% in the hepatic iron overload group compared with an overall survival rate of 62% for all patient groups from the UNOS registry (P =.0009). Although sepsis was the cause of 53% of all deaths occurring within the first year after OLT, cardiac complications accounted for 50% of the late mortality in patients with hepatic iron overload. In conclusion, long-term survival after OLT is significantly decreased in patients with hepatic iron overload. Infectious and cardiac complications are the most common causes of death in these patients. Further studies are needed to define the relationship between hepatic iron overload and mortality and to examine the effect of iron depletion on outcome after OLT in this patient population.     

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.     

Current concepts in transplant surgery: liver transplantation today

Introduction The discipline of liver transplantation (LTx) has been developed over the past decades, and LTx is now considered the gold standard for the treatment of patients with end-stage liver diseases and early liver tumors in cirrhotic livers. This procedure is now performed routinely in many transplant centers, and it has provided an enormous technical innovation to the field of hepatobiliary surgery. Allocation decision of liver organs is based on medical need and timing. Materials and methods The Mayo Model for End Stage Liver Disease based on patient-specific criteria was developed and applied to prioritize patients on the waiting list. From the donor aspects of LTx, sources of organ, excluding xenotransplantation, can be brain-dead donors, living donors, and non-heart-beating donors. Today, the majority of livers are procured from cadaveric donors. In addition to the conventional LTx, other types are living-donor LTx, reuse of grafts as domino transplantation, ex situ as well as in situ split LTx, and reduced-size LTx. The transplantation procedure consists of several steps including donor selection and management, liver procurement and preservation, back-table preparation, recipient operation with liver implantation, postoperative care, immunosuppression, and follow-up. Results The postoperative complications are divided into surgical, non-surgical, and multifactorial complications. Surgical complications account about 34% of morbidities after LTx and are mainly categorized to vascular and biliary complications. The main medical ones are non-surgical bleeding and infections. The multifactorial complications include primary non- or poor function and small-for-size syndrome. The pretransplant outcome predictors of LTx can be divided into donor, recipient, operative, and postoperative factors. Conclusion LTx is now considered a safe and standardized procedure with a substantially improved graft and patient survival and acceptable morbidity rates. However, the new problems, including recurrence of hepatitis C or hepatocellular carcinoma, chronic biliary complications, opportunistic infections, and development of de-novo malignancies are the major problems affecting the long-term outcome of transplanted patients. Mehrabi and Fonouni contributed equally to this work. An invited review about the different techniques in liver transplantation was submitted for publication in “Der Chirurg.”     

Psychiatric differences between liver transplant candidates with familial amyloid polyneuropathy and those with alcoholic liver disease

BACKGROUND: Psychiatric diagnoses are very common in liver transplant candidates, and such diagnoses are predictive of a poor clinical evolution and quality of life after transplantation. Also, nonadherence before the transplant is predictive of nonadherence after the transplant. METHODS: We studied the psychiatric and psychosocial profiles of 85 liver transplant candidates, comprising consecutive patients attending outpatient clinics of a liver transplantation unit at a public hospital. Interviews and questionnaires were used to measure personality traits, symptoms of anxiety and depression, social support, and adherence. These patients were broken into 3 groups: patients with familial amyloid polyneuropathy (n = 20), patients with alcoholic liver disease (n = 33), and patients with other liver diseases (n = 32). RESULTS: About 58% of patients had a current psychiatric diagnosis (24.8%, major depressive disorder, 22.3% generalized anxiety disorder, 8.3% adaptive disorder, 2.3% abuse of or dependence on substances other than alcohol). Current psychiatric diagnosis did not differ between patients with familial amyloid polyneuropathy and patients with alcoholic liver disease. Patients with alcoholic liver disease showed lower scores for 2 protective personality traits, social support and adherence to medication, than other patients. Patients with familial amyloid polyneuropathy showed higher scores for those traits. CONCLUSIONS: All patients waiting for a liver transplant should undergo psychiatric and psychological assessment. Some psychological characteristics such as personality traits and social support differ between clinical groups, so it may be useful to design different approaches for each group. Patients with alcoholic liver disease may require a special approach to improve adherence to medication.     

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

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

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

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

Domino liver transplantation in maple syrup urine disease.

Liver transplantation has been reported in a few cases of maple syrup urine disease (MSUD), but is controversial. Many patients with approved indications for liver transplantation die before grafts are available. A 25-yr-old man with MSUD underwent liver transplantation, and his liver was used as a domino graft for a 53-yr-old man with hepatocellular carcinoma who had low priority on the liver transplant waiting list and was unlikely to survive until routine organ procurement. Both transplants were performed as "piggy back" procedures, reconstructing the domino graft with caval segments from the cadaveric donor. Neither required veno-venous bypass. Whole body leucine oxidation was estimated by 13CO2 in breath after oral boluses of L-[1-13C]-leucine, before and after transplantation in both patients and a control subject. The surgical outcome was successful. The patient with MSUD had marked decreases in plasma branched-chain amino acids (BCAAs) and alloisoleucine (from 255 +/- 66 to 16 +/- 7 micromol/L), despite advancement of dietary protein from 6 to >40 gm/day. The domino recipient maintained near-normal levels of plasma amino acids with no detectable alloisoleucine on unrestricted diet. Leucine oxidation increased in the patient with MSUD (from 2.2 to 5.6% recovered in 4 hours) and decreased in the recipient (from 9.7 to 6.2%). Neither patient demonstrated any apparent symptoms of MSUD over more than 7 months. In conclusion, liver transplantation substantially corrects whole body BCAA metabolism in MSUD and greatly attenuates the disease. Livers from patients with MSUD may be considered as domino grafts for patients who might otherwise not survive until transplantation.     

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 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.     

Feasibility of auxiliary partial orthotopic liver transplantation from living donors for patients with adult-onset type II citrullinemia.

More than 20 patients with adult-onset type II citrullinemia have undergone liver transplantation, showing dramatic therapeutic effects. In Japan, living donor liver transplantation is the standard technique of liver transplantation because of the rare availability of cadaveric donors. The feasibility of auxiliary partial orthotopic liver transplantation (APOLT) for adult-onset type II citrullinemia to overcome the problem of a small-for-size graft in living donor liver transplantation has not been defined. We recently performed APOLT for patients with type II citrullinemia. Here, we present 2 patients: patient 1 was a 32-year-old man and patient 2 was a 43-year-old woman. Both patients suffered from hepatic encephalopathy, and laboratory data showed highly elevated plasma levels of ammonia and citrulline. In patient 1, the liver graft was obtained from a patient with familial amyloid polyneuropathy as a domino liver transplant. In patient 2, APOLT was performed after graft donation from her husband. The postoperative clinical courses of both patients were uneventful, and the neurological symptoms were completely resolved. The plasma concentrations of ammonia and citrulline normalized rapidly in both patients. APOLT can provide an adequate hepatocyte mass to correct the underlying enzyme deficiency in adult patients with type II citrullinemia. In addition, APOLT can be carried out safely to overcome the limitation of graft volume in living donor liver transplantation.     

The utility of extended criteria donor organs in severely ill liver transplant recipients

Organ shortage in liver transplantation has led the transplant community to expand the donor organ pool and reduce waiting list mortality by using so-called marginal donor or extended criteria donor (ECD) livers. The exact impact of these criteria on graft function and recipient survival are still under investigation. Most reports, however, show a clear correlation between organ quality and the posttransplant outcome. The role of ECD liver transplantation for severely ill recipients with high model for end stage liver disease (MELD) scores needs further clarification since transplant surgeons tend to allocate these grafts to more stable patients with lower MELD scores. Especially in the setting of ECD liver transplantation, strategies to improve graft quality and mitigate preservation and reperfusion injury may prove beneficial and play an important role in the future.     

Domino hepatic transplantation using the liver from a patient with primary hyperoxaluria

BACKGROUND: We report a case of domino liver transplantation using the liver harvested from a patient who underwent a combined liver and kidney transplantation for primary hyperoxaluria (PH). METHOD: A cadaveric liver transplantation was performed in a 19-year-old man with PH. In a second step, the PH liver harvested from the first patient was transplanted in a 69-year-old man with hepatitis C-related cirrhosis, not a candidate for a classic liver graft owing to multifocal hepatocellular carcinoma. RESULTS: At 8 months after transplantation, the domino recipient has normal hepatic function and no signs of tumoral recurrence, but he progressively developed hyperoxalemia, hyperoxaluria, and renal insufficiency. CONCLUSION: Regarding the favorable postoperative clinical evolution, domino liver transplantations using livers from PH patients may represent a new opportunity for marginal candidates for liver transplantation. However, the progressive renal insufficiency expected in such domino recipients should limit this procedure to selected cases.