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Ann Liver Transplant 2023; 3(2): 73-79

Published online November 30, 2023 https://doi.org/10.52604/alt.23.0020

Copyright © The Korean Liver Transplantation Society.

Living donor liver transplantation for Wilson disease: A collective review

Jeong-Ik Park1 , Yong-Kyu Chung2

1Department of Surgery, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
2Department of Surgery, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea

Correspondence to:Jeong-Ik Park
Department of Surgery, Ulsan University Hospital, 877 Bangeojinsunhwando-ro, Dong-gu, Ulsan 44033, Korea
E-mail: jipark@uuh.ulsan.kr
https://orcid.org/0000-0002-1986-9246

Received: November 4, 2023; Revised: November 7, 2023; Accepted: November 8, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/bync/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Wilson disease (WD) is a recognized metabolic disorder characterized by abnormal copper accumulation and excretion in the human body. The liver-related symptoms may range from acute liver failure to chronic liver disease. Liver transplantation (LT) is primarily indicated for two conditions of WD as acute liver failure and chronic liver disease. LT offers a crucial lifeline for those with WD, with high success rates for graft and patient survival. Living donor liver transplantation (LDLT) recipients for WD generally exhibit superior survival rates, including graft survival, compared to those undergoing LT for other conditions. However, they are still susceptible to the usual risks associated with LDLT. This study intended to review the LDLT cases for WD with acute liver failure and chronic liver disease in the literature. This review included 12 LDLT studies and case reports from Japan (n=3), Turkey (n=2), India (n=2), China (n=2), Saudi Arabia (n=1), Korea (n=1), and United Arab Emirates (n=1). The findings of this review reinforce the efficacy of LDLT in WD, particularly in instances of acute liver failure, while also acknowledging its effectiveness in chronic liver disease.

Keywords: Wilson disease, Acute liver failure, Copper metabolism, Living donors, Liver transplantation

Wilson disease (WD) is a recognized metabolic disorder characterized by abnormal copper accumulation and excretion in the human body. This infrequent condition impacts both the central nervous system (CNS) and the liver, leading to a diverse array of clinical symptoms. Despite being genetically transmitted in an autosomal recessive manner, it affects approximately 1 in every 30,000 individuals in the general population [1,2]. The ATP7B gene is responsible for producing a protein vital for transporting metals, crucial for the regulation of copper levels within the hepatocytes. This gene has been linked to over 300 different mutations, all contributing to impaired copper elimination from the liver and subsequent buildup in various organs, most notably the CNS and liver, as well as the eyes, kidneys, heart, and bones. Consequently, the manifestations of WD are varied. Over time, the accumulation of copper can lead to neurological symptoms, even in the absence of liver impairment. The liver-related symptoms may range from acute liver failure (ALF) to chronic liver disease (CLD) [3-5].

In cases of ALF as an initial symptom of the disease, liver transplantation (LT) is often the preferred treatment due to its urgent and potentially fatal nature, especially when conventional medical treatments are ineffective [6-9]. Conversely, patients with liver conditions other than ALF can remain asymptomatic with proper treatment. However, without adequate treatment, these patients may develop decompensated CLD with common CNS complications, making LT a potentially curative option [10-12].

LT offers a crucial lifeline for those with WD, with high success rates for graft and patient survival following LT, including living donor liver transplantation (LDLT). LDLT recipients for WD generally exhibit superior survival rates, including graft survival, compared to those undergoing LT for other conditions. However, they are still susceptible to the usual risks associated with LT [13-16]. This study intended to review the LDLT cases for WD in the literature.

A Series of 29 Cases of LDLT in Turkey [17]

Between 2006 and 2020, 29 LDLT cases were performed for 27 WD patients. The study included 11 female and 16 male patients, with a mean age of 20.8±11.1 years and a mean body mass index of 20.5±3.2 kg/m2. The mean model for end-stage liver disease (MELD) score of the adult patients was 16.5±6.3, and the mean pediatric end-stage liver disease (PELD) score of the pediatric patients was 19.6±17.2. Five patients underwent transplantation due to ALF, and 22 patients with low MELD score underwent LT due to CLD. Three patients who were referred with ALF died in the perioperative period; no mortality was observed in the 22 elective patients. The overall survival was calculated as 88.8%. The 1-, 3-, and 5-year survival were 100% among elective early transplanted patients. Authors concluded that LT is the most effective treatment for liver failure caused by WD. When performed promptly, LDLT results in high survival rates in cases of both ALF and CLD.

A Case of Emergency LDLT for ALF Secondary to WD in United Arab Emirates [18]

Emergent LDLT in adults with fulminant hepatic failure secondary to WD is rarely performed. Authors report a case of decompensated WD presenting with fulminant hepatic failure treated with an emergent LDLT. A 25-year-old female presented with fulminant hepatic failure and underwent an emergent LDLT using a left-lobe graft from her brother. Explant revealed a nodular, cirrhotic liver with numerous yellow-green nodules on the cut surface, and histopathology revealed confluent necrosis and cholestasis with positive copper immunostain. Quantitative hepatic copper was 2,119 μg/g (range, 10–35 μg/g). Recipient genetic testing revealed c.2930C>T p.(Thr977Met) homozygous variant in the ATP7B gene. The donor was heterozygous for the mutation. The recipient continues to do well three years later with normal ceruloplasmin and urinary copper excretion.

A Series of 18 Cases of LDLT from Turkey [2]

Eighteen adults underwent LDLT for WD. The presentations before LDLT were decompensated cirrhosis (n=16), acute-on-CLD (n=1) and ALF (n=1). The donors were parents (n=2), siblings (n=3), cousin (n=1), daughter (n=1), nephew (n=1), spouse or relatives of spouse (n=9) and from swap transplantation (n=1). All genetically related donors were negative for screening of WD. The study cohort comprised of 15 males and 3 females, aged 32±10 years. Severity of liver disease (excluding ALF patient) was as follows; Child’s score 10±2, MELD score 18±6. The graft-to-recipient weight ratio was 1±0.2. The intensive care unit and hospital stay were 5.5±0.9 and 15±5 days. Two patients died in first month after LT, rest of patients are doing well at median 15 months (8–38 months). Two patients had acute cellular rejection that responded to steroids, one had hepatic artery thrombosis and 2 had biliary strictures. Three patients had neurological symptoms; 2 of these patients had partial recovery while one had complete recovery. There was no significant difference between LDLT from genetically related or unrelated donors.

A Case of Emergency LDLT for WD-Induced ALF in India [19]

Authors report the clinical outcome of an emergency ABO incompatible LT for an 8-year-old child with WD-induced ALF. The pretransplant anti-A antibody titer was 1:64, and hence he underwent three cycles of conventional plasma exchange as pretransplant liver supportive treatment for deranged coagulopathy and liver function followed by one cycle of immunoadsorption prior to LT. The posttransplant immunosuppression consisted of rituximab, tacrolimus, mycophenolate mofetil, and corticosteroid. The patient had anti-A isoagglutinin rebound with elevated aminotransferases levels from postoperative day 7 for which he was restarted on immunoadsorption plasmapheresis, but antibody titers did not decrease. Hence, he was switched to conventional plasmapheresis with which anti-A antibody titers decreased. The total dose of rituximab (150 milligrams/square meter of body surface area) was given in two divided doses of 75 mg at day-1 and day+8 which was much less than the dose conventionally advocated (375 milligrams/square meter of body surface area). He is clinically well with good graft function without rejection after 1 year of follow-up. This case illustrates that immunoadsorption and conventional plasmapheresis in conjunction with adequate immunosuppression is a viable approach in emergency ABO incompatible LT in WD-induced ALF.

A Case of LDLT for WD-Induced ALF in Japan [20]

Authors report the case of a patient with WD associated with fulminant hepatic failure (WD-FHF) who underwent LDLT. A 17-year-old female was diagnosed with WD-FHF based on high uric copper (10,603 μg/day, normal <100 μg/day), low serum ceruloplasmin (15 mg/dL, normal >20 mg/dL) and Kayser–Fleischer corneal ring, and ALF, acute renal failure and grade 2 hepatic encephalopathy. The MELD score was 35. Due to her critical condition, the patient underwent LDLT utilizing a right liver graft from her 44-year-old mother. The right hepatic vein and inferior right hepatic vein were reconstructed. She developed severe liver dysfunction due to a crooked hepatic vein caused by compression from the large graft. To straighten the bend, a reoperation was performed. During the operation, we tried to relieve the compressed hepatic vein by adjusting the graft location, but the benefits were limited. We therefore performed stenting in both the right hepatic vein and inferior right hepatic vein on postoperative day 9. The patient gradually improved, exhibiting good liver and renal functions, and was finally discharged on postoperative day 114. Authors concluded that, when WD-FHF deteriorates too rapidly for conservative management, LDLT is an effective therapeutic strategy.

A Series of 5 Cases of LDLT for WD in Japan [21]

Five (two pediatric and three adult recipients) underwent LDLT for WD at the University of Tokyo. Two patients presented with fulminant hepatic failure with hemolysis, and the other three presented with decompensating cirrhosis, one with an overlapping neurologic WD. All recipients had a low serum ceruloplasmin level (median 18 mg/dL), high urinary copper level (mean 1,119 μg/day), and presented with Kayser–Fleischer rings before transplantation. Although one patient died from early graft thrombosis unrelated to WD, the other four patients have shown an excellent long-term prognosis. Following successful transplantation, there was a significant reduction in urinary copper excretion (median: 64 μg/day) in all patients. The neurologic symptoms of WD in one patient, however, worsened after 2 months and gradually subsided, but not completely, over the 2-year follow-up. For advanced liver failure in WD, authors consider LDLT a valuable life-saving option. The improvement of neurologic symptoms, however, requires further evaluation.

A Series of 22 Cases of LDLT for WD in China [22]

Between January 2001 and November 2003, 22 LDLTs were performed on patients (19 pediatric, three adults) with WD in LT center. Two patients were transplanted because of a presentation coexistent with fulminant hepatic failure. Twenty presented with chronic advanced liver disease with (n=9) or without (n=11) associated neurologic manifestations. All the recipients had low serum ceruloplasmin levels with a mean value of 12.8±3.2 mg/dL before transplantation and increased to an average of 26.0±3.6 mg/dL after LDLT at the latest evaluation. The survival patients with neurologic manifestations such as tremor, dysarthria, dysphagia, dystonia and sialorrhea had improved after LDLT. This suggests that LDLT not only resolves the hepatic but also ameliorates the neurologic consequences of WD.

A Case of Emergency ABO-Incompatible LDLT for WD-Induced ALF in India [23]

ABO-incompatible LDLT is on the rise as a viable option in countries with limited access to deceased donor grafts. While reported outcomes of ABO-incompatible LDLT in children are similar to ABO-compatible LT, most children beyond 1 to 2 years of age will need desensitization to overcome the immunological barrier of incompatible blood groups. The current standard protocol for desensitization is Rituximab that targets B lymphocytes and is given 2 to 3 weeks prior to LT. However, this timeline may not be feasible in children requiring emergency LT for ALF or acute-on-CLD. In this emergency situation of ABO-incompatible LT, a safe multipronged approach may be an acceptable alternative solution. Authors report a child with acute WD with rapidly deteriorating liver function who underwent a successful ABO-incompatible LDLT using a rapid desensitization protocol.

A Series of 36 Cases of LDLT for WD in China [24]

Authors report a retrospective analysis of LDLT for 36 cases of WD patients. The indications for LDLT were fulminant hepatic failure in two patients and chronic advanced liver disease in 32 patients including 13 patients with Wilsonian neurologic manifestations. Two patients presented with severe Wilsonian neurologic manifestations even though their liver functions were stable. Results revealed that the survival of posttransplant patients or grafts at 1, 3, and 5 years was 91.7%, 83.3%, 75%, or 86.1%, 77.8%, 75%, respectively. Pretransplant intensive care unit-bound and MELD score were indicated as independent factors predictive of patient survival. Patients with neurologic abnormalities showed significant improvement after LT. Authors’ results indicate LDLT is an excellent therapeutic modality for WD patients with end-stage liver disease. Better pretransplant conditions appeared to be advantageous in gaining better survival outcomes of patients undergoing LDLT.

A Series of 3 Cases of LDLT for WD in Saudi Arabia [25]

This retrospective study assessed data from 16 WD patients (nine males, 56%) who had liver transplants between 1991 and 2007. Survival, graft function, and neurological complications were assessed during a follow-up period of up to 15 years. End-stage liver disease was the indication for LT in all 16 WD patients. Four patients displayed WD-related neurological symptoms in addition to liver disease. LDLT was done in three cases. One patient died on postoperative day 6 due to primary graft non-function. One-year post liver transplant survival was 94%. Neurological manifestations of all four patients disappeared during their follow-up. Four patients developed acute cellular rejection, but all responded to treatment. One patient developed chronic ductopenic rejection after 15 years post-transplantation and their graft failed; this patient is currently waiting for re-transplantation. Fourteen patients (88%) are still living. The long-term average survival is currently 10.5 years, with a current median survival of 8 years. Long-term graft survival is currently 81%. Short- and long-term survival in WD patient LT was excellent, and neurological and psychological WD manifestations disappeared during long-term follow-up.

A Series of 4 Pediatric Cases of LDLT for WD in Japan [26]

Authors retrospectively reviewed four fulminant cases and two chronic cases who underwent LDLT. There were two boys and two girls. Four adolescents of average age 11.3 years underwent LDLT. Duration from onset to transplantation ranged from 10 to 23 days. Average MELD score was 27.8 (range, 24–31). All patients were administrated chelates prior to transplantation. MELD, New Wilson’s index, Japanese scoring for LT, and liver atrophy were useful tools for transplantation decision making; however, none of them was an independent decisive tool. Clinical courses after transplantation were almost uneventful. One girl, however, developed an acute rejection episode due to noncompliance at 3 years after transplantation. All patients currently survive without a graft loss. No disease recurrence had been noted even using living related donors.

A Case of Auxiliary Partial LDLT for WD in Korea [27]

A patient with end-stage liver cirrhosis and neurological disorder due to WD underwent auxiliary partial orthotopic liver transplantation (APOLT) using a living donor. He first visited our institute complaining of hand tremor, which was diagnosed as WD. Despite medical therapy, hepatic impairment progressed toward portal hypertensive complications. He was considered a suitable candidate for LDLT. However, because of the impossibility of mobilization of the lateral section due to severe splenomegaly at the time of the recipient operation, we performed an APOLT using a right lobe graft. After transplantation, he suffered hepatic vein stenosis and biliary stenosis, receiving interventional therapy. The remnant native liver volume decreased, and the volume of the graft increased serially after transplantation. At the time of reporting, the patient had a normal working life with normal serum ceruloplasmin level and without neurologic problems at 26 months post-transplantation. APOLT may be a therapeutic option for patients with WD.

LT is primarily indicated for two conditions of WD: ALF and CLD. ALF is the initial presentation in 5% of WD patients and its rate has been reported as 4%–6% in the United States [28]. It was reported that mortality in these ALF cases reaches 100% without LT [28,29].

LDLT is considered a life-saving procedure for ALF. Deceased donor liver transplantation (DDLT) often faces a high mortality rate on the waiting list due to a shortage of available donors. LDLT has been proven to be effective in reducing waiting list mortality [30], and has demonstrated outcomes comparable to those of DDLT. A Chinese study reported that 1-year and 3-year survival rates for ALF patients were 65% [31], while a Japanese study [32] involving 212 ALF patients reported 1-year and 5-year survival rates of 79% and 74%, respectively. A study conducted in Pittsburgh [33] comparing the outcomes of LDLT and DDLT found a similar 5-year survival rate of 71%. However, a study from Chicago [34], which focused on pediatric patients and involved longer cold ischemia time and waiting time with DDLT, showed significantly higher survival rates for LDLT. It is worth noting that the number of patients in the LDLT and DDLT groups in these studies was not comparable, but they collectively suggest that LDLT can be considered a viable alternative. An Indian study reported that ALF patients had a 1-year survival rate of 86.1%, and 80.5% of patients remained alive after a median follow-up period of 56 months [35].

In situations where ABO-compatible living donors are not available, the only viable option in critical circumstances is to consider ABO-incompatible living donors. Presently, ABO-incompatible LDLT can be performed successfully with outcomes similar to ABO-compatible LDLT by strategies aimed at depleting B-cells and reducing anti-blood type isoagglutinin [36,37]. Typically, the depletion of B-cells is achieved through the administration of rituximab 2 to 3 weeks before LT, followed by plasma exchange or plasmapheresis to reduce anti-blood type isoagglutinin levels. This process usually takes 2 to 3 weeks to bring isoagglutinin levels to an acceptable range for LDLT [36-38]. However, it is perilous for patients with ALF to wait for a liver graft for more than 2 to 3 weeks. Clearly, overcoming the ABO barrier within such a short timeframe to perform ABO-incompatible LDLT for ALF presents a significant challenge.

To address this issue, a rapid preparation regimen has been developed to deplete plasma cells using bortezomib and reduce isoagglutinin levels through plasma exchange, enabling timely LDLT. B-cells can be effectively depleted using rituximab on postoperative day 1. In a Taiwanese study, this quick preparation regimen allowed for ABO-incompatible LDLT readiness in just 4.75±1.58 days [39]. The core idea of this quick preparation regimen is to first deplete plasma cells and reduce isoagglutinin levels to facilitate LT. Subsequently, B-cell depletion is achieved promptly on postoperative day 1 to prevent antibody-mediated rejection. To prevent continuous antibody release from plasma cells and reduce the risk of pre-formed antibodies attacking the implanted graft, plasma cells are depleted using bortezomib [40,41], and isoagglutinin is removed through plasma exchange prior to LT. Rituximab is administered on postoperative day 1 to effectively deplete activated B-cells, which may encounter alloantigens and become activated upon graft implantation, as rituximab can target B-cell lineage from premature B-cells to activated B-cells [42].

The consideration of LT for individuals with CLD associated with WD has not been extensively explored yet. It is essential to note that in countries where DDLT is the primary approach, decisions regarding LT eligibility are typically guided by the MELD score. This means that patients become eligible for LT as their MELD score rises. Conversely, LDLT presents an opportunity for WD patients with CLD who are in better clinical condition to access LT through a deliberate process of identifying suitable living donors. This elective approach allows for proactive planning and donor selection.

Through this review, it is concluded that LDLT is associated with good outcomes in WD patients with ALF not to mention of CLD.

Conceptualization: JIP. Data curation: JIP. Formal analysis: JIP. Investigation: All. Methodology: All. Validation: JIP. Writing – original draft: YKC. Writing – review & editing: All.

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Article

Review Article

Ann Liver Transplant 2023; 3(2): 73-79

Published online November 30, 2023 https://doi.org/10.52604/alt.23.0020

Copyright © The Korean Liver Transplantation Society.

Living donor liver transplantation for Wilson disease: A collective review

Jeong-Ik Park1 , Yong-Kyu Chung2

1Department of Surgery, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
2Department of Surgery, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea

Correspondence to:Jeong-Ik Park
Department of Surgery, Ulsan University Hospital, 877 Bangeojinsunhwando-ro, Dong-gu, Ulsan 44033, Korea
E-mail: jipark@uuh.ulsan.kr
https://orcid.org/0000-0002-1986-9246

Received: November 4, 2023; Revised: November 7, 2023; Accepted: November 8, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/bync/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Wilson disease (WD) is a recognized metabolic disorder characterized by abnormal copper accumulation and excretion in the human body. The liver-related symptoms may range from acute liver failure to chronic liver disease. Liver transplantation (LT) is primarily indicated for two conditions of WD as acute liver failure and chronic liver disease. LT offers a crucial lifeline for those with WD, with high success rates for graft and patient survival. Living donor liver transplantation (LDLT) recipients for WD generally exhibit superior survival rates, including graft survival, compared to those undergoing LT for other conditions. However, they are still susceptible to the usual risks associated with LDLT. This study intended to review the LDLT cases for WD with acute liver failure and chronic liver disease in the literature. This review included 12 LDLT studies and case reports from Japan (n=3), Turkey (n=2), India (n=2), China (n=2), Saudi Arabia (n=1), Korea (n=1), and United Arab Emirates (n=1). The findings of this review reinforce the efficacy of LDLT in WD, particularly in instances of acute liver failure, while also acknowledging its effectiveness in chronic liver disease.

Keywords: Wilson disease, Acute liver failure, Copper metabolism, Living donors, Liver transplantation

INTRODUCTION

Wilson disease (WD) is a recognized metabolic disorder characterized by abnormal copper accumulation and excretion in the human body. This infrequent condition impacts both the central nervous system (CNS) and the liver, leading to a diverse array of clinical symptoms. Despite being genetically transmitted in an autosomal recessive manner, it affects approximately 1 in every 30,000 individuals in the general population [1,2]. The ATP7B gene is responsible for producing a protein vital for transporting metals, crucial for the regulation of copper levels within the hepatocytes. This gene has been linked to over 300 different mutations, all contributing to impaired copper elimination from the liver and subsequent buildup in various organs, most notably the CNS and liver, as well as the eyes, kidneys, heart, and bones. Consequently, the manifestations of WD are varied. Over time, the accumulation of copper can lead to neurological symptoms, even in the absence of liver impairment. The liver-related symptoms may range from acute liver failure (ALF) to chronic liver disease (CLD) [3-5].

In cases of ALF as an initial symptom of the disease, liver transplantation (LT) is often the preferred treatment due to its urgent and potentially fatal nature, especially when conventional medical treatments are ineffective [6-9]. Conversely, patients with liver conditions other than ALF can remain asymptomatic with proper treatment. However, without adequate treatment, these patients may develop decompensated CLD with common CNS complications, making LT a potentially curative option [10-12].

LT offers a crucial lifeline for those with WD, with high success rates for graft and patient survival following LT, including living donor liver transplantation (LDLT). LDLT recipients for WD generally exhibit superior survival rates, including graft survival, compared to those undergoing LT for other conditions. However, they are still susceptible to the usual risks associated with LT [13-16]. This study intended to review the LDLT cases for WD in the literature.

COLLECTIVE LITERATURE REVIEW OF LDLT FOR WD

A Series of 29 Cases of LDLT in Turkey [17]

Between 2006 and 2020, 29 LDLT cases were performed for 27 WD patients. The study included 11 female and 16 male patients, with a mean age of 20.8±11.1 years and a mean body mass index of 20.5±3.2 kg/m2. The mean model for end-stage liver disease (MELD) score of the adult patients was 16.5±6.3, and the mean pediatric end-stage liver disease (PELD) score of the pediatric patients was 19.6±17.2. Five patients underwent transplantation due to ALF, and 22 patients with low MELD score underwent LT due to CLD. Three patients who were referred with ALF died in the perioperative period; no mortality was observed in the 22 elective patients. The overall survival was calculated as 88.8%. The 1-, 3-, and 5-year survival were 100% among elective early transplanted patients. Authors concluded that LT is the most effective treatment for liver failure caused by WD. When performed promptly, LDLT results in high survival rates in cases of both ALF and CLD.

A Case of Emergency LDLT for ALF Secondary to WD in United Arab Emirates [18]

Emergent LDLT in adults with fulminant hepatic failure secondary to WD is rarely performed. Authors report a case of decompensated WD presenting with fulminant hepatic failure treated with an emergent LDLT. A 25-year-old female presented with fulminant hepatic failure and underwent an emergent LDLT using a left-lobe graft from her brother. Explant revealed a nodular, cirrhotic liver with numerous yellow-green nodules on the cut surface, and histopathology revealed confluent necrosis and cholestasis with positive copper immunostain. Quantitative hepatic copper was 2,119 μg/g (range, 10–35 μg/g). Recipient genetic testing revealed c.2930C>T p.(Thr977Met) homozygous variant in the ATP7B gene. The donor was heterozygous for the mutation. The recipient continues to do well three years later with normal ceruloplasmin and urinary copper excretion.

A Series of 18 Cases of LDLT from Turkey [2]

Eighteen adults underwent LDLT for WD. The presentations before LDLT were decompensated cirrhosis (n=16), acute-on-CLD (n=1) and ALF (n=1). The donors were parents (n=2), siblings (n=3), cousin (n=1), daughter (n=1), nephew (n=1), spouse or relatives of spouse (n=9) and from swap transplantation (n=1). All genetically related donors were negative for screening of WD. The study cohort comprised of 15 males and 3 females, aged 32±10 years. Severity of liver disease (excluding ALF patient) was as follows; Child’s score 10±2, MELD score 18±6. The graft-to-recipient weight ratio was 1±0.2. The intensive care unit and hospital stay were 5.5±0.9 and 15±5 days. Two patients died in first month after LT, rest of patients are doing well at median 15 months (8–38 months). Two patients had acute cellular rejection that responded to steroids, one had hepatic artery thrombosis and 2 had biliary strictures. Three patients had neurological symptoms; 2 of these patients had partial recovery while one had complete recovery. There was no significant difference between LDLT from genetically related or unrelated donors.

A Case of Emergency LDLT for WD-Induced ALF in India [19]

Authors report the clinical outcome of an emergency ABO incompatible LT for an 8-year-old child with WD-induced ALF. The pretransplant anti-A antibody titer was 1:64, and hence he underwent three cycles of conventional plasma exchange as pretransplant liver supportive treatment for deranged coagulopathy and liver function followed by one cycle of immunoadsorption prior to LT. The posttransplant immunosuppression consisted of rituximab, tacrolimus, mycophenolate mofetil, and corticosteroid. The patient had anti-A isoagglutinin rebound with elevated aminotransferases levels from postoperative day 7 for which he was restarted on immunoadsorption plasmapheresis, but antibody titers did not decrease. Hence, he was switched to conventional plasmapheresis with which anti-A antibody titers decreased. The total dose of rituximab (150 milligrams/square meter of body surface area) was given in two divided doses of 75 mg at day-1 and day+8 which was much less than the dose conventionally advocated (375 milligrams/square meter of body surface area). He is clinically well with good graft function without rejection after 1 year of follow-up. This case illustrates that immunoadsorption and conventional plasmapheresis in conjunction with adequate immunosuppression is a viable approach in emergency ABO incompatible LT in WD-induced ALF.

A Case of LDLT for WD-Induced ALF in Japan [20]

Authors report the case of a patient with WD associated with fulminant hepatic failure (WD-FHF) who underwent LDLT. A 17-year-old female was diagnosed with WD-FHF based on high uric copper (10,603 μg/day, normal <100 μg/day), low serum ceruloplasmin (15 mg/dL, normal >20 mg/dL) and Kayser–Fleischer corneal ring, and ALF, acute renal failure and grade 2 hepatic encephalopathy. The MELD score was 35. Due to her critical condition, the patient underwent LDLT utilizing a right liver graft from her 44-year-old mother. The right hepatic vein and inferior right hepatic vein were reconstructed. She developed severe liver dysfunction due to a crooked hepatic vein caused by compression from the large graft. To straighten the bend, a reoperation was performed. During the operation, we tried to relieve the compressed hepatic vein by adjusting the graft location, but the benefits were limited. We therefore performed stenting in both the right hepatic vein and inferior right hepatic vein on postoperative day 9. The patient gradually improved, exhibiting good liver and renal functions, and was finally discharged on postoperative day 114. Authors concluded that, when WD-FHF deteriorates too rapidly for conservative management, LDLT is an effective therapeutic strategy.

A Series of 5 Cases of LDLT for WD in Japan [21]

Five (two pediatric and three adult recipients) underwent LDLT for WD at the University of Tokyo. Two patients presented with fulminant hepatic failure with hemolysis, and the other three presented with decompensating cirrhosis, one with an overlapping neurologic WD. All recipients had a low serum ceruloplasmin level (median 18 mg/dL), high urinary copper level (mean 1,119 μg/day), and presented with Kayser–Fleischer rings before transplantation. Although one patient died from early graft thrombosis unrelated to WD, the other four patients have shown an excellent long-term prognosis. Following successful transplantation, there was a significant reduction in urinary copper excretion (median: 64 μg/day) in all patients. The neurologic symptoms of WD in one patient, however, worsened after 2 months and gradually subsided, but not completely, over the 2-year follow-up. For advanced liver failure in WD, authors consider LDLT a valuable life-saving option. The improvement of neurologic symptoms, however, requires further evaluation.

A Series of 22 Cases of LDLT for WD in China [22]

Between January 2001 and November 2003, 22 LDLTs were performed on patients (19 pediatric, three adults) with WD in LT center. Two patients were transplanted because of a presentation coexistent with fulminant hepatic failure. Twenty presented with chronic advanced liver disease with (n=9) or without (n=11) associated neurologic manifestations. All the recipients had low serum ceruloplasmin levels with a mean value of 12.8±3.2 mg/dL before transplantation and increased to an average of 26.0±3.6 mg/dL after LDLT at the latest evaluation. The survival patients with neurologic manifestations such as tremor, dysarthria, dysphagia, dystonia and sialorrhea had improved after LDLT. This suggests that LDLT not only resolves the hepatic but also ameliorates the neurologic consequences of WD.

A Case of Emergency ABO-Incompatible LDLT for WD-Induced ALF in India [23]

ABO-incompatible LDLT is on the rise as a viable option in countries with limited access to deceased donor grafts. While reported outcomes of ABO-incompatible LDLT in children are similar to ABO-compatible LT, most children beyond 1 to 2 years of age will need desensitization to overcome the immunological barrier of incompatible blood groups. The current standard protocol for desensitization is Rituximab that targets B lymphocytes and is given 2 to 3 weeks prior to LT. However, this timeline may not be feasible in children requiring emergency LT for ALF or acute-on-CLD. In this emergency situation of ABO-incompatible LT, a safe multipronged approach may be an acceptable alternative solution. Authors report a child with acute WD with rapidly deteriorating liver function who underwent a successful ABO-incompatible LDLT using a rapid desensitization protocol.

A Series of 36 Cases of LDLT for WD in China [24]

Authors report a retrospective analysis of LDLT for 36 cases of WD patients. The indications for LDLT were fulminant hepatic failure in two patients and chronic advanced liver disease in 32 patients including 13 patients with Wilsonian neurologic manifestations. Two patients presented with severe Wilsonian neurologic manifestations even though their liver functions were stable. Results revealed that the survival of posttransplant patients or grafts at 1, 3, and 5 years was 91.7%, 83.3%, 75%, or 86.1%, 77.8%, 75%, respectively. Pretransplant intensive care unit-bound and MELD score were indicated as independent factors predictive of patient survival. Patients with neurologic abnormalities showed significant improvement after LT. Authors’ results indicate LDLT is an excellent therapeutic modality for WD patients with end-stage liver disease. Better pretransplant conditions appeared to be advantageous in gaining better survival outcomes of patients undergoing LDLT.

A Series of 3 Cases of LDLT for WD in Saudi Arabia [25]

This retrospective study assessed data from 16 WD patients (nine males, 56%) who had liver transplants between 1991 and 2007. Survival, graft function, and neurological complications were assessed during a follow-up period of up to 15 years. End-stage liver disease was the indication for LT in all 16 WD patients. Four patients displayed WD-related neurological symptoms in addition to liver disease. LDLT was done in three cases. One patient died on postoperative day 6 due to primary graft non-function. One-year post liver transplant survival was 94%. Neurological manifestations of all four patients disappeared during their follow-up. Four patients developed acute cellular rejection, but all responded to treatment. One patient developed chronic ductopenic rejection after 15 years post-transplantation and their graft failed; this patient is currently waiting for re-transplantation. Fourteen patients (88%) are still living. The long-term average survival is currently 10.5 years, with a current median survival of 8 years. Long-term graft survival is currently 81%. Short- and long-term survival in WD patient LT was excellent, and neurological and psychological WD manifestations disappeared during long-term follow-up.

A Series of 4 Pediatric Cases of LDLT for WD in Japan [26]

Authors retrospectively reviewed four fulminant cases and two chronic cases who underwent LDLT. There were two boys and two girls. Four adolescents of average age 11.3 years underwent LDLT. Duration from onset to transplantation ranged from 10 to 23 days. Average MELD score was 27.8 (range, 24–31). All patients were administrated chelates prior to transplantation. MELD, New Wilson’s index, Japanese scoring for LT, and liver atrophy were useful tools for transplantation decision making; however, none of them was an independent decisive tool. Clinical courses after transplantation were almost uneventful. One girl, however, developed an acute rejection episode due to noncompliance at 3 years after transplantation. All patients currently survive without a graft loss. No disease recurrence had been noted even using living related donors.

A Case of Auxiliary Partial LDLT for WD in Korea [27]

A patient with end-stage liver cirrhosis and neurological disorder due to WD underwent auxiliary partial orthotopic liver transplantation (APOLT) using a living donor. He first visited our institute complaining of hand tremor, which was diagnosed as WD. Despite medical therapy, hepatic impairment progressed toward portal hypertensive complications. He was considered a suitable candidate for LDLT. However, because of the impossibility of mobilization of the lateral section due to severe splenomegaly at the time of the recipient operation, we performed an APOLT using a right lobe graft. After transplantation, he suffered hepatic vein stenosis and biliary stenosis, receiving interventional therapy. The remnant native liver volume decreased, and the volume of the graft increased serially after transplantation. At the time of reporting, the patient had a normal working life with normal serum ceruloplasmin level and without neurologic problems at 26 months post-transplantation. APOLT may be a therapeutic option for patients with WD.

DISCUSSION

LT is primarily indicated for two conditions of WD: ALF and CLD. ALF is the initial presentation in 5% of WD patients and its rate has been reported as 4%–6% in the United States [28]. It was reported that mortality in these ALF cases reaches 100% without LT [28,29].

LDLT is considered a life-saving procedure for ALF. Deceased donor liver transplantation (DDLT) often faces a high mortality rate on the waiting list due to a shortage of available donors. LDLT has been proven to be effective in reducing waiting list mortality [30], and has demonstrated outcomes comparable to those of DDLT. A Chinese study reported that 1-year and 3-year survival rates for ALF patients were 65% [31], while a Japanese study [32] involving 212 ALF patients reported 1-year and 5-year survival rates of 79% and 74%, respectively. A study conducted in Pittsburgh [33] comparing the outcomes of LDLT and DDLT found a similar 5-year survival rate of 71%. However, a study from Chicago [34], which focused on pediatric patients and involved longer cold ischemia time and waiting time with DDLT, showed significantly higher survival rates for LDLT. It is worth noting that the number of patients in the LDLT and DDLT groups in these studies was not comparable, but they collectively suggest that LDLT can be considered a viable alternative. An Indian study reported that ALF patients had a 1-year survival rate of 86.1%, and 80.5% of patients remained alive after a median follow-up period of 56 months [35].

In situations where ABO-compatible living donors are not available, the only viable option in critical circumstances is to consider ABO-incompatible living donors. Presently, ABO-incompatible LDLT can be performed successfully with outcomes similar to ABO-compatible LDLT by strategies aimed at depleting B-cells and reducing anti-blood type isoagglutinin [36,37]. Typically, the depletion of B-cells is achieved through the administration of rituximab 2 to 3 weeks before LT, followed by plasma exchange or plasmapheresis to reduce anti-blood type isoagglutinin levels. This process usually takes 2 to 3 weeks to bring isoagglutinin levels to an acceptable range for LDLT [36-38]. However, it is perilous for patients with ALF to wait for a liver graft for more than 2 to 3 weeks. Clearly, overcoming the ABO barrier within such a short timeframe to perform ABO-incompatible LDLT for ALF presents a significant challenge.

To address this issue, a rapid preparation regimen has been developed to deplete plasma cells using bortezomib and reduce isoagglutinin levels through plasma exchange, enabling timely LDLT. B-cells can be effectively depleted using rituximab on postoperative day 1. In a Taiwanese study, this quick preparation regimen allowed for ABO-incompatible LDLT readiness in just 4.75±1.58 days [39]. The core idea of this quick preparation regimen is to first deplete plasma cells and reduce isoagglutinin levels to facilitate LT. Subsequently, B-cell depletion is achieved promptly on postoperative day 1 to prevent antibody-mediated rejection. To prevent continuous antibody release from plasma cells and reduce the risk of pre-formed antibodies attacking the implanted graft, plasma cells are depleted using bortezomib [40,41], and isoagglutinin is removed through plasma exchange prior to LT. Rituximab is administered on postoperative day 1 to effectively deplete activated B-cells, which may encounter alloantigens and become activated upon graft implantation, as rituximab can target B-cell lineage from premature B-cells to activated B-cells [42].

The consideration of LT for individuals with CLD associated with WD has not been extensively explored yet. It is essential to note that in countries where DDLT is the primary approach, decisions regarding LT eligibility are typically guided by the MELD score. This means that patients become eligible for LT as their MELD score rises. Conversely, LDLT presents an opportunity for WD patients with CLD who are in better clinical condition to access LT through a deliberate process of identifying suitable living donors. This elective approach allows for proactive planning and donor selection.

Through this review, it is concluded that LDLT is associated with good outcomes in WD patients with ALF not to mention of CLD.

FUNDING

There was no funding related to this study.

CONFLICT OF INTEREST

All authors have no conflicts of interest to declare.

AUTHORS’ CONTRIBUTIONS

Conceptualization: JIP. Data curation: JIP. Formal analysis: JIP. Investigation: All. Methodology: All. Validation: JIP. Writing – original draft: YKC. Writing – review & editing: All.

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The Korean Liver Transplantation Society

Vol.3 No.2
November 2023

pISSN 2765-5121
eISSN 2765-6098

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