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.     

辅助性原位尸肝部分移植治疗Wilson病的疗效初探

目的:总结我院2002年7月19日施行的辅助性原位尸体肝部分移植治疗Wilson病(肝豆状核变性)病例,探讨该移植技术的可行性和初步临床疗效。方法:通过双灌注快速取肝法获取血型为A型的供肝;在整型台上用CUSA沿肝脏镰状韧带的左侧劈离肝脏,取第Ⅱ、Ⅲ段为重230g的部分移植供肝,仔细结扎断面的管道系统,历时185min。受体女性,22岁,血型A型,因锥体外系症状逐渐加重而具肝移植指征,切除受体病肝左外侧叶(Ⅱ、Ⅲ段),将供肝(Ⅱ、Ⅲ段)原位植入。用5鄄0Prolene缝线分别对供体鄄受体的肝左静脉和门静脉左支行端端连续吻合,均预留“增宽因子”,于受体胃十二指肠动脉水平与供肝的左肝动脉以8鄄0Prolene缝线间断吻合。胆道对合取左肝管鄄空肠Roux鄄en鄄Y式吻合。术中予甲基泼尼松龙静脉注射1000mg,术后采用激素、FK506和骁悉联合免疫抑制治疗。结果:热缺血时间为6min,冷缺血时间15.5h,手术时间6.5h,术中输血1400ml。术后第3天开始进食和离床活动,至今病人已生存16个月,完全恢复正常生活,血清铜和铜蓝蛋白水平恢复正常,移植肝脏体积无明显萎缩,手足震颤明显减轻。结论:辅助性原位尸体部分肝移植是治疗Wilson病的良好方法,同时可避免活体部分肝移植给供体带来的风险。     

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.     

First case of cadaveric liver transplantation in Japan

The first case of liver transplantation from a brain-dead donor in Japan is described. The recipient was a 43-year-old man with familial amyloid polyneuropathy who manifested various neuropathic symptoms and autonomic dysfunction at the time of transplantation. The graft had three arteries, for which a single trunk was created at the back table. A side-to-side cavacaval anastomosis was performed as an outflow reconstruction. To avoid portal congestion, a temporary shunt between the right posterior branch of the portal vein and the vena cava was constructed, instead of a venovenous bypass. The graft preservation time was 7.2 h and the operation time was 12.2 h. Although sufficient blood flow in the hepatic artery, portal vein, and hepatic vein was confirmed intra- and postoperatively, using Doppler ultrasound, transient graft dysfunction was observed immediately after surgery, but there was spontaneous improvement. The patient was discharged 100 days after transplantation. Received for publication on July 31, 1999; accepted on Sept. 8, 1999     

The long-term impact of liver transplantation on kidney function in familial amyloidotic polyneuropathy patients

The aim of the study is to evaluate the long-term kidney function after liver transplantation (LTx) in familial amyloidotic polyneuropathy (FAP) Portuguese type patients and compare the findings with patients transplanted for chronic liver disease of other origin. We analysed the medical records of 32 FAP patients who underwent transplantation between 1990 and 1999 with a follow-up of more than 1 year after LTx. The control group consisted of 61 patients who had undergone LTx for chronic liver disease. Kidney function was measured by the glomerular filtration rate (GFR), serum creatinine and urea. There were no differences between the groups in creatinine and urea levels during the follow-up. However, during the first year after transplantation, the increase in creatinine and urea was significantly higher in the control group (P < 0.01). The decline in GFR after transplantation was also more pronounced in the controls (P < 0.01). Initially after LTx, kidney function deteriorated in both FAP and control patients, but the deterioration was more pronounced in the controls. The decline of the FAP patients' kidney function after LTx was not more pronounced than that observed in control patients, although many FAP patients' kidney function was impaired before the procedure, suggesting that LTx may halt the progression of kidney damage caused by amyloid deposition.     

Sequential (domino) transplantation of the liver in a transthyretin-50 familial amyloid polyneuropathy

Background: General shortage of cadaveric organs has led to a search for alternative methods to expand the donor pool. Sequential (domino) transplantation is yet another attempt to compensate for the declining consent to organ donation. Patients and methods: To qualify for a domino liver transplantation, the following preconditions must be fulfilled: (1) extrahepatic disease must exist, (2) liver must be fully functional, and (3) the genetic defect in the host should recur within a sufficient latency period. Familial amyloid polyneuropathy (FAP) is an autosomal dominant disease which involves a genetic defect for transthyretin (TTR), which is predominantly produced in the liver. Results: In this report, we describe a rare case of a FAP TTR-50 variant undergoing domino liver transplantation. Since myocardial symptoms precede peripheral polyneuropathy, special emphasis should be placed on arrhythmias and the restrictive cardiomyopathy necessitating a veno-venous bypass or a cardiac pacemaker in order to improve cardiac contractility. The type of anastomosis of the suprahepatic inferior vena cava and possible alternatives are discussed. Conclusion: Despite ethical problems, the advantages of the domino procedure are obvious: (1) expansion of the donor pool, (2) ability to use living donors, and (3) presence of very short ischemic time and thus excellent liver function. Due to the kinetics of TTR production and deposition, donors and recipients of FAP livers should be followed up using an extensive neurological and cardiological protocol. Received: 15 June 1999 Accepted: 12 November 1999     

Liver transplantation for familial amyloidotic polyneuropathy in Australia

Familial amyloidotic polyneuropathy type 1 (FAP-1) is a type of systemic amyloidosis caused by mutant transthyretin (mTTR) that is mainly produced in the liver. Most patients have progressive peripheral and autonomic neuropathy. Ten patients with FAP underwent orthotopic liver transplantation (OLT) at the Queensland Liver Transplant Service (Princess Alexandra Hospital, Brisbane, Australia). Nine patients are still alive, and one patient died of cardiac failure 10 days after OLT. Some symptoms of FAP were alleviated in some of the patients. OLT seems to be a worthwhile treatment for FAP, because it halts the progression of symptoms and achieves improvement in some patients. Received for publication on July 15, 1999; accepted on April 14, 2000     

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目的 报告国内首例同种异体肝小肠联合移植，并就肝肠联合移植适应证、排斥诊断与治疗、感染防治、肠功能恢复与营养支持进行讨论。方法 供肠长380cm，供肠肠系膜上动脉、门静脉分别与受体腹主动脉、下腔静脉端侧吻合；供肝行改良背驮式肝移植。术后免疫抑制剂采用FK506 激素 骁悉 赛尼哌方案。排斥监测采用内镜指导下肠粘膜活检病理学检查及临床观察。并采取措施防治感染和促进移植肠功能的恢复。结果病人恢复顺利，移植肠和移植肝功能良好，未发生排斥反应，术后3个月时已摆脱全肠外营养，依靠肠内营养维持营养状态。结论 肝小肠联合移植对肠衰竭合并全肠外营养所致肝功能损害病人，是可行、有效的治疗方法。     

High incidence of thrombotic complications early after liver transplantation for familial amyloidotic polyneuropathy

Early thrombotic complications are critical causes of in-hospital morbidity after orthotopic liver transplantation (OLT), potentially culminating in graft loss. The aim of this study was to retrospectively analyse these complications, trying to identify associated independent risk factors. This retrospective analysis included 223 OLTs performed on 213 patients, in a 30-month period. Eighty-six OLTs were performed on familial amyloidotic polyneuropathy (FAP) patients. Preoperative details (primary diagnosis and Child-Turcotte-Pugh classification, when applicable), surgical features (including type of arterial reconstruction), postoperative variables and outcome were analysed. The observation period ended 30 days post-OLT, until discharge or in-hospital death. Early thrombotic complications were diagnosed in 16 cases (7.2%), affecting mainly FAP patients ( n  = 12). Hepatic artery thrombosis (HAT) was the most frequent early thrombotic event ( n  = 12): incidence in FAP patients 11.6% ( n  = 10) versus incidence in non FAP patients 1.5% ( n  = 2), P  = 0.001. By logistic regression analysis, FAP turned out to be an independent risk factor for early thrombotic complications, and specifically for HAT. The type of arterial reconstruction and other analysed surgical and medical factors did not influence early HAT occurrence. In conclusion, FAP was identified in this study as an independent risk factor for early HAT, a new datum not yet described in the literature.     

Transthyretin amyloidosis with cardiomyopathy after domino liver transplantation: Results of a cross-sectional study

Domino liver transplantation (DLT) has been used widely in patients with hereditary amyloid transthyretin (ATTR) amyloidosis. New-onset polyneuropathy in recipients of DLT has been reported, but there are few cases of cardiac involvement reported. We aimed to perform a cross-sectional study for ATTR amyloidosis with cardiomyopathy (ATTR-CM) in DLT recipients. We evaluated 23 living DLT recipients a median of 9 years since DLT at 2 referral centers with a systematic cardiac evaluation, including bone scintigraphy. Median age was 72 years, 91% had hypertension, 35% had diabetes mellitus, 67% had chronic renal failure, and 8 patients (35%) developed new-onset polyneuropathy. Only 13% had a normal electrocardiogram and a normal echocardiography, and most of them showed some conduction disturbance or increase in left ventricular wall thickness, but only 1 patient with a Glu89Lys mutation developed ATTR-CM diagnosed by bone scintigraphy and endomyocardial biopsy. None of the recipients of a DLT with Val30Met mutation showed cardiac involvement by bone scintigraphy. In conclusion, DLT from Val30Met donors seems to be safe regarding the development of ATTR-CM. Evaluation of cardiomyopathy in DLT recipients is challenging due to concomitant comorbidities and in this context, bone scintigraphy can be helpful to evaluate ATTR-CM.     

Cadaveric small bowel/split liver transplantation in a child

Scarcity of size-matched grafts continues to be a major limiting factor for liver and combined liver/intestinal transplants in the pediatric population. It is reported that 29 % of pediatric patients listed for hepatic transplantation die while waiting for a donor. The reported mortality of pediatric patients awaiting intestinal transplantation is about 40 %. We report on a technique of segmental liver and intestinal transplantation in a child. To our knowledge, this is the first report of a combined split liver-intestinal transplantation. We used a cadaveric donor, but the technique can also be performed with a live donor. The adult recipient of one segment of the liver was discharged home without complications. The child who received the combined liver intestinal graft developed intestinal perforation and severe rejection and died. If this technique is applied successfully, the adverse effects and mortality of a long pretransplant waiting period in pediatric patients may be avoided. Received: 7 May 1998 Received after revision: 29 September 1998 Accepted: 12 October 1998     

Early renal failure after domino hepatic transplantation using the liver from a compound heterozygous patient with primary hyperoxaluria.

BACKGROUND: To cover the shortage of cadaveric organs, new approaches to expand the donor pool are needed. Here we report on a case of domino liver transplantation (DLT) using an organ harvested from a compound heterozygous patient with primary hyperoxaluria (PHO), who underwent combined liver and kidney transplantation. The DLT recipient developed early renal failure with oxaluria. The time to the progression to oxalosis with renal failure in such situations is unknown, but, based on animal data, we hypothesize that calcineurin inhibitors may play a detrimental role. METHODS: A cadaveric liver and kidney transplantation was performed in a 52-year-old male with PHO. His liver was used for a 64-year-old patient with a non-resectable, but limited cholangiocarcinoma. RESULTS: While the course of the PHO donor was uneventful, in the DLT recipient early post-operative, dialysis-dependent renal failure with hyperoxaluria developed. Histology of a kidney biopsy revealed massive calcium oxalate crystal deposition as the leading aetiological cause. CONCLUSIONS: DLT using PHO organs for marginal recipients represents a possible therapeutic approach regarding graft function of the liver. However, it may negatively alter the renal outcome of the recipient in an unpredictable manner, especially with concomitant use of cyclosporin. Therefore, we suggest that, although DLT should be promoted, PHO organs are better excluded from such procedures.     

Cadaveric renal transplantation in children under 5 years of age

From March 1987 to August 1990 23 cadaveric renal transplants were performed in 19 children under the age of 5 years at the time of transplantation. The mean age of the recipients was 3.3 years (range 1.3–4.7) and the mean weight 13.0 kg (range 9.3–19.2). The mean donor age was 7.8 years (range 1.5–25). All children received triple immunosuppression with prednisolone, cyclosporin A and azathioprine, and 4 who had 2 grafts during this period also received antithymocyte globulin at the time of the second transplant. Patient survival is 100%. Actuarial first cadaveric graft survival was 57% at 1 year and remains unchanged at 3 years. There were 10 graft losses, 4 were associated with renal venous thrombosis without apparent rejection. Two were lost due to acute vascular rejection with associated renal venous thrombosis, and the remaining 4 losses followed cellular or chronic vascular rejection. The mean glomerular filtration rate ±SD was 51.4±23.6 ml/min per 1.73 m² (n=11) at 1 year and 43.5±25.3 at 2 years (n=6). The mean height standard deviation score improved from –2.2±1.1 at the time of transplantation to –1.3±1.0 1 year post transplant (n=11). The immunosuppression was well tolerated with a low incidence of side effects. Cadaveric renal transplantation remains a difficult but rewarding undertaking in children under 5 years of age.     

Complete hepatic ischemia due to torsion of a large accessory liver lobe: first case to require transplantation

Anatomical abnormalities of the liver are extremely rare. Although the majority of cases with an accessory liver are not detected, it can give rise to various clinical symptoms like recurrent abdominal pain and impaired liver function. Here we present the first case of orthotopic liver transplantation in a patient with hepatic ischemia caused by complete vascular occlusion due to a twisted accessory liver lobe. Although rare, an accessory liver lobe may cause serious and life-threatening problems and should therefore be kept in mind in patients presenting with acute abdominal pain.     

Liver Transplantation for Familial Amyloidotic Polyneuropathy (FAP): A Single-Center Experience Over 16 Years

Orthotopic liver transplantation (LTx) is currently the only available treatment that has been proven to halt the progress of familial amyloidotic polyneuropathy (FAP). The aim of this study was to assess mortality and symptomatic response to LTx for FAP. All 86 FAP patients transplanted at our hospital between April 1990 and November 2005 were included in the study. Five patients underwent retransplantation. The 1-, 3- and 5-year patient survival rates in patients transplanted during 1996-2005 were 94.6%, 92.3% and 92.3%, respectively, a significant difference from the rates of 76.7%, 66.7% and 66.7%, respectively, during 1990-1995 (p = 0.0003). Multivariate analysis revealed that the age at the time of LTx (>or=40 years), duration of the disease (>or=7 years) and modified body mass index (mBMI) (<600) were independent prognostic factors for patient survival. A halt in the progress of symptoms was noted in most patients, but only a minority experienced an improvement after LTx. To optimize the posttransplant prognosis, LTx should be performed in the early stages of the disease, and close post-LTx monitoring of heart function by echocardiography and of heart arrhythmia by Holter ECG is mandatory.     

Orthotopic liver transplantation in hemophilia B: a case report

Liver transplantation is a treatment modality that is being used with increasing frequency in cases of liver-based metabolic defects. This is a case report of a patient with hemophilia B who was treated since childhood with factor IX replacement for recurrent hemarthroses. Subsequent hepatitis B (HBV) and C (HCV) infection had resulted in the development of chronic active hepatitis, ultimately leading to cirrhosis. Orthotopic liver transplantation performed for endstage liver disease resulted in a rise in factor IX levels from 2% to 83% of normal values within 24 h post-operatively, and levels remained above 90% of normal values after postoperative day 3 without factor IX replacement. To our knowledge, only two cases of hemophilia B treated by orthotopic liver transplantation have been reported. This procedure has, however, only been implemented in cases of terminal liver insufficiency in hemophiliacs.     

Progressive Wild-Type Transthyretin Deposition after Liver Transplantation Preferentially Occurs onto Myocardium in FAP Patients

To elucidate whether progressive wild-type transthyretin (TTR) deposition can actually occur after liver transplantation (LT), amyloid fibrils were investigated in two familial amyloid polyneuropathy patients with TTR Val30Leu variant, who died 1 year after LT. Amyloid fibrils were extracted from cardiac muscles, sciatic nerves and kidney, which were investigated by the immunoprecipitation-mass spectrometry method and liquid chromatography-ion trap mass spectrometry analysis. The ratio of wild-type to variant TTR in cardiac muscle was approximately 5:5 before LT, but greatly increased to about 9:1 after transplantation. The ratios in sciatic nerves and kidney obtained at autopsy were approximately 5:5. Wild-type TTR was undetectable in kidney amyloid obtained before LT. Our results indicate that paradoxical wild-type TTR deposition after LT can preferentially occur in myocardium, leading to fatal cardiac dysfunction, but it is quite likely that this phenomenon can also occur in other visceral organs.     

Pulmonary thromboembolism in liver transplantation: a retrospective review of the first 25 years

The evidence on the state of ‘haemostasis’ at the time of liver transplantation (LT) is conflicting, with recent publications that suggest a hypercoagulable state, in contrast to traditionally held views. These findings raise the issue of thrombo‐embolic complications after LT, an area of interest which has received little attention in recent published literature. We therefore conducted a retrospective review of our experience of 3000 liver transplants over 25 years. Our prospective transplant database was reviewed to find all patients who were suspected to have had a pulmonary embolism (PE) during or following LT. Paediatric transplants were excluded. A part of this database was cross referenced against hospital records to corroborate its accuracy. Clinical records of all these patients were reviewed and relevant aspects collated and analyzed. Following exclusion of the paediatric recipients, 2 149 adults were reviewed to find 36 patients in whom a PE was suspected (median age 49), 21 of whom were within 90 days of transplant (median duration 22 days). PE was ruled out in 10, unconfirmed in two, confirmed in eight patients; and in one, air embolism was found. All PEs occurred in hospital, but aetiology of liver failure was varied. Of note, two patients died of an on‐table PE and one patient of chronic rejection/disease recurrence (Primary Sclerosing Cholangitis). The remaining five are still alive (median survival of 65 months). Although thromboprophylaxis is now routine in our unit, its use in these patients could not be confirmed from records available. Fifteen PE were suspected and confirmed after 90 days from transplant (six within, and nine out with the first year). Acute PE in the setting of LT has an incidence rate in our series of 0.37% that would appear to be lower than previously reported and lower than one would expect after a ‘major complex’ category operation. This potentially suggests that the overall haemostatic function in these patients is still weighted towards hypocoagulation with the resultant risk of excessive bleeding. Aetiology of liver disease did not seem to confer a higher risk in our series. The prognosis after post‐operative PE appears good although sudden death due to an on‐table embolism is a rare but significant risk.     

Clinical analysis of emergency liver transplantation: the role of living donor liver transplantation

The current liver allocation system requires reevaluation because of the advancements in peri‐transplantation care and surgical techniques. And, the role of living donor liver transplantation (LDLT) in an emergency has not been determined yet. Retrospective review of all patients undergoing emergency liver transplantation (LT) from January 2000 to June 2010 was conducted, and clinical data were analyzed. Of the total 505 LTs, 69 patients (13.7%) underwent an emergency LT. Of these, 54 patients (78.3%) underwent LDLT using a right liver, and 15 patients (21.7%) underwent deceased donor liver transplantation (DDLT). The overall hospital mortality was 21.7% (15/69). The leading cause of death after transplantation was sepsis (60.0%). Multivariate analysis demonstrated that a model for end‐stage liver disease (MELD) >33 [hazard ratio (HR), 16.6; 95% confidence interval (CI), 1.443–191.632; p = 0.024] and existence of pre‐transplantation intubation (HR, 18.2; 95% CI, 1.463–225.483; p = 0.024) were independent factors associated with poor survival after emergency LT. LDLT group and DDLT group showed no difference in hospital mortality (p = 0.854) and graft survival (p = 0.861). Thus, MELD score and respiratory insufficiency could be parameters predicting post‐transplant survival. And, LDLT using the right liver could be an appropriate alternative to DDLT in an emergency.