Toshihiko Ikegami

Living related liver transplantation in adults.

OBJECTIVE To evaluate the outcome of living related liver transplantation (LRLT) in adult patients and to assess graft size disparity and graft regeneration. SUMMARY BACKGROUND DATA Although LRLT has been accepted as an optional life-saving procedure for pediatric patients with end-stage liver disease, the feasibility of LRLT for adult patients has not been reported with reference to a clinical series. METHODS Adult-to-adult LRLT was performed using whole left lobar grafts in 13 patients (5 with primary biliary cirrhosis, 6 with familial amyloid polyneuropathy, 1 with biliary atresia, and 1 with citrullinemia). The 13 donors comprised 5 husbands, 3 sons, 2 sisters, 2 fathers, and 1 mother. The ratio of the graft volume to standard liver volume (GV/SV ratio) was calculated for use as a parameter of graft size disparity. RESULTS Although the liver graft was markedly small for size (GV/SV ratio 32%-59% at the time of LRLT), none of the 13 patients developed postoperative liver failure. Eleven of the patients are still alive and well with satisfactory graft function 2 to 35 months after LRLT. Graft liver volume increased rapidly after LRLT and approximated the standard liver volume with time. CONCLUSIONS Our LRLT program for adult patients has produced good results. LRLT in adults can be indicated for selected donor-recipient combinations.

CONCOMITANT CAUDATE LOBE RESECTION AS AN OPTION FOR DONOR HEPATECTOMY IN ADULT LIVING RELATED LIVER TRANSPLANTATION

In this article, we describe a successful adult living related partial liver transplantation (LRLT) using the left lobe with the left-side caudate lobe (the Spiegel lobe and the left side of the paracaval portion). The size of the donors left lobe was 29% of the recipients standard liver volume and did not seem to meet our criteria for adult-to-adult LRLT. However, the donor had a thick left-side caudate lobe. The estimated volume of the left lobe with the left-side caudate lobe was 32%, which met our criteria for the adult recipient. The recipients CT scan on day 87 after transplantation showed the preserved blood flow and no biliary congestion in the left-side caudate lobe, which suggests maintenance of lobe function. This procedure may be an option for adult-to-adult LRLT in which the donor has a thick left-side caudate lobe.

Prevention of hepatic artery thrombosis in pediatric liver transplantation.

Hepatic artery thrombosis after orthotopic liver transplantation is a serious complication, especially in children. We report our experience with intensive anticoagulant therapy during and after living-related liver transplantation in pediatric recipients. Twenty-four patients between 5 months and 15 years of age were studied. The mean diameter of the anastomosed hepatic arteries was 2.7 mm. The anticoagulant therapy consisted of low-molecular-weight heparin, antithrombin III concentrates, prostaglandin E1, fresh frozen plasma, and a protease inhibitor. The profiles of the coagulation and fibrinolytic systems were monitored by measuring several parameters, including plasma levels of thrombin-antithrombin III complex, antithrombin III, plasmin-alpha 2 plasmin inhibitor complex, fibrin degradation product D-dimer, tissue type-plasminogen activator, and plasminogen activator inhibitor-1. Acceleration of the coagulation system and delayed recovery of the fibrinolytic system were observed during the early postoperative days. The plasma level of antithrombin III activity was maintained within the normal range by the administration of antithrombin III concentrates. None of the recipients developed hepatic artery thrombosis. Children have been reported to be at a greater risk of developing hepatic artery thrombosis than adults due to the small diameters of their hepatic arteries and the postoperative hypercoagulable state. We believe that the intensive anticoagulation therapy described in this study, the main concept of which is the early correction of imbalance between the coagulant and anticoagulant systems, could become a model for the prevention of hepatic artery thrombosis in pediatric liver transplantation patients.

A study of factors influencing prognosis after resection of hepatic metastases from colorectal and gastric carcinoma.

OBJECTIVE:The aim of this study is to determine the absolute contraindication for hepatic resection for colorectal metastases and investigate the value of hepatectomy for gastric metastases by comparing it with the results of colorectal metastases performed with the same criteria.METHODS:A retrospective cohort study was conducted in patients undergoing hepatic resection for metastatic colorectal (n = 64) and gastric (n = 17) carcinomas. Common predictive factors for both metastases were analyzed by the stratified Cox proportional hazard model. In this model, the different baseline hazard was set for each disease, whereas the risk of each covariate was assumed to be equal in both gastric and colorectal metastases.RESULTS:Overall 1-, 2-, and 5-yr survival rates after hepatectomy for colorectal and gastric metastases were 90%, 73%, 42%, and 47%, 22%, 0%, respectively. Factors controlling prognosis were as follows: age ≥ 60, extrahepatic metastases, serosal invasion, grade of lymph node metastases, tumor cell differentiation of the primary lesion(s), carcinoembryonic antigen level, tumor-exposed surgical margin, and blood transfusion. In particular, presence of extrahepatic metastases showed the markedly high-risk ratio among these eight variables.CONCLUSIONS:Hepatectomy, if possible, is indicated in patients with hepatic metastases from colorectal carcinoma if there are no extrahepatic metastases and if the primary disease is controlled. It is indicated only in carefully selected patients with metastases from gastric carcinoma.

Should all hepatic arterial branches be reconstructed in living-related liver transplantation?

BACKGROUND Because graft arteries are smaller and shorter in living-related liver transplantation (LRLT) than in whole or reduced-size liver transplantation from cadavers, arterial reconstruction is thought to be one of the critical points for success. METHODS Thirty LRLT patients were classified into two groups: those in whom all graft hepatic arteries were reconstructed (group A), and those whom only had some were reconstructed (group B). In group A 17 patients had a single hepatic artery and three had two hepatic arteries. In group B the thickest one of several arteries was reconstructed, but the others were ligated after pulsatile back-bleeding from their cut stumps had been confirmed. The clinical results were compared between the two groups. RESULTS Neither arterial thrombosis nor liver dysfunction related to the arterial blood supply was observed during the postoperative course. One case of bile leakage and two cases of bile duct stenosis occurred in group A. No significant difference was noted in the postoperative values of aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase between the two groups. Overall patient and graft survival was 90%. CONCLUSIONS Although several hepatic arteries may supply the potential allograft in LRLT, it is not always necessary to reconstruct all of them.

Type II (adult onset) citrullinaemia: clinical pictures and the therapeutic effect of liver transplantation

OBJECTIVE Adult onset type II citrullinemia is an inherited disorder of amino acid metabolism caused by a deficiency of liver specific argininosuccinate synthetase activity. Most of the patients with this disease were reported in Japan and therefore, this disease has not been well recognised outside this country. The detailed clinical pictures of the patients with type II citrullinaemia are reported and their outcomes after liver transplantation referred to. METHODS Ten patients with this disease were evaluated. Seven of them underwent liver transplants using a graft obtained from a healthy family member. RESULTS There were six men and four women; the age of onset of encephalopathy ranged from 17 to 51 years. The initial symptom in nine patients was sudden onset disturbance of consciousness, and one patient had long been regarded as having a chronic progressive psychotic illness. High concentrations of plasma citrulline and ammonia were commonly seen on admission. Although brain CT or MRI lacked any consistent findings, the EEG was abnormal in all patients, showing diffuse slow waves. Additionally, in five patients chronic pancreatitis preceded the onset of encephalopathy. After liver transplantation the metabolic abnormalities, including abnormal plasma concentrations of citrulline and ammonia, were immediately corrected and all neuropsychic symptoms soon disappeared, except for impaired cognitive function in one patient. Six out of these seven patients returned to their previous social lives, including work. CONCLUSIONS The clinical concept of adult onset type II citrullinaemia coincides well with the range of hepatic encephalopathy, and liver transplantation is a very promising therapeutic approach.

Long-term results of living-related donor liver graft transplantation: a single-center analysis of 110 transplants.

BACKGROUND Difficulties of cadaveric donation and serious donor shortage have led to the development and popularization of living-related donor liver graft transplantation (LRLT). Because the history of this procedure is rather short, important aspects specific to this procedure have not been sufficiently documented. The objective of this study was to analyze a single centers 10-year experience with 110 LRLT in pediatric and adult patients with end-stage liver diseases. METHODS The medical records of 110 consecutive patients who underwent LRLT were reviewed. The recipients were comprised of 72 children and 38 adults. The graft volume corresponded to 26-192% of the recipients standard liver volume. The relationship between pretransplant covariates and patient and graft survival was analyzed. Actuarial patient/graft survival rates were determined at 1, 3, and 5 years. The type and incidence of posttransplant complications were analyzed, as was long-term graft function. RESULTS The 1-, 3-, and 5-year actuarial patient and graft survival rates were 88%, 85%, and 85%, respectively. Log-rank test demonstrated that ABO-compatibility predicted patient survival rate, whereas patient age, underlying disease, patients clinical status, donor-recipient relation, donor age, and graft volume/standard liver volume ratio did not. Long-term liver function remains excellent. All the donors have returned to normal daily lives with an uneventful course. CONCLUSIONS LRLT is an efficacious procedure that provides excellent short-term and long-term survival. The indication criteria for both recipient and donor were legitimate in this series, except for transplant across ABO-incompatibility. Cautious expansion of this procedure may be justified under the situation of serious shortage of cadaveric donor.

Partial-Liver Transplantation To Treat Familial Amyloid Polyneuropathy: Follow-up of 11 Patients

Familial amyloid polyneuropathy (FAP) is characterized by progressive polyneuropathy and autonomic failure (1). Three large foci of patients with this disease are known to exist in Portugal, Sweden, and Japan (2). In FAP, the precursor of amyloid fibril is variant transthyretin in serum (3). Because the liver produces the greater part of the transthyretin in serum (4), it has been assumed that the replacement of a patients liver that is expressing an abnormal transthyretin gene might stop the production of the serum amyloid precursor in FAP. Since the first successful liver transplantation for a patient with FAP was performed in Sweden in 1990 (5, 6), this challenging operation has been widely accepted (7-11). In Japan, full-liver transplantation is uncommon because brain death is not recognized as a definition of death. As an alternative, we performed partial-liver transplantation for patients with FAP using grafts from living donors (12). We report on the outcomes of 11 patients with FAP who underwent this operation at our institution. Methods From November 1993 to November 1998, 11 patients with FAP who had a transthyretin gene mutation (one amino acid substitution of methionine for valine at position 30, shown by DNA testing [13]) underwent partial-liver transplantation from living donors. The patients, who were 25 to 47 years of age, had had symptoms of FAP for 6 months to 10 years. All 11 donors were shown to be free of an abnormal transthyretin gene; 4 donors were spouses, and the other 7 were brothers, sisters, or parents of the patient. The operations were performed after approval was obtained from the local ethics committee. The details of the operative technique have been reported elsewhere (14, 15). During the operation, the patients entire liver was removed. The left lobe, including the middle hepatic vein, was harvested from the living donor and was transplanted orthotopically. Either corticosteroid and tacrolimus or corticosteroid, cyclosporine, and azathioprine were used as immunosuppression agents. The postoperative follow-up for the patients ranged from 3 to 64 months. During the study period, 20 patients with FAP did not have transplantation because of advanced disease or poor clinical condition. Before surgery, all patients underwent thorough general physical and neurologic evaluations. Routine laboratory data, including blood cell counts, serum protein analyses, and liver and renal function tests, were examined. Nerve conduction studies were performed on the right ulnar and tibial nerves. Left sural nerve biopsies were performed, and myelinated fiber lesions were quantitatively examined (16). After surgery, neurologic findings were regularly examined by the same neurologist once a month. Serial measurements of nerve conduction velocities and body weight were performed every 6 months. During the final preoperative examinations, patients were clinically staged according to the criteria proposed by Coutinho and colleagues (17): group 1, patients with gastrointestinal autonomic disorders without apparent polyneuropathy (FAP stage 0); group 2, patients with polyneuropathy localized to the lower limbs (FAP stage I); group 3, patients with polyneuropathy involving both upper and lower limbs (FAP stage II). Results The results are summarized in the Table. Table. Clinical and Laboratory Data and Patient Outcomes Group 1 Severe nausea and vomiting were the initial symptoms for patients 1, 2, and 3 and resulted in rapid weight loss (patient 1, 10 kg in 9 months; patient 2, 7 kg in 6 months; patient 3, 5 kg in 3 months). These patients also had a history of chronic constipation but no other autonomic symptoms. Routine laboratory data and upper- and lower-limb nerve conduction velocities were normal. Sural nerve biopsy specimens revealed small deposits of amyloid, mainly on the epineurium, in all three patients. Patients 1 and 2 had slightly decreased density of myelinated fibers and patient 3 had moderately decreased density, showing more selective involvement of small myelinated fibers (18) (Figure, part A). All three patients had been ill less than 1 year before transplantation. After surgery, the nausea and vomiting subsided and appetite returned within 3 months for all patients in group 1. At last follow-up, they had no polyneuropathy and no deterioration of nerve conduction velocities. Figure. Myelinated fiber lesions in sural nerve biopsy specimens. A. B. C. Group 2 The four patients in group 2 (patients 4, 5, 6, and 7) had polyneuropathy, which involved only the lower limbs, and autonomic disorders, such as orthostatic hypotension, alternating constipation and diarrhea, and dysuria. However, they did not experience any serious physical disabilities. Laboratory data were normal for all patients, except for slightly decreased creatinine clearance in patients 4 and 7. All patients had normal upper-limb nerve conduction velocities, but patient 7 had below-normal velocity in the tibial nerve. Sural nerve biopsies for patient 4, whose amyloid deposition pattern resembled that of patients in group 1, showed a slight reduction in myelinated fiber density. The other three patients in group 2 showed significant amounts of amyloid deposition in the endoneurium and a greatly reduced density of myelinated fibers (Figure, part B). Patients in group 2 had been ill 1 to 4 years before transplantation. Polyneuropathy and autonomic symptoms gradually improved postoperatively in all patients; leg paresthesia and abnormal bowel function improved within 1 year. Patients 5 and 7, who had longer postoperative courses, showed improvement in leg strength. Nerve conduction velocities did not deteriorate and actually returned to normal in 3 of the 4 patients. Group 3 Patients 8, 9, 10, and 11 were disabled by sensorimotor neuropathy and also had various autonomic dysfunctions. Patient 8 could walk unaided, whereas patients 9, 10, and 11 frequently used wheelchairs. Routine laboratory data showed low serum albumin levels in patients 9, 10, and 11, and creatinine clearance was significantly decreased in all four patients. Nerve conduction velocities were abnormal in the lower limbs or the upper limbs in patients 8 and 9 and were not detectable in the lower limbs of patients 10 and 11. Heavy amyloid deposits and marked reduction of myelinated fiber density were observed in the sural nerve biopsy specimens of patients 8 and 9; myelinated fibers were almost completely lost in patients 10 and 11 (Figure, part C). Patients in group 3 had been ill 4 to 10 years before transplantation. After transplantation, patient 8 gradually improved. In patient 9, polyneuritic symptoms progressed; she is now confined to a wheelchair. The postoperative course of patient 10 was complicated by the Stokes-Adams syndrome, bacterial pneumonia, and sepsis. When she was discharged 10 months after transplantation, her neurologic state was worse than it was before surgery. She died 21 months after transplantation. Patient 11 developed rapidly progressive renal dysfunction soon after operation and died on the 84th postoperative day. Discussion By May 1999, liver transplantations had been performed on 368 patients with FAP in 16 countries (19). Several follow-up studies (7-12) have shown beneficial therapeutic effects, but 78 of the 368 patients were reported to have died after surgery, mainly secondary to infection and cardiac disorders (19). Suhr and colleagues (11) reported that a modified body mass index and duration of illness, especially gastrointestinal illness, were reliable indicators of the prognosis after liver transplantation in patients with FAP. During the past 5 years, we have performed partial-liver transplantation in 11 patients with FAP. The patients in groups 1 and 2 recovered from the operation; at transplantation, they had had FAP for 4 years or less. However, the patients in group 3, especially those who had been ill for 6 years or more, had unfavorable postoperative outcomes. These results suggest that severity of polyneuropathy and duration of illness are associated with liver transplantation outcomes for patients with FAP. Serum levels of urea nitrogen and creatinine did not correspond with the severity of FAP symptoms or the duration of illness. No significant association between a modified body mass index and outcome was observed in 9 of 11 patients (data not shown). However, all 4 patients with greatly decreased creatinine clearance had advanced stages of FAP, and 3 of these 4 had longer histories of the disease and unfavorable outcomes after transplantation. Tibial nerve conduction velocities were also significantly delayed or undetectable in these patients. In addition, the severity of sural nerve fiber loss clearly reflected the duration of illness and the patients postoperative prognosis. Patients 1 to 4, who had myelinated fiber populations greater than 2500, had shorter histories of FAP (<2 years) and had excellent clinical outcomes after liver transplantation. Patients 5 to 9, who had myelinated fiber populations of 1000 to 2500, had 4- to 6-year histories of illness, and the severity of renal impairment seemed to be a crucial factor in their postoperative prognosis. Patients 10 and 11, who had myelinated fiber populations less than 1000, had longer clinical histories (>6 years) and experienced unfavorable outcomes after transplantation. In conclusion, patients in our series who had an early stage of FAP did well after liver transplantation, whereas those at advanced stages had adverse postoperative results, presumably because of serious dysfunctions of amyloid-laden systemic organs.

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

Familial amyloid polyneuropathy (FAP) is a form of hereditary generalized amyloidosis. Liver tissue explanted from FAP patients has normal structure and function, except for the production of amyloidogenic variant transthyretin (TTR), and domino liver transplantation (DLT) using grafts from FAP patients was first performed in 1995. FAP symptoms usually develop in genetically determined individuals after the age of 20, but it is difficult to estimate when FAP symptoms will appear in domino recipients. Concerning this problem, histological findings showing amyloid deposition have recently been obtained in a few domino recipients of FAP livers. This study investigated the presence of de novo amyloid deposition in the gastroduodenal mucosa of domino recipients transplanted at our institution. Biopsy of gastroduodenal mucosa was carried out in 5 recipients of FAP livers and TTR‐derived amyloid deposits were detected in 2 patients, both of whom had undergone DLT 47 months previously. In FAP liver recipients, de novo systemic amyloid deposition may begin much sooner than previously supposed. Therefore, careful follow‐up of domino recipients of FAP livers is required. Liver Transpl, 2006.

Peripheral nerves regenerated in familial amyloid polyneuropathy after Liver transplantation

Familial amyloid polyneuropathy is a form of hereditary generalized amyloidosis that is characterized by progressive polyneuropathy and failure of the autonomic nervous system [1]. In patients with this disease, amyloid fibril proteins are single amino acid-substituted variants of transthyretin [2]; the liver produces most of the amyloid fibril proteins present in serum [3]. Liver transplantation has recently been used to treat patients with familial amyloid polyneuropathy [4-7], but little objective evidence supports the use of this treatment. In this report, we show a clear histopathologic finding that peripheral nerves regenerated in a patient with familial amyloid polyneuropathy after liver transplantation. Case Report A 31-year-old woman with a 3-year history of type I familial amyloid polyneuropathy had undergone living-related partial liver transplantation, as reported elsewhere [8, 9]. Liver transplantation from a cadaveric donor is not performed in Japan because the Japanese do not believe that brain death constitutes death. The patient had a mutant transthyretin gene with a valine to methionine substitution at position 30 (30Met transthyretin). The donor was the patients healthy 33-year-old sister. After surgery, the patients autonomic neurologic dysfunction (bowel and bladder dysfunction and orthostatic hypotension) and neuropathic symptoms in the lower limbs gradually disappeared. In addition, 30Met transthyretin in serum almost disappeared [8]. One year after transplantation, the patient returned to her previous activities. Three years after transplantation, she has no residual symptoms ascribed to familial amyloid polyneuropathy. A series of motor and sensory nerve conduction studies on the right tibial nerve showed slight improvement after transplantation: Motor nerve conduction was 43.0 m/s before and 41.0 m/s 3 years after transplantation; sensory nerve conduction was 38.0 m/s before and 48.0 m/s 3 years after transplantation (normal values: motor nerve conduction, 40 m/s; sensory nerve conduction, 35 m/s). Methods Biopsy was done on the left sural nerve before liver transplantation and on the right sural nerve 3 years after transplantation. Formalin-fixed and paraffin-embedded sections were stained with alkaline Congo red, and the characteristic apple-green birefringence of amyloid was identified under a polarizing microscope. So that we could study myelinated fiber lesions, the specimens were fixed in 3% glutaraldehyde in 0.1 mole of cacodylate buffer at a pH of 7.4, postfixed in 1% osmium tetroxide in the same buffer, and embedded in epoxy resin. Transverse sections of 1-m thickness were cut, stained with 1% toluidine blue, and examined by light microscopy. The diameter of the myelinated fiber and the density of the fiber per square millimeter of the endoneurial area were estimated from photographs enlarged to a final magnification of x1000. From these results, histograms of diameter frequency were constructed. Results Before transplantation, amyloid deposits were seen in the epineurium, perineurium, and endoneurium of the left sural nerve; a nodular pattern of amyloid deposits in the endoneurium predominated. A generalized, severe reduction in the density of nerve fibers was seen in each fascicle (Figure 1, left; Figure 2). After transplantation, a similar pattern of amyloid deposits was seen in the right sural nerve but the size of these deposits seemed stable (Figure 1, middle inset). The density of myelinated fibers was much higher after transplantation than before transplantation. In particular, the number of small myelinated fibers was much higher after transplantation than before transplantation (Figure 1, middle and right; Figure 2). Figure 1. Histopathologic and morphometric findings in the biopsy specimens obtained from the sural nerves. Left. Middle. Figure 2. Diameter-frequency histogram of myelinated fibers in the sural nerves before transplantation (black bars) and after transplantation (white bars). Discussion Before 1990, no effective treatment was available for the many intolerable symptoms of familial amyloid polyneuropathy. In 1990, physicians used liver transplantation to treat patients with this disease. Since the success of this surgery was reported [4], more than 150 patients with familial amyloid polyneuropathy throughout the world have had this treatment [10]. Follow-up studies [6, 9, 11-13], conducted over a 5-year period after transplantation, have shown early disappearance of variant transthyretins from serum and no further disease progression. In some patients, neurologic symptoms have improved and autonomic neuropathy was alleviated sooner than was peripheral somatic neuropathy. Quality of life has improved in patients who successfully recovered from surgery [14]. Most postoperative deaths occurred in patients with advanced disease [7, 9, 12]. The clinical evidence has led to a consensus that liver transplantation is a promising treatment for familial amyloid polyneuropathy. The need for early transplantation in less symptomatic patients is now emphasized. However, little objective evidence has documented the regression of amyloid deposits or the recovery of peripheral nerves. Studies of scintigraphy done by using radiolabeled serum amyloid P component have shown a significant decrease in whole-body uptake of this tracer after liver transplantation; this finding indicates that amyloid-laden lesions regressed [6]. Results on autonomic function tests improved in a patient with familial amyloid polyneuropathy who survived 8 months after liver transplantation [15]. Type I familial amyloid polyneuropathy with variant 30Met transthyretin usually features distal to proximal symmetrical involvement of peripheral nerves that starts in the legs [1]. A primary neuropathic process in this disorder is axonal degeneration caused by local amyloid deposits [16]. It is well known that the pathologic feature of sural nerve biopsy specimens is selective loss of unmyelinated and small myelinated fibers in the early stage of disease [17]. In our patient, clinical improvement was accompanied by a change in the population of myelinated fibers in the left and right sural nerves. The diffuse pattern of nerve fiber loss in the biopsy specimen of the left sural nerve obtained before liver transplantation coincided with the findings of sural nerves seen in patients with advanced type I familial amyloid polyneuropathy. The biopsy specimen obtained from the right sural nerve 3 years after transplantation revealed a substantial increase in the number of myelinated fibers and many small myelinated fibers. Because patients in whom type I familial amyloid polyneuropathy has a progressively deteriorating course seldom have well-preserved small myelinated fibers in the biopsy specimens obtained from the sural nerves [16], our findings indicate that myelinated fibers regenerate in the peripheral nerves after liver transplantation. Moreover, the reduction of amyloid mass seems to occur in the proximal portions of the long extremity nerves. This report provides valuable histopathologic evidence of the usefulness of liver transplantation as therapy for familial amyloid polyneuropathy.