Yuki Ohya

Impact of liver transplantation on transthyretin-related ocular amyloidosis in Japanese patients

OBJECTIVE To evaluate the long-term impact of liver transplantation on ocular manifestations of familial amyloid polyneuropathy (FAP) in Japanese patients. METHODS Medical records were retrospectively reviewed in a long-term follow-up study. Of 52 patients with FAP amyloidogenic transthyretin Val30Met, 22 patients underwent liver transplantation. We assessed ocular manifestations, including amyloid deposition at the pupillary border, pupillary border with irregularity, vitreous opacities, and glaucoma, in patients who underwent liver transplantation. In addition, we compared the clinical characteristics of vitreous opacities-the most common ocular manifestation of FAP-in patients who underwent liver transplantation and those who did not to determine the effect of transplantation on the progression of ocular amyloidosis. RESULTS Mean time after FAP onset was 10 years and after liver transplantation was 7 years in patients who underwent liver transplantation. All ocular manifestations increased with time after transplantation. Eight patients (36%) developed vitreous opacities and 4 patients (18%) developed glaucoma during follow-up. Mean time from FAP onset to vitreous opacities onset was significantly shorter in patients with early-onset disease who underwent liver transplantation than in those who did not. CONCLUSIONS Patients with FAP who undergo liver transplantation continue to have a long-term risk of severe ocular manifestations, especially vitreous opacities and glaucoma, which can restrict their daily lives, even after liver transplantation.

Manifestations of Transthyretin-Related Familial Amyloidotic Polyneuropathy: Long-Term Follow-Up of Japanese Patients After Liver Transplantation

PurposeTo observe which symptoms of transthyretinrelated familial amyloidotic polyneuropathy (FAP) progressed in the long term after liver transplantation (LT), focusing on cardiac, kidney, and ocular symptoms.MethodsWe reviewed the medical records of 34 Japanese patients with FAP, who underwent LT between 1994 and 2006. The mean follow-up period (±SD) after LT was 9.6 ± 3.4 years. Of the 34 patients, 30 had FAP amyloidogenic transthyretin (ATTR) Val30Met, 1 had FAP ATTR Ser50Ile, and 3 had FAP ATTR Tyr114Cys.ResultsThe 10-year survival rates from the onset of FAP and from the time of LT were 100% and 91.4%, respectively. Progression of ocular amyloidosis was seen in 17 (50%) patients, 13 of whom had de novo amyloid deposits in the vitreous body; progression of cardiac amyloidosis was seen in 10 (29%) patients, 4 of whom had newly granular sparkling echo on echocardiography, and 9 of whom had newly implanted pacemakers or implantable cardioverter-defibrillators. Although the mean serum creatinine levels did not increase significantly after LT in any of the patients, the estimated glomerular filtration rate had decreased significantly by 7 years after LT.ConclusionAlthough LT is life-saving for patients with FAP, we observed progression of the ocular and cardiac symptoms of FAP in a significant number of these patients over the long term after LT.

Changes in pathological and biochemical findings of systemic tissue sites in familial amyloid polyneuropathy more than 10 years after liver transplantation

Objective To elucidate the long-term effects of liver transplantation (LT) on familial amyloid polyneuropathy (FAP). Methods We investigated clinicopathological and biochemical characteristics of systemic tissues in four autopsied cases of FAP patients surviving more than 10 years after LT and seven autopsied cases without LT. For analysing the truncated form of transthyretin (TTR) in amyloid, we also employed specimens from additional 18 FAP patients. Results Several tissue sites such as the heart, tongue and spinal cord had moderate-to-severe amyloid deposits but other tissues showed no or mild amyloid deposition. Those findings seemed similar to those observed in senile systemic amyloidosis (SSA), a sporadic amyloidosis caused by wild-type (WT) TTR. Also, amyloid deposits in systemic tissue sites except for the spinal cord in patients after LT derived mostly from WT TTR secreted from the normal liver grafts. In addition, in non-transplantation patients, proportions of WT TTR seemed to be relatively high in those tissue sites in which patients after LT had severe amyloid deposition, which suggests that WT TTR tends to form amyloid in those tissue sites. Finally, although the truncation of TTR in amyloid deposits did not depend on undergoing LT, we elucidated the truncation of TTR occurred predominantly in patients from non-endemic areas of Japan, where FAP amyloidogenic TTR V30M patients are late onset and low penetrance, compared with patients from an endemic area of Japan. Conclusions FAP may shift to systemic WT TTR amyloid formation after LT, which seems to be similar to the process in SSA. The truncation of TTR in amyloid deposits may depend on some genetic or environmental factors other than undergoing LT.

Incidence and risk factors for new-onset diabetes in living-donor liver transplant recipients.

With the increased number of long‐term survivors after liver transplantation, new‐onset diabetes after transplantation (NODAT) is becoming more significant in patient follow‐up. However, the incidence of new‐onset diabetes after living‐donor liver transplantation (LDLT) has not been well elucidated. The aim of this study was to evaluate the incidence and risk factors for NODAT in adult LDLT recipients at a single center in Japan. A retrospective study was performed on 161 adult patients without diabetes who had been followed up for ≥three months after LDLT. NODAT was defined according to the 2003 American Diabetes Association/World Health Organization guidelines. The recipient‐, donor‐, operation‐, and immunosuppression‐associated risk factors for NODAT were assessed. Overall, the incidence of NODAT was 13.7% (22/161) with a mean follow‐up of 49.8 months. In a multivariate analysis, the identified risk factors for NODAT were donor liver‐to‐spleen (L‐S) ratio (hazard ratio [HR] = 0.022, 95% confidence interval [CI] = 0.001–0.500, p = 0.017), and steroid pulse therapy for acute rejection (HR = 3.320, 95% CI = 1.365–8.075, p = 0.008). In conclusion, donor L‐S ratio and steroid pulse therapy for acute rejection were independent predictors for NODAT in LDLT recipients. These findings can help in screening for NODAT and applying early interventions.

Management of undifferentiated sarcoma of the liver including living donor liver transplantation as a backup procedure

We present the cases of 3 children with huge undifferentiated sarcoma of the liver who were treated with surgical excision including liver transplantation as an option and adjuvant chemotherapy. All 3 patients were males aged 10, 13, and 15 years old. The size of the tumor was 10, 15, and 20 cm in diameter, respectively. The youngest patient is disease free and doing well 43 months after resection. The 13-year-old patient presented with tumor rupture and underwent operation. The primary tumor and the ruptured tissue fragments were removed and he was given postoperative chemotherapy. The patient is disease free and doing well 52 months after surgery. The oldest patient had an unresectable tumor in the hilar region. Preoperative chemotherapy was given but later discontinued owing to severe side effects. He underwent living donor liver transplantation followed by postoperative chemotherapy. The patient had recurrent tumor 24 months after transplantation that was excised at reoperation. He is doing well and is disease free 18 months after the second procedure. Complete removal of the tumor including total hepatectomy and transplantation when indicated and suitable pre- and/or postoperative chemotherapy is an effective treatment for children with undifferentiated sarcoma of the liver.

Biliary Reconstruction for Infantile Living Donor Liver Transplantation: Roux-en-Y Hepaticojejunostomy or Duct-to-Duct Choledochocholedochostomy?

Hepaticojejunostomy is a standard biliary reconstruction method for infantile living donor liver transplantation (LDLT), but choledochocholedochostomy for infants is not generally accepted yet. Ten pediatric recipients weighing no more than 10 kg underwent duct‐to‐duct choledochocholedochostomy (DD) for biliary reconstruction for LDLT. Patients were followed up for a median period of 26.8 months (range: 4.0–79.0 months). The incidence of posttransplant biliary complications for DD was compared with that for Roux‐en‐Y hepaticojejunostomy (RY). No DD patients and 1 RY patient (5%) developed biliary leakage (P > 0.05), and biliary stricture occurred in 1 DD patient (10%) and none of the RY patients (P > 0.05); none of the DD patients and 5 RY patients (25%) suffered from uncomplicated cholangitis after LDLT (P > 0.05), and 1 DD patient (10%) and 2 RY patients (10%) died of causes unrelated to biliary complications. In conclusion, both hepaticojejunostomy and choledochocholedochostomy resulted in satisfactory outcome in terms of biliary complications, including leakage and stricture, for recipients weighing no more than 10 kg. Liver Transpl 14:1761–1765, 2008.

Duct‐to‐duct biliary reconstruction in pediatric living donor liver transplantation

Abstract:  The results of duct‐to‐duct biliary reconstruction in six pediatric patients who received a living donor liver transplant aged from 2 months to 11 yr old are reported. The graft was either entire or a part of the left lateral segments. The orifice of the bile duct of the graft was anastomosed to the recipients’ hepatic duct in an end‐to‐end fashion by interrupted suture using 6–0 absorbable material. A transanastomotic external stent tube (4 Fr) was passed through the stump of the recipients’ cystic duct. Mean time for reconstruction was 24 min. All the recipients survived the operation and reinitiated oral intake on postoperative day 3. There were no early biliary complications. One 5‐yr‐old boy suffered from an anastomotic stenosis 9 months after transplantation. He underwent re‐anastomosis by Roux‐en Y (R‐Y) procedure and recovered uneventfully. Duct‐to‐duct anastomosis in pediatric living donor liver transplantation has benefits while the complication rate is comparable to R‐Y reconstruction.

Reduction of left-lateral segment from living donors for liver transplantation in infants weighing less than 7 kg: Technical aspects and outcome

Shirouzu Y, Ohya Y, Hayashida S, Yoshii T, Asonuma K, Inomata Y. Reduction of left‐lateral segment from living donors for liver transplantation in infants weighing less than 7 kg: Technical aspects and outcome. Pediatr Transplantation 2010: 14:709–714.

Difficulty in sustaining hepatic outflow in left lobe but not right lobe living donor liver transplantation.

Shirouzu Y, Ohya Y, Hayashida S, Asonuma K, Inomata Y. Difficulty in sustaining hepatic outflow in left lobe but not right lobe living donor liver transplantation.
Clin Transplant 2011: 25: 625–632.

Intravital Imaging of Neutrophil Recruitment Reveals the Efficacy of FPR1 Blockade in Hepatic Ischemia-Reperfusion Injury

Neutrophils are considered responsible for the pathophysiological changes resulting from hepatic ischemia-reperfusion (I/R) injury, which is a complication of trauma, shock, liver resection, and transplantation. Recently, evidence is accumulating that formyl-peptide receptor (FPR) signaling constitutes an important danger signal that guides neutrophils to sites of inflammation. This study aimed to investigate dynamic neutrophil recruitment using two-photon laser-scanning microscopy (TPLSM) in response to FPR1 blockade during hepatic I/R. LysM-eGFP mice were subjected to partial warm hepatic I/R. They were pretreated with an FPR1 antagonist, cyclosporine H (CsH), or formyl peptide, fMLF. Liver was imaged after hepatic laser irradiation or I/R using the TPLSM technique. CsH treatment alleviated hepatic I/R injury, as evidenced by decreased serum transaminase levels, reduced hepatocyte necrosis/apoptosis, and diminished inflammatory cytokine, chemokine, and oxidative stress. In contrast, systemic administration of fMLF showed few effects. Time-lapse TPLSM showed that FPR1 blockade inhibited the accumulation of neutrophils in the necrotic area induced by laser irradiation in vivo. In the CsH-treated I/R group, the number and crawling velocity of neutrophils in the nonperfused area were lower than those in the control group. Meanwhile, FPR1 blockade did not affect monocyte/macrophage recruitment. Hepatic I/R promoted the retention of neutrophils and their active behavior in the spleen, whereas CsH treatment prevented their changes. Intravital TPLSM revealed that formyl-peptide–FPR1 signaling is responsible for regulating neutrophil chemotaxis to allow migration into the necrotic area in hepatic I/R. Our findings suggest effective approaches for elucidating the mechanisms of immune cell responses in hepatic I/R.