Ryuhei Hara

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.

Suppression of Choroidal Neovascularization by N-Acetyl-Cysteine in Mice

Purpose: N-acetyl-cysteine (NAC) is a potent antioxidant known to be a precursor of glutathione. The purpose of this study was to investigate the role of NAC in the development of choroidal neovascularization (CNV). Methods: CNV was induced in C57BL/6 mice by laser photocoagulation of the ocular fundus. Mice were injected intraperitoneally with NAC or vehicle alone. The levels of 4-hydoroxy-2-nonenal (4-HNE)-modified protein and nucleus factor (NF)-κB were determined by wester blotting. The recruitment of macrophages and neutrophils after laser injury was analyzed immunohistochemically and in myeloperoxidase (MPO) assays. Enzyme-linked immunosorbent assays (ELISA) were used to measure monocyte chemotactic protein (MCP)-1, CXCL1, vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR)-1, and VEGFR-2. The extent of CNV was evaluated 7 d after laser injury by lectin staining. Results: In NAC-treated mice with laser-induced injuries, the induction of 4-HNE-modified protein after 3 hr and the activation of NF-κB in nuclear extracts after 6 hr were markedly suppressed compared to vehicle-treated mice. Macrophage and neutrophil recruitment were inhibited and the levels of MCP-1, CXCL1, VEGF, and VEGFR-1 were also lower in NAC-treated mice compared to vehicle-treated mice. Furthermore, the extent of CNV induced was significantly lower in NAC-treated compared to vehicle-treated mice (p = 0.027). Conclusions: Our results clearly showed that NAC inhibited indicators of oxidative stress and the activation of NF-κB induced by laser injury, and, consequently, suppressed macrophage and neutrophil infiltration and the development of CNV. This suggests novel preventative and interventional therapeutic strategies for age-related macular degeneration.

Novel Therapy for Transthyretin―related Ocular Amyloidosis: A Pilot Study of Retinal Laser Photocoagulation

OBJECTIVE The occurrence of ocular complications associated with transthyretin-related familial amyloidotic polyneuropathy increases with time, even after liver transplantation, which leads to a halt in the progression of systemic neurologic complications. This study investigated a new strategy to prevent ocular involvements. DESIGN Two interventional case reports. PARTICIPANTS Two patients with familial amyloidotic polyneuropathy who had progressive ocular manifestations. METHODS We used panretinal laser photocoagulation, which damages the retinal pigment epithelium, the main location for synthesis of amyloidogenic transthyretin in ocular tissues, to treat 1 eye of each patient. After laser photocoagulation, we performed general ophthalmic examinations every 3 months for 3 years. MAIN OUTCOME MEASURES Fundus photography, visual acuity, and intraocular pressure. RESULTS Panretinal laser photocoagulation clearly prevented progression of amyloid deposition in the vitreous and on the retinal surface in both cases during 3 years of follow-up. No serious complications occurred. CONCLUSIONS Panretinal laser photocoagulation is a safe and well-known procedure that offers a new treatment option to mitigate ocular manifestations in patients with transthyretin-related familial amyloidotic polyneuropathy.

Long-term relationship between intraocular pressure and visual field loss in primary open-angle glaucoma.

PurposeTo investigate the dependence upon intraocular pressure (IOP) of the progression of visual field defects in eyes with primary open-angle glaucoma (POAG), in which the mean IOP was maintained at ≤21 mm Hg. MethodsThis study involved 100 eyes with POAG, which were followed up for ≥5 years. The mean IOP levels were maintained at ≤21 mm Hg during the follow-up period. The relationship between the IOP and the progression of visual field defects, which was scored using the Advanced Glaucoma Intervention Study criteria, was investigated retrospectively. ResultsCompared with the baseline scores, the visual field defect scores had significantly worsened by the end of the follow-up period (P<0.0001, Wilcoxon paired signed rank test). The change in the visual field defect score (2.5±0.5) in eyes with average IOP levels of ≥16 mm Hg (n=36) was significantly greater (P=0.031, Mann-Whitney U test) than the change (1.3±0.3) in eyes with average IOP levels of <16 mm Hg (n=64). Moreover, IOP of ≥18 mm Hg made a major contribution to the aggravation of visual field defects in eyes with POAG. ConclusionsEyes with POAG and with mean IOP levels maintained at ≤21 mm Hg underwent IOP-dependent progression of their visual field defects. Our results suggest that further IOP lowering would be beneficial in such cases.

Suppression of choroidal neovascularization in lectin-like oxidized low-density lipoprotein receptor type 1-deficient mice

PURPOSE To elucidate the role of the scavenger receptor, lectin-like oxidized low-density lipoprotein receptor type 1 (LOX-1), in the formation of choroidal neovascularization (CNV). METHODS CNV was induced by laser photocoagulation of the ocular fundus in mice. The expression of LOX-1 mRNA and protein after laser injury was determined by real-time RT-PCR and Western blot analysis. Gelatin zymography was used to measure the activity of matrix metalloproteinase (MMP)-2 and pro-MMP-9, and ELISA was used to determine monocyte chemoattractant protein (MCP)-1 and vascular endothelial growth factor (VEGF) levels. At 14 days after laser injury, the extent of CNV was evaluated by fluorescein angiography and lectin staining using confocal microscopy. RESULTS In wild-type mice, the relative expression level of LOX-1 mRNA compared with the control increased significantly 6 hours after laser injury and peaked 12 hours after laser injury (P = 0.011 and P = 0.0006, respectively), and the expression of LOX-1 protein was also detected 1 and 3 days after laser injury. Increases in MMP-2, pro-MMP2, and pro-MMP-9 after laser injury were reduced in LOX-1-deficient mice compared with wild-type mice. At 3 days after laser injury, increases in MCP-1 and VEGF significantly decreased in LOX-1-deficient mice compared with wild-type mice (P = 0.014 and P = 0.001, respectively). Morphometric analyses revealed that the induction of CNV formation was significantly inhibited in LOX-1-deficient mice. CONCLUSIONS These results suggest that LOX-1 plays an important role in the formation of CNV. This scavenging system might thus be a novel therapeutic target for CNV.

Long-Term Outcomes and Complications of Trabeculectomy for Secondary Glaucoma in Patients with Familial Amyloidotic Polyneuropathy

Objective Secondary glaucoma is a serious complication in patients with transthyretin (TTR)-related familial amyloidotic polyneuropathy (FAP). We assessed the long-term outcomes and complications of trabeculectomy with mitomycin C (MMC) for secondary glaucoma associated with FAP. Methods Medical case records of Kumamoto University Hospital were retrospectively reviewed. Twenty-one eyes of 13 patients (10 with FAP ATTR Val30Met; 3 with FAP ATTR Tyr114Cys) underwent trabeculectomy with MMC and follow-up of at least 2 years. The primary outcome measure was Kaplan-Meier survival, with failure of this treatment being defined as an intraocular pressure (IOP) of ≤5 mm Hg or ≥22 mm Hg on two consecutive visits or as additional operations needed to reduce IOP. Secondary outcome measures included complications, bleb characteristics, and additional postoperative interventions required. Results The mean postoperative follow-up period was 5.7 years (range, 2.2–12.7 years). Kaplan-Meier analysis indicated probabilities of success of 0.76, 0.67, and 0.53 at 1, 2, and 3 years after operation, respectively. Significant complications included ocular decompression retinopathy in 7 eyes (33%) and bleb encapsulation in 10 eyes (48%). Twelve eyes (57%) needed additional surgery, such as bleb revision or trabeculectomy with MMC, to reduce IOP. Conclusions Trabeculectomy with MMC may not be optimal for patients with FAP-related glaucoma and may have several significant complications.