Amyloid-Journal of Protein Folding Disorders最新文献

{"title":"A multicentric study of the disease risks and first manifestations in hereditary transthyretin amyloidosis (ATTRv): insights for an earlier diagnosis.","authors":"Violaine Planté-Bordeneuve,&nbsp;Farida Gorram,&nbsp;Malin Olsson,&nbsp;Intissar Anan,&nbsp;Anna Mazzeo,&nbsp;Luca Gentile,&nbsp;Eugenia Cisneros-Barroso,&nbsp;Juan Gonzalez-Moreno,&nbsp;Ines Losada,&nbsp;Marcia Waddington-Cruz,&nbsp;Luiz Felipe Pinto,&nbsp;Yeşim Parman,&nbsp;Pascale Fanen,&nbsp;Flora Alarcon,&nbsp;Gregory Nuel","doi":"10.1080/13506129.2023.2178891","DOIUrl":"https://doi.org/10.1080/13506129.2023.2178891","url":null,"abstract":"<p><strong>Background: </strong>In hereditary transthyretin amyloidosis (ATTRv), early manifestation and age at onset (AO) may vary strikingly. We assessed the disease'risk (penetrance), AO and initial features in ATTRv families to gain insights on the early disease presentation.</p><p><strong>Methods: </strong>Genealogical information, AO and first disease manifestations were collected in ATTRv families, from Sweden, Italy (Sicily), Spain (Mallorca), France, Turkey, Brazil. Penetrance was computed using a non-parametric survival method.</p><p><strong>Results: </strong>We analysed 258 TTRV30M kindreds and 84 carrying six other variants (TTRT49A, F64L, S77Y, S77F, E89Q, I107V). In ATTRV30M families, the earliest disease risk was found at age 20 years in the Portuguese and Mallorcan families and at age 30-35 years, in the French and Swedish groups. The risks were higher in men and in carriers of maternal descent. In families carrying TTR-nonV30M variants, the earliest disease risk ranged from 30 y-o in TTRT49A to 55 y-o in TTRI107V families. Peripheral neuropathy symptoms were the most frequent initial manifestations. Among patients carrying TTRnonV30M variants, about 25% had an initial cardiac phenotype, one third a mixed phenotype.</p><p><strong>Conclusion: </strong>Our work provided solid data on the risks and early features of ATTRv in a spectrum of families to enhance an early diagnosis and treatment.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10418213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A phase 1b dose-escalation study of carfilzomib in combination with thalidomide and dexamethasone in patients with relapsed/refractory systemic immunoglobulin light chain amyloidosis.","authors":"Sriram Ravichandran, Andrew Hall, Matthew Jenner, Mamta Garg, Bhuvan Kishore, Helen Lachmann, Julian Gillmore, Alexandra Pitchford, Jamie B Oughton, Shameem Mahmood, Sajitha Sachchithantham, Philip Hawkins, Sarah Brown, Ashutosh Wechalekar","doi":"10.1080/13506129.2023.2169124","DOIUrl":"10.1080/13506129.2023.2169124","url":null,"abstract":"<p><strong>Introduction: </strong>Proteasome inhibitors are the backbone of AL amyloidosis treatment - bortezomib being most widely used. Carfilzomib is a proteasome inhibitor licenced to treat multiple myeloma; autonomic and peripheral neuropathy are uncommon toxicities with carfilzomib. There is limited data on the use of carfilzomib in AL amyloidosis. Here, we report the results of a phase Ib dose-escalation study of Carfilzomib-Thalidomide-Dexamethasone (KTD) in relapsed/refractory AL amyloidosis.</p><p><strong>Results: </strong>The trial registered 11 patients from 6 UK centres from September 2017 to January 2019; 10 patients received at least one dose of trial treatment. 80 adverse events were reported from 10 patients in the 1^st three cycles. One patient experienced dose-limiting toxicity (acute kidney injury) at a dose of 45 mg/m^2, and another patient had a SAR (fever). Five patients experienced an AE ≥ grade 3. There were no haematologic, infectious, or cardiac AE ≥ grade 3. The overall haematological response rate (ORR) at the end of three cycles of treatment was 60%.</p><p><strong>Conclusion: </strong>Carfilzomib 45 mg/m² weekly can be safely given with thalidomide and dexamethasone. The efficacy and tolerability profile appears comparable to other agents in relapsed AL amyloidosis. These data provide a framework for further studies of carfilzomib combinations in AL amyloidosis.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10041435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Steep increase in the number of transthyretin-positive cardiac biopsy cases in Japan: evidence obtained by the nation-wide pathology consultation for the typing diagnosis of amyloidosis.","authors":"Hironobu Naiki,&nbsp;Aina Yamaguchi,&nbsp;Yoshiki Sekijima,&nbsp;Mitsuharu Ueda,&nbsp;Kenichi Ohashi,&nbsp;Kinta Hatakeyama,&nbsp;Yoshihiko Ikeda,&nbsp;Yoshinobu Hoshii,&nbsp;Yukako Shintani-Domoto,&nbsp;Aya Miyagawa-Hayashino,&nbsp;Hanako Tsujikawa,&nbsp;Jin Endo,&nbsp;Tomio Arai,&nbsp;Yukio Ando","doi":"10.1080/13506129.2023.2180334","DOIUrl":"https://doi.org/10.1080/13506129.2023.2180334","url":null,"abstract":"<p><strong>Background: </strong>In 2019, 2020 and 2022, the Japanese Government approved the use of tafamidis and two technetium-scintigraphies for transthyretin amyloid (ATTR) cardiomyopathy, and announced the patient criteria for tafamidis therapy. In 2018, we had started a nation-wide pathology consultation of amyloidosis.</p><p><strong>Objective: </strong>To reveal the impact of approval of tafamidis and technetium-scintigraphy on the diagnosis of ATTR cardiomyopathy.</p><p><strong>Methods: </strong>Ten institutes participated in this study on the pathology consultation of amyloidosis and shared rabbit polyclonal anti-κ_116-133, anti-λ_118-134, and anti-transthyretin_115-124 antibodies. Proteomic analysis was performed when the typing diagnosis by immunohistochemistry was unavailable.</p><p><strong>Results: </strong>Out of 5400 consultation cases received from April 2018 to July 2022, the type of amyloidosis by immunohistochemistry was determined in 4119 of the 4420 Congo-red positive cases. The incidences of AA, ALκ, ALλ, ATTR, Aβ2M and others were 3.2, 11.3, 28.3, 54.9, 0.6 and 1.8%, respectively. Out of 2208 cardiac biopsy cases received, 1503 cases were ATTR positive. There were 4.0 and 4.9 times more total cases and ATTR-positive cases, respectively, in the last 12 months as compared to the first 12 months.</p><p><strong>Conclusions: </strong>The approval of tafamidis and technetium-scintigraphy raised the awareness of ATTR cardiomyopathy, leading to an upsurge in ATTR-positive cardiac biopsy cases.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10111255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Apolipoprotein A-IV amyloidosis in a cotton-top tamarin (<i>Saguinus oedipus</i>).","authors":"Niki Sedghi Masoud,&nbsp;Susumu Iwaide,&nbsp;Yoshiyuki Itoh,&nbsp;Miki Hisada,&nbsp;Yumi Une,&nbsp;Tomoaki Murakami","doi":"10.1080/13506129.2023.2169603","DOIUrl":"https://doi.org/10.1080/13506129.2023.2169603","url":null,"abstract":"Apolipoprotein A-IV (ApoAIV) amyloidosis is a rare type of systemic amyloidosis characterised by ApoAIV-derived amyloid deposits in the kidney and heart [1,2]. To date, ApoAIV amyloidosis has been reported only in humans and not in animals. In this study, we performed a mass spectrometry-based proteomic analysis on a case of systemic amyloidosis in cotton-top tamarin (Saguinus oedipus) and identified ApoAIV amyloidosis with unique pathological characteristics that differ from humans. A 17-year-old female cotton-top tamarin who died in the Japanese zoo was used for the research. She had a medical history of pulmonary edema, hypothermia, diarrhoea, and loss of energy. Histologically, amyloid deposits in kidneys were severe in the cortical interstitium and glomeruli, but mild in the medulla (Figure 1(a–c)). Severe amyloid deposition was also observed in lamina propria of the intestine (Figure 1(d-f)) and in the space of Disse in the liver (Supplementary Figure 1(m–o)). In the spleen (Figure 1(g-i)),","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10073508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardiac amyloidosis remains significantly underdiagnosed in patients undergoing TAVR: analysis of National Inpatient Sample.","authors":"Dimitrios Terentes-Printzios,&nbsp;Alexios S Antonopoulos,&nbsp;Mohamed Omer,&nbsp;Ioannis Panagiotopoulos,&nbsp;Konstantinos Toutouzas,&nbsp;Konstantinos Tsioufis,&nbsp;Islam Elgendy,&nbsp;Charalambos Vlachopoulos","doi":"10.1080/13506129.2022.2159369","DOIUrl":"https://doi.org/10.1080/13506129.2022.2159369","url":null,"abstract":"Transthyretin cardiomyopathy (ATTR-CM) is among the causes of heart failure with the gravest prognosis. It is estimated that approximately one in four patients with ATTRCM die within 2 years from diagnosis [1]. Recent studies [2,3] have demonstrated that the prevalence of cardiac amyloidosis, mainly wild type ATTR-CM, is as high as 15% in patients with severe aortic stenosis undergoing transcatheter aortic valve replacement (TAVR). In a meta-analysis of all published evidence, we have recently shown that the pooled estimates for the prevalence of cardiac amyloidosis in TAVR is 11.2%, 95% confidence intervals (CI) 9.4–13.3% [1]. Whilst awareness for this condition is increasing, there are still concerns that ATTR-CM remains underdiagnosed and undertreated [4]. In the present study, we sought to explore the prevalence of cardiac amyloidosis cases among patients undergoing TAVR in the United States (U.S). We used data from the U.S. National Inpatient Sample (NIS) from October 2015 to the end of 2019 (Figure 1(A)) [5]. First, we identified hospital admissions with performed TAVR operations using the following ICD-10-PCS Procedure Codes: ‘02RF37H’, ‘02RF38H’, ‘02RF3J’, ‘02RF3KH’, ‘02RF37Z’, ‘02RF38Z’, ‘02RF3JZ’, ‘02RF3KZ’). Then we searched for all hospitalisations with a diagnosis of amyloidosis based on the ICD-10-CM codes (E850, E851, E852, E853, E854, E858, E8582, E8589, E859). In total we identified n1⁄4 45,660 hospital admissions that underwent a TAVR procedure. Extrapolating evidence from our recent meta-analysis on the estimates for cardiac amyloidosis in TAVR, we estimated that the incident amyloidosis cases in this population would be expected to be 5114 cases (95%CI: between 4292 and 6073). However, in the NIS data sample only n1⁄4 47 hospitalised TAVR cases had an ICD-10-CM code relevant to amyloidosis (Figure 1(B)). This accounts for only 1% of the expected patient sample with concomitant severe aortic stenosis undergoing TAVR and potentially latent amyloidosis (n1⁄4 5114). Patients with amyloidosis were less likely to be females, with a non-significant trend for being younger, undergoing non-elective TAVR procedure, having a longer length of in-hospital stay and higher hospitalisation costs (Figure 1(C)) compared to TAVR cases without concomitant amyloidosis; there were no significant differences in the need for permanent pacemaker implantation. Importantly, in-hospital mortality rates were higher in CA amyloidosis patients (4.3% vs. 1.4%, adjusted p1⁄4 0.086, Figure 1(D)). The NIS approximates a 20% stratified sample of discharges from U.S. community hospitals. Extrapolation of the NIS data to all U.S hospitalisations, would yield a statistically significant association between amyloidosis and TAVR in-hospital mortality (unadjusted OR 1⁄4 3.04, 95%CI 1.610–5.73, p< 0.001, and adjusted OR 2.84, 95%CI 1.50–5.38, p< 0.001 after adjustment for age, sex, and nonelective status of the procedure, Figure 1(E)). According to these findings only ","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9783775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phenotype and clinical outcomes of Glu89Lys hereditary transthyretin amyloidosis: a new endemic variant in Spain.","authors":"Fernando de Frutos,&nbsp;Juan Pablo Ochoa,&nbsp;Cristina Gómez-González,&nbsp;David Reyes-Leiva,&nbsp;Juan I Aróstegui,&nbsp;Carlos Casasnovas,&nbsp;Roberto Barriales-Villa,&nbsp;Teresa Sevilla,&nbsp;Esther Gonzalez-Lopez,&nbsp;Elvira Ramil,&nbsp;Lucia Galan,&nbsp;Jose González-Costello,&nbsp;Ana García-Álvarez,&nbsp;Ricard Rojas-Garcia,&nbsp;Maria Angeles Espinosa,&nbsp;Pablo Garcia-Pavia","doi":"10.1080/13506129.2022.2142110","DOIUrl":"https://doi.org/10.1080/13506129.2022.2142110","url":null,"abstract":"<p><strong>Background: </strong>The p.Glu109Lys variant (Glu89Lys) is a rare cause of hereditary transthyretin amyloidosis (ATTRv) for which clinical spectrum remains unresolved. We sought to describe the clinical characteristics and outcomes of ATTR Glu89Lys amyloidosis and assess a potential founder effect in Spain.</p><p><strong>Methods: </strong>Patients with the p.Glu109Lys ATTRv variant from 14 families were recruited at 7 centres. Demographics, complementary tests and clinical course were analysed. Haplotype analysis was performed in 7 unrelated individuals.</p><p><strong>Results: </strong>Thirty-eight individuals (13 probands, mean age 40.4 ± 13.1 years) were studied. After median follow-up of 5.1 years (IQR 1.7-9.6), 7 patients died and 7 required heart transplantation (median age at transplantation 50.5 years). Onset of cardiac and neurological manifestations occurred at a mean age of 48.4 and 46.8 years, respectively. Median survival from birth was 61.6 years and no individual survived beyond 65 years. Patients treated with disease-modifying therapies exhibited better prognosis (<i>p</i> < 0.001). Haplotype analysis revealed a common origin from an ancestor who lived ∼500 years ago in southeast Spain.</p><p><strong>Conclusions: </strong>Glu89Lys ATTRv is a <i>TTR</i> variant with a founder effect in Spain. It is associated with near complete penetrance, early onset and mixed cardiac and neurologic phenotype. Patients have poor prognosis, particularly if not treated with disease-modifying therapies.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10161675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Macrophages in the reticuloendothelial system inhibit early induction stages of mouse apolipoprotein A-II amyloidosis.","authors":"Hiroki Miyahara,&nbsp;Jian Dai,&nbsp;Ying Li,&nbsp;Xiaoran Cui,&nbsp;Hibiki Takeuchi,&nbsp;Naomi Hachiya,&nbsp;Fuyuki Kametani,&nbsp;Masahide Yazaki,&nbsp;Masayuki Mori,&nbsp;Keiichi Higuchi","doi":"10.1080/13506129.2022.2153667","DOIUrl":"https://doi.org/10.1080/13506129.2022.2153667","url":null,"abstract":"<p><p>Amyloidosis refers to a group of degenerative diseases that are characterized by the deposition of misfolded protein fibrils in various organs. Deposited amyloid may be removed by a phagocyte-dependent innate immune system; however, the precise mechanisms during disease progression remain unclear. We herein investigated the properties of macrophages that contribute to amyloid degradation and disease progression using inducible apolipoprotein A-II amyloidosis model mice. Intravenously injected AApoAII amyloid was efficiently engulfed by reticuloendothelial macrophages in the liver and spleen and disappeared by 24 h. While cultured murine macrophages degraded AApoAII <i>via</i> the endosomal-lysosomal pathway, AApoAII fibrils reduced cell viability and phagocytic capacity. Furthermore, the depletion of reticuloendothelial macrophages before the induction of AApoAII markedly increased hepatic and splenic AApoAII deposition. These results highlight the physiological role of reticuloendothelial macrophages in the early stages of pathogenesis and suggest the maintenance of phagocytic integrity as a therapeutic strategy to inhibit disease progression.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10144784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pulmonary function tests reveal unrecognised lung dysfunction and have independent prognostic significance in patients with systemic AL amyloidosis.","authors":"Georgia Trakada,&nbsp;Despina Fotiou,&nbsp;Anastasios Kallianos,&nbsp;Foteini Theodorakakou,&nbsp;Magdalini Migkou,&nbsp;Maria Gavriatopoulou,&nbsp;Nikolaos Kanellias,&nbsp;Panagiotis Malandrakis,&nbsp;Ioannis Ntanasis-Stathopoulos,&nbsp;Evangelos Eleutherakis-Papaiakovou,&nbsp;Ioanna Dialoupi,&nbsp;Evangelos Terpos,&nbsp;Meletios A Dimopoulos,&nbsp;Efstathios Kastritis","doi":"10.1080/13506129.2022.2136519","DOIUrl":"https://doi.org/10.1080/13506129.2022.2136519","url":null,"abstract":"<p><strong>Background: </strong>Lung involvement in AL amyloidosis is not very common, but post-mortem data and retrospective studies suggest it is likely underrecognized.</p><p><strong>Aim: </strong>To perform a comprehensive evaluation of lung function with pulmonary function tests (PFTs) in patients with newly diagnosed AL amyloidosis.</p><p><strong>Methods: </strong>A prospective, non-interventional study of 139 consecutive patients with newly diagnosed AL amyloidosis.</p><p><strong>Results: </strong>PFTs indicated normal breathing physiology in 68% of patients, obstructive in 9% and restrictive in 23%; the latter was associated with worse survival (28.6 vs 76 months for obstructive/normal physiology, <i>p</i> = 0.002) and remained significant after adjustment for Mayo stage and abnormal chest-CT. Forced vital capacity <80% of predicted value, forced expiratory volume <80% of predicted value, and carbon monoxide diffusion capacity <70% were independently associated with poorer survival. Respiratory muscle strength (as assessed by maximal expiratory (Pe) and inspiratory (Pi) pressure) was affected in most patients (64% had Pi < 55% and 57% had Pe < 70% of predicted values). Pe% was an independent prognostic factor for survival (HR: 0.984 per 1% unit increase, <i>p</i> = 0.007).</p><p><strong>Conclusions: </strong>Pulmonary dysfunction, as assessed with PFTs, is common and underrecognized in patients with systemic AL amyloidosis, with significant prognostic and potentially therapeutic implications, independent of the degree of cardiac dysfunction or chest-CT findings.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9785342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A second case of liraglutide-type localised amyloidosis.","authors":"Sara Muhammad,&nbsp;Ellen D McPhail,&nbsp;W Oliver Tobin,&nbsp;Surendra Dasari,&nbsp;Jason Theis,&nbsp;Julie A Vrana,&nbsp;Elie Naddaf","doi":"10.1080/13506129.2022.2151889","DOIUrl":"https://doi.org/10.1080/13506129.2022.2151889","url":null,"abstract":"Amyloidosis is characterised by extracellular deposition of proteinaceous fibrils, disrupting tissue structure and function. There are at least 36 different types of amyloid, and correct identification of the specific amyloid precursor protein is of paramount importance, as therapy varies dramatically depending on the amyloid type. The most common amyloid types encountered in peripheral nerves are AL (immunoglobulin light chain) and ATTR (transthyretin) [1]. Iatrogenic amyloidosis is a form of localised amyloidosis, caused by the repetitive injection of protein medications, such as insulin [2]. A 78-year-old male, with a history of well-controlled diabetes mellitus, presented with a 30-year history of bilateral foot soreness and numbness. Six months prior to the presentation, he developed intermittent burning and a hot/cold sensation in his feet which spontaneously improved. He also reported a 15-year history of nonradiating low back pain. He had no weakness, weight loss, orthostatic light-headedness, or bowel or bladder dysfunction. Other family members have reported similar sensory symptoms. Neurological examination was remarkable for decreased pinprick sensation from the mid-shin down to the toes, and mildly decreased hot temperature sensation in the right foot. Reflexes were decreased at the right patella, absent at the left patella and bilateral ankles. Motor and gait examination were normal. Nerve conduction studies/electromyography demonstrated mild bilateral old or chronic L5 radiculopathies with no evidence of ongoing denervation, and no evidence of a large fibre peripheral neuropathy. Thermoregulatory sweat test showed no evidence of a small fibre neuropathy either. However, serologic evaluation, performed to screen for potential peripheral neuropathy causes prior to our evaluation, showed a triclonal gammopathy of uncertain significance (IgG j, IgG k and IgA j). Congo red stain performed on an abdominal fat aspirate was positive for amyloid (Figure 1), raising the possibility of systemic amyloidosis. The patient had TTR sequencing which revealed no mutation. Upon questioning about insulin injections, known to cause focal amyloid deposits, the patient acknowledged using liraglutide 0.6mg subcutaneously once daily. Typing of the amyloid deposit by mass spectrometry-based proteomics (liquid chromatography with tandem mass spectrometry; LC-MS-MS) using previously published methods confirmed the presence of liraglutide-type amyloid deposit (Figure 1) [3]. Immunohistochemical studies were not performed because the specimen was a fat aspirate and hence, paraffin-embedded samples were not available. Liraglutide is an acylated glucagon-like peptide-1 analogue that is administered as a subcutaneous injection for the treatment of type 2 diabetes mellitus. To date, a single case of liraglutide-type amyloidosis has been reported [4]. Liraglutide should be considered as a potential amyloidogenic agent. Our case highlights the importance of","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9786739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Relationship of binding-site occupancy, transthyretin stabilisation and disease modification in patients with tafamidis-treated transthyretin amyloid cardiomyopathy.","authors":"David A Tess,&nbsp;Tristan S Maurer,&nbsp;Zhenhong Li,&nbsp;Christine Bulawa,&nbsp;James Fleming,&nbsp;Amy T Moody","doi":"10.1080/13506129.2022.2145876","DOIUrl":"https://doi.org/10.1080/13506129.2022.2145876","url":null,"abstract":"<p><strong>Background: </strong>Tafamidis inhibits progression of transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) by binding TTR tetramer and inhibiting dissociation to monomers capable of denaturation and deposition in cardiac tissue. While the phase 3 ATTR-ACT trial demonstrated the efficacy of tafamidis, the degree to which the approved dose captures the full potential of the mechanism has yet to be assessed.</p><p><strong>Methods: </strong>We developed a model of dynamic TTR concentrations in plasma to relate TTR occupancy by tafamidis to TTR stabilisation. We then developed population pharmacokinetic-pharmacodynamic models to characterise the relationship between stabilisation and measures of disease progression.</p><p><strong>Results: </strong>Modelling individual patient data of tafamidis exposure and increased plasma TTR confirmed that single-site binding provides complete tetramer stabilisation <i>in vivo</i>. The approved dose was estimated to reduce unbound TTR tetramer by 92%, and was associated with 53%, 56% and 49% decreases in the rate of change in NT-proBNP, KCCQ-OS, and six-minute walk test disease progression measures, respectively. Simulating complete TTR stabilisation predicted slightly greater reductions of 58%, 61% and 54%, respectively.</p><p><strong>Conclusions: </strong>These findings support the value of TTR stabilisation as a clinically beneficial treatment option in ATTR-CM and the ability of tafamidis to realise nearly the full therapeutic benefit of this mechanism.</p><p><strong>Clinicaltrials.gov identifier: </strong>NCT01994889.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10161693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}