Search

Introduction. A clinical case of an 80-year-old patient with clinical and instrumental manifestations of amyloidosis caused by the deposition of non-mutant (“wild type”) transthyretin (Amyloidosis “wild type” TransThyRetin, ATTRwt) is described. A special feature of this case was the diagnosis of amyloidosis at the same time as the identification of symmetrical polyarthritis.Aim. To present an example of successful diagnosis and timely treatment of ATTRwt amyloidosis.Materials and methods. Male patient (80 years old) consulted a rheumatologist in an outpatient clinic with complaints of weakness and pain in the muscles of the upper and lower extremities, swelling and soreness of both wrist joints; with manifestations of multiple tunnel syndromes (ulnar canal, Guyon canals, bilateral carpal tunnel syndrome). In addition, the patient had a heart involvement which appeared as left ventricle hypertrophy, paroxysmal form of atrial fibrillation, chronic heart failure with preserved ejection fraction, intraventricular conduction defect and low QRS voltage. Due to the presence of cardiac manifestations along with neuropathy, transthyretinic amyloidosis was suspected.Results. Polyneuropathy was confirmed by the results of electroneuromyography. AL-amyloidosis (immunoglobulin Light chain Amyloidosis) is excluded due to the absence of monoclonal proteins in the blood. The diagnosis was confirmed by the results of scintigraphy with with labeled technetium-99m pyrophosphate. Intensive accumulation of radiopharmaceutical was detected in the myocardium of the left ventricle. The study also confirmed the presence of polyarthritis, manifested by increased accumulation, in the area of the I metatarsophalangeal joint on the left, both wrist, shoulder and knee joints. The hereditary nature of ATTR amyloidosis was excluded by the results of genetic analysis, which did not reveal mutations in the transthyretin gene. The singularity of this case was in development of a symmetrical polyarthritis during amyloidosis manifestation. Pathogenetic therapy with tafamidis was initiated. Arthritis regressed after starting treatment with methotrexate.Conclusion. Transthyretin amyloidosis is a chronic progressive life-threatening disease caused by the formation and deposition of transthyretin-derived amyloid fibrils. The variety of amyloid tropicity to various organs and tissues leads to it phenotypic heterogeneity, which makes it difficult to make a diagnosis on early stages. However, the detection of «red flags» symptoms signaling the presence of transthyretin amyloidosis can shorten the time before initiation of targeted treatment, contributing to the improvement of the patient’s quality of life.

Extracellular aggregates of wild-type human transthyretin are associated with heart diseases such as wild-type transthyretin (TTR)-derived amyloidosis (ATTR-wt). Due to their strategic location, cardiac fibroblasts act as sentinel cells that sense injury and activate the inflammasome. No studies of the effects of TTR amyloid aggregation on the secretion of inflammatory factors by primary human cardiac fibroblasts (hCFs) have been reported yet. The intracellular internalization of TTR aggregates, which correspond to the early stage of ATTR-wt, were determined using immunofluorescence and Western blotting of cell lysates. A further objective of this study was to analyze the secretion of inflammatory factors by hCFs after analysis of TTR amyloid aggregation using X-MAP® Luminex Assay techniques. We show that TTR aggregates are internalized in hCFs and induce the secretion of both Brain Natriuretic Peptide (BNP) and N-terminal pro B-type Natriuretic Peptide(NT-proBNP). Also, pro-inflammatory mediators such as interleukin-6 (IL-6) and IL-8 are secreted without significant changes in the levels of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). In conclusion, these findings suggest that IL-6 and IL-8 play important roles in the development of ATTR-wt, and indicate that IL-6 in particular could be a potentially important therapeutic target in patients with ATTR-wt. • TTR aggregates induce the secretion of both Brain Natriuretic Peptide and N-terminal pro B-type Natriuretic Peptide. • TTR aggregates induce pro-inflammatory mediators such as interleukin-6 and IL-8..TTR aggregates don't change in the levels of matrix metalloproteinases and tissue inhibitors of metalloproteinases. • IL-6 in particular could be a potentially important therapeutic target in patients with TTRwt during the early stages of the disease. [ABSTRACT FROM AUTHOR]

Familial amyloidotic polyneuropathy (FAP) is caused by a mutation in the transthyretin (TTR) gene. In addition, deposition of wild-type TTR can cause senile systemic amyloidosis (SSA). To date, we have produced several transgenic mouse models for FAP and SSA by introducing TTR genes with different promoters or mutations. However, mouse TTR can associate with human TTR to produce hybrid tetramers in transgenic mice. Thus, these transgenic mice cannot be used to test the efficacy of a new therapy. In this study, we attempted to construct an optimized mouse model to verify a new therapy. The TTR gene consists of 4 exons and 3 introns. We prepared two gRNAs, one for the exon 1 and the other for exon 4, and a single donor vector carrying the whole TTR gene in which mouse exons were replaced with human exons. Using these vectors, we produced a TTR exon-humanized mouse with human exons and mouse introns using genome editing technology. These TTR exon-humanized mice showed normal TTR expression patterns in terms of serum TTR level and spatial specificity. These TTR exon-humanized mice will be useful for devising new treatment methods for FAP, including gene therapy. • Transgenic mouse models for FAP cannot be used to test the efficacy of a new therapy. • TTR exon-humanized mice were created genome editing technology. • In these mice only mouse TTR exons were replaced by the corresponding human exons. • These TTR exon-humanized mice showed normal TTR expression patterns. [ABSTRACT FROM AUTHOR]

IntroductionAmyloidosis derived from transthyretin (TTR) molecules is typically caused by mutations of the TTR gene.MethodsWe describe an elderly patient with a severe length-dependent polyneuropathy that unexpectedly proved to be caused by wild-type transthyretin amyloidosis.ResultsThe diagnosis was made by muscle biopsy, because no amyloid deposits were found in the biopsied nerve segment. Most cases of wild-type transthyretin amyloidosis occur in elderly patients with cardiomyopathy, but a few cases of polyneuropathy have been reported.ConclusionsThis entity is especially noteworthy in light of emerging treatment options for hereditary transthyretin amyloidosis, which are likely to also be beneficial in wild-type disease.

Transthyretin (TTR) tetramer dissociation is rate limiting for aggregation and subunit exchange. Slowing of TTR tetramer dissociation via kinetic stabiliser binding slows cardiomyopathy progression. Quadruplicate subunit exchange comparisons of the drug candidate AG10, and the drugs tolcapone, diflunisal, and tafamidis were carried out at 1, 5, 10, 20 and 30 µM concentrations in 4 distinct pooled wild type TTR (TTRwt) human plasma samples. These experiments reveal that the concentration dependence of the efficacy of each compound at inhibiting TTR dissociation was primarily determined by the ratio between the stabiliser's dissociation constants from TTR and albumin, which competes with TTR to bind kinetic stabilisers. The best stabilisers, tafamidis (80 mg QD), AG10 (800 mg BID), and tolcapone (3 x 100 mg over 12 h), exhibit very similar kinetic stabilisation at the plasma concentrations resulting from these doses. At a 10 µM plasma concentration, AG10 is slightly more potent as a kinetic stabiliser vs. tolcapone and tafamidis (which are similar), which are substantially more potent than diflunisal. Dissociation of TTR can be limited to 10% of its normal rate at concentrations of 5.7 µM AG10, 10.3 µM tolcapone, 12.0 µM tafamidis, and 188 µM diflunisal. The potency similarities revealed by our study suggest that differences in safety, adsorption and metabolism, pharmacokinetics, and tissue distribution become important for kinetic stabiliser clinical use decisions. [ABSTRACT FROM AUTHOR]

Rate-limiting dissociation of the tetrameric protein transthyretin (TTR), followed by monomer misfolding and misassembly, appears to cause degenerative diseases in humans known as the transthyretin amyloidoses, based on human genetic, biochemical and pharmacologic evidence. Small molecules that bind to the generally unoccupied thyroxine binding pockets in the native TTR tetramer kinetically stabilize the tetramer, slowing subunit dissociation proportional to the extent that the molecules stabilize the native state over the dissociative transition state—thereby inhibiting amyloidogenesis. Herein, we use previously reported structure-activity relationship data to develop two semi-quantitative algorithms for identifying the structures of potent and selective transthyretin kinetic stabilizers/amyloidogenesis inhibitors. The viability of these prediction algorithms, in particular the more robust in silico docking model, is perhaps best validated by the clinical success of tafamidis, the first-in-class drug approved in Europe, Japan, South America, and elsewhere for treating transthyretin aggregation-associated familial amyloid polyneuropathy. Tafamidis is also being evaluated in a fully-enrolled placebo-controlled clinical trial for its efficacy against TTR cardiomyopathy. These prediction algorithms will be useful for identifying second generation TTR kinetic stabilizers, should these be needed to ameliorate the central nervous system or ophthalmologic pathology caused by TTR aggregation in organs not accessed by oral tafamidis administration. [ABSTRACT FROM AUTHOR]

Background:Wild-type transthyretin amyloidosis (ATTRwt) is an age-related life-threatening condition. Prognosis is mainly dependent on cardiac involvement. Other organs and tissues may be affected. Their early recognition may increase awareness of physicians and positively affects the prognosis. Presbycusis is another age-related disorder. Whether this disease is associated to ATTRwt amyloidosis is unknown. Methods:Sixteen consecutive patients with confirmed diagnosis of ATTRwt amyloidosis at the Mondor Amyloidosis Network, France, underwent otoscopy and audiological tests including pure tone audiometry, speech reception threshold and speech discrimination score. Results:The mean age was 79 ± 5 years. All were male with an NYHA average of 2.5 ± 0.8. All the patients had sensorineural hearing loss that seemed to preexist to cardiac disorder with greater severity than expected for their age. For speech discrimination test, the mean speech reception threshold was 28 ± 15 dB and the mean speech discrimination score was 68 ± 16 at 40 dB. Ten patients (62.5%) failed to recognize 100% of the words. Compared to age-related expectations according to statistical distribution (ISO), hearing loss included all frequencies and was more severe in patients with ATTRwt amyloidosis. Conclusions:These findings suggest that amyloid deposits could infiltrate the various anatomical structures of the inner ear. Description of specific audiologic pattern of ATTRwt amyloidosis might be proposed as a “red flag” and could help for early identification of patients who may be at high risk of ATTRwt amyloidosis as specific treatments are available. [ABSTRACT FROM AUTHOR]

Background: Wild-type transthyretin cardiac amyloidosis (ATTRwt) is increasingly recognized as an important cause of heart failure.Objectives: The purpose of this study was to determine the natural history of ATTRwt and the predictors of survival.Methods: We retrospectively reviewed patients diagnosed with ATTRwt at the Mayo Clinic through 2013 and recorded clinical data and survival data. Factors affecting overall survival (OS) were identified, and a prognostic staging system was developed.Results: The median age of the 360 patients diagnosed before death was 75 years (range: 47 to 94 years), and 91% were male. Presenting signs and symptoms included dyspnea or heart failure in 67% and atrial arrhythmias in 62%. Median OS from diagnosis was 3.6 years and did not change over time. Multivariate predictors of mortality included age, ejection fraction, pericardial effusion, N-terminal pro-B-type natriuretic peptide, and troponin T. A staging system was developed that used thresholds of troponin T (0.05 ng/ml) and N-terminal pro-B-type natriuretic peptide (3,000 pg/ml). The respective 4-year OS estimates were 57%, 42%, and 18% for stage I (both values below cutoff), stage II (one above), and stage III (both above), respectively. Stage III patients were at an increased risk of mortality after adjustment for age and sex compared with stage I patients (hazard ratio: 3.6; p < 0.001).Conclusions: The natural history of ATTRwt is poor. We report a novel cardiac biomarker staging system that enables risk stratification in an era of emerging treatment strategies. [ABSTRACT FROM AUTHOR]

Transthyretin (TTR) transports the retinol-binding protein-vitamin A complex and is a minor transporter of thyroxine in blood. Its tetrameric structure undergoes rate-limiting dissociation and monomer misfolding, enabling TTR to aggregate or to become amyloidogenic. Mutations in the TTR gene generally destabilize the tetramer and/or accelerate tetramer dissociation, promoting amyloidogenesis. TTR-related amyloidoses are rare, fatal, protein-misfolding disorders, characterized by formation of soluble aggregates of variable structure and tissue deposition of amyloid. The TTR amyloidoses present with a spectrum of manifestations, encompassing progressive neuropathy and/or cardiomyopathy. Until recently, the only accepted treatment to halt progression of hereditary TTR amyloidosis was liver transplantation, which replaces the hepatic source of mutant TTR with the less amyloidogenic wild-type TTR. Tafamidis meglumine is a rationally designed, non-NSAID benzoxazole derivative that binds with high affinity and selectivity to TTR and kinetically stabilizes the tetramer, slowing monomer formation, misfolding, and amyloidogenesis. Tafamidis is the first pharmacotherapy approved to slow the progression of peripheral neurologic impairment in TTR familial amyloid polyneuropathy. Here we describe the mechanism of action of tafamidis and review the clinical data, demonstrating that tafamidis treatment slows neurologic deterioration and preserves nutritional status, as well as quality of life in patients with early-stage Val30Met amyloidosis. [ABSTRACT FROM AUTHOR]

Background: Systemic wild-type ATTR (ATTRwt) amyloidosis is a prevalent aging-related disorder. However, a limited number of systemic ATTRwt amyloidosis patients have been diagnosed antemortem, and therefore, the prevalence of ATTRwt is underestimated. Here, we investigated clinical findings of a series of systemic ATTRwt amyloidosis patients with antemortem diagnosis. Methods: Thirty-one consecutive patients diagnosed with systemic ATTRwt amyloidosis at Shinshu University Hospital were included in this study. Systemic ATTRwt amyloidosis was diagnosed based on proven ATTR amyloid deposition in biopsy specimens and confirmation of wild-type TTR genotype. Results: The systemic ATTRwt amyloidosis patients consisted of 24 men and seven women, and mean age of onset was 69.8 ± 9.0 years. The most common initial symptom was carpal tunnel syndrome (CTS, 17 patients), followed by heart failure symptoms (14 patients). The mean age at diagnosis was 74.5 ± 8.3 years and the duration of illness from onset to diagnosis was 5.4 ± 4.4 years. Cardiogenic embolism and renal dysfunction are also frequently seen during the course of the disease. Conclusions: CTS is the most common initial symptom of systemic ATTRwt amyloidosis. Our results suggest the possibility of systemic ATTRwt amyloidosis diagnosis at an early stage by carefully examining patients with CTS. [ABSTRACT FROM PUBLISHER]

Objective: A nationwide survey on systemic wild-type ATTR (ATTRwt) amyloidosis was conducted to elucidate the frequency, clinical picture and possible diagnostic issues of ATTRwt amyloidosis in Japan. Methods: A questionnaire was sent to 4629 clinical departments across Japan. A total of 2341 (50.6%) responses were returned completed for further analysis. Results: Fifty-one patients with ATTRwt amyloidosis (82% male) were identified between January 2012 and December 2014. The study subjects were identified in 11 departments at 10 institutes. The mean age of onset and diagnosis were 71.6 and 73.6 years, respectively. The main clinical findings were cardiac failure (76%), cardiac conduction defects/arrhythmia (59%), renal dysfunction (49%), carpal tunnel syndrome (45%) and spinal canal stenosis (22%). Conclusions: ATTRwt amyloidosis is diagnosed in a limited number of institutes in Japan and is therefore considered to be underdiagnosed. [ABSTRACT FROM AUTHOR]

Aims Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous clinical syndrome with multiple underlying causes.Wild-type transthyretin (TTR) amyloidosis (ATTRwt) is an underdiagnosed cause of HFpEF that might benefit from new specific treatments. ATTRwt can be diagnosed non-invasively by 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) scintigraphy. We sought to determine the prevalence of ATTRwt among elderly patients admitted due to HFpEF. Methods and results We prospectively screened all consecutive patients ≥60 years old admitted due to HFpEF [left ventricular (LV) ejection fraction ≥50%] with LV hypertrophy (≥12mm).All eligible patientswere offered a 99mTc-DPD scintigraphy. The study included 120 HFpEF patients (59% women, 82±8 years). A total of 16 patients (13.3%; 95% confidence interval: 7.2-19.5) showed a moderate-to-severe uptake on the 99mTc-DPD scintigraphy. All patients with a positive scan underwent genetic testing of the TTR gene, and no mutationswere found. An endomyocardial biopsywasperformed in four patients, confirming ATTRwt inall cases. There were no differences in age, gender, hypertension, diabetes, coronary artery disease, or atrial fibrillation between ATTRwt patients and patients with other HFpEF forms. Although patients with ATTRwt exhibited higher median N-terminal pro-brain natriuretic peptide (6467 vs. 3173 pg/L; P = 0.019), median troponin I (0.135 vs. 0.025 mg/L; P, 0.001), mean LV maximal wall thickness (17+3.4 vs. 14±2.5 mm; P = 0.001), rate of pericardial effusion (44 vs. 19%; P = 0.047), and rate of pacemakers (44 vs. 12%; P = 0.004), clinical overlap between ATTRwt and other HFpEF forms was high. Conclusion ATTRwt is an underdiagnosed disease that accounts for a significant number (13%) of HFpEF cases. The effect of emerging TTR-modifying drugs should be evaluated in these patients. [ABSTRACT FROM AUTHOR]

Placebo-controlled clinical trials are useful for identifying the dose of a drug candidate that produces a meaningful clinical response in a patient population. Currently, Pfizer, Inc. is enrolling a 400-person clinical trial to test the efficacy of 20 or 80 mg of tafamidis to ameliorate transthyretin (TTR)-associated cardiomyopathy using clinical endpoints. Herein, we provide guidance for how to optimize the dose of tafamidis for each WT TTR cardiomyopathy patient using its mechanism of action as the key readout, i.e. we identify the dose of tafamidis that maximally kinetically stabilizes TTR in the blood. Tetramer dissociation is rate limiting for TTR aggregation, which appears to drive the pathology of the TTR amyloidoses. Hence, we measure the TTR tetramer dissociation rate (kinetic stability) in the patient's plasma as a function of tafamidis dose to optimize the dose employed to maximize kinetic stability. Historical data tell us that a subset of patients exhibiting higher tafamidis plasma concentrations are maximally kinetically stabilized at the 20-mg tafamidis dose, whereas the patient studied herein required a 60 mg once daily dose to achieve maximum kinetic stabilization. We anticipate that establishing the dose of tafamidis that achieves maximal TTR kinetic stabilization will translate into a maximal clinical effect, but that remains to be demonstrated. [ABSTRACT FROM AUTHOR]

Transthyretin-cardiac amyloidoses (ATTR-CA) are an underdiagnosed but increasingly recognized cause of heart failure. Extracellular deposition of fibrillary proteins into tissues due to a variety of inherited transthyretin mutations in ATTRm or due to advanced age in ATTRwt eventually leads to organ failure. In the heart, amyloid deposition causes diastolic dysfunction, restrictive cardiomyopathy with progressive loss of systolic function, arrhythmias, and heart failure. While traditional treatments have consisted of conventional heart failure management and supportive care for systemic symptoms, numerous disease-modifying therapies have emerged over the past decade. From organ transplantation to transthyretin stabilizers (diflunisal, tafamidis, AG-1), TTR silencers (ALN-ATTR02, ISIS-TTR(Rx)), and degraders of amyloid fibrils (doxycycline/TUDCA), the potential for effective transthyretin amyloid therapy is greater now than ever before. In light of these multiple agents under investigation in human clinical trials, clinicians should be familiar with the systemic cardiac amyloidoses, their differing pathophysiology, natural histories, and unique treatment strategies. [ABSTRACT FROM AUTHOR]

Cardiac amyloidosis (CA) is often misdiagnosed because of both physician-related and disease-related reasons including: fragmented knowledge among different specialties and subspecialties, shortage of centres and specialists dedicated to disease management, erroneous belief it is an incurable disease, rarity of the condition, intrinsic phenotypic heterogeneity, genotypic heterogeneity in transthyretin-related forms and the necessity of target organ tissue histological diagnosis in the vast majority of cases. Pitfalls, incorrect beliefs and deceits challenge not only the path to the diagnosis of CA but also the precise identification of aetiological subtype. The awareness of this condition is the most important prerequisite for the management of the risk of underdiagnoses and misdiagnosis. Almost all clinical, imaging and laboratory tests can be misinterpreted, but fortunately each of these diagnostic steps can also offer diagnostic 'red flags' (i.e. highly suggestive findings that can foster the correct diagnostic suspicion and facilitate early, timely diagnosis). This is especially important because outcomes in CA are largely driven by the severity of cardiac dysfunction and emerging therapies are aimed at preventing further amyloid deposition. [ABSTRACT FROM AUTHOR]

Background. Senile systemic amyloidosis (SSA) derived from wild-type transthyretin is a fairly common condition of old individuals, particularly men. The main presentation is by cardiac involvement, which can lead to severe restrictive cardiomyopathy. SSA is, however, a systemic disease, and amyloid deposits may appear in many other tissues but are thought to be without clinical symptoms outside the heart. Amyloid is a very common finding in cartilage and ligaments of elderly subjects, and transthyretin has been demonstrated in some deposits. Lumbar spinal stenosis is also a condition of usually elderly individuals in whom narrowing of the lumbar spinal canal leads to compression of nerves to the lower limbs. Results. We questioned whether lumbar spinal stenosis sometimes could be a manifestation of undiagnosed SSA. In this first report we have studied the presence of amyloid in material obtained at surgery for spinal stenosis in 26 patients. Amyloid was found in 25 subjects. Transthyretin was demonstrated immunohistochemically in 5 out of 15 studied resected tissues. Four of the positive materials were analyzed with Western blot revealing both full-length transthyretin (TTR) and C-terminal TTR fragments, typically seen in SSA. Conclusion. We conclude that lumbar spinal stenosis quite frequently may be a consequence of SSA and that further studies are warranted. [ABSTRACT FROM AUTHOR]

What is known and objective Transthyretin ( TTR) is a representative amyloidogenic protein in humans. Rate-limiting tetramer dissociation and rapid monomer misfolding and misassembly of variant TTR result in autosomal dominant familial amyloidosis. Analogous misfolding of wild-type TTR results in senile systemic amyloidosis ( SSA) presenting as sporadic amyloid disease in the elderly. The objective of this review is to summarize recent progress in our understanding and treatment of TTR amyloidosis. Methods Literature searches were conducted on the topics of transthyretin, familial amyloid polyneuropathy and clinical trials, using PubMed, the United States clinical trials directory, pharmaceutical company websites and news reports. The information was collected, evaluated for relevance and quality, critically assessed and summarized. Results and discussion The current standard first-line treatment of familial TTR amyloidosis is liver transplantation. However, large numbers of patients are not suitable transplant candidates. Recently, the clinical effects of TTR tetramer stabilizers, tafamidis and diflunisal, were demonstrated in randomized clinical trials, and tafamidis has been approved for the treatment of FAP in European countries and Japan. In addition, gene therapies with antisense oligonucleotides and small interfering RNAs are promising strategies to ameliorate TTR amyloidoses and are currently in clinical trials. What is new and conclusions Liver transplantation to treat the familial TTR amyloidosis will likely be replaced by other less invasive therapies, such as TTR tetramer stabilizers and possibly gene therapy approaches. These newly developed therapies are expected to be effective for not only familial TTR amyloidosis but also SSA, based on their mechanisms of action. [ABSTRACT FROM AUTHOR]

Systemic amyloidosis is caused by extracellular deposition of insoluble fibrillar proteins arranged in β-pleated sheets. [11C]PIB has been used in PET studies to assess Aβ deposition in brain of patients with Alzheimer's disease (AD). The possibility to visualize other types of amyloid deposits with [11C]PIB would be of potential clinical importance in early diagnosis and for following therapeutic effects. In the present study, we evaluated in vitro binding of [3H]PIB to tissues containing transthyretin (ATTR), immunoglobulin light-chain (AL), amyloid protein A (AA) and Aβ amyloid. We found significantly higher binding of [3H]PIB in tissue from systemic amyloidoses than in control tissue, i.e. 4.7 times higher ( p < 0.05). [3H]PIB showed the highest affinity to cortex of AD brain (IC50 = 3.84 nM), while IC50 values were much higher for ATTR, AA and AL type of amyloidosis and large variations in affinity were observed even within tissues having the same type of amyloidosis. Extraction with guanidine-HCl, which disrupts the β-sheet structure, decreased the protein levels and, concomitantly, the binding of [3H]PIB in all four types of amyloidoses. [ABSTRACT FROM AUTHOR]

The article focuses on the biochemical and molecular transthyretin assays. Topics discussed include genetic testing involving detection of genetic changes that allows for appropriate diagnosis, causes for discordance in transthyretin testing at U.S.-based Mayo Clinic identifies domino liver transplants and noninvasive testing of serum. Also presents a chart depicting m result of ass spectrometry of 13 cases of transthyretin testing.

Objective: To investigate histological features of deposited amyloid in the synovial tissue and its clinical significance in knee joint osteoarthritis (OA) patients. Methods: We prospectively enrolled 232 consecutive patients who underwent arthroplasty or total replacement of the knee joint for treatment of OA. Congo red staining and immunohistochemistry were performed in the synovial tissue obtained at surgery. When transthyretin (TTR)-derived amyloid was positive, we analyzed all 4 exons of the TTR gene using the direct DNA sequencing method in order to detect mutations. Results: We analyzed 322 specimens in this study. Twenty-six specimens (8.1%) obtained from 21 patients (5 men and 16 women; mean, 79.0 ± 4.6 years) showed deposition of amyloid, which was positively stained with the anti-TTR antibody. Eighteen patients showed inhomogeneous accumulations of amyloid in the loose connective tissue under the synovial epithelia sometimes with nodule formation, while in the remaining three, small vessels in the adipose tissue were involved. Medical records of these patients revealed nothing remarkable in the clinical course, laboratory data or macroscopic intraarticular findings at surgery. No mutations were detectable in the TTR gene analysis. Conclusion: Wild-type TTR-derived amyloid may affect the synovial tissue as a result of long-term mechanical stress or as a part of senile systemic amyloidosis in approximately 8% of knee joint OA patients. No obvious clinical significance was found in synovial deposition of amyloid. [ABSTRACT FROM AUTHOR]

Abstract: Background: Senile systemic amyloidosis (SSA) is a common aging phenomenon in the elderly population. Nevertheless, pre-mortem diagnosis of SSA is rare. Thus, data on clinical characterization and disease severity are limited. Methods: 36 consecutive SSA patients (71.6 [64.7–82.7]years) were evaluated by electrocardiography, echocardiography, laboratory tests, and 99mTechnetium-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) scintigraphy (n=20). Results: In addition to cardiac involvement, amyloid deposition was found in rectum (n=6), peripheral nerves (n=2), and urinary bladder (n=2). Five patients showed low voltage pattern. Thickness of interventricular septum (IVS) was 20 [12–27]mm. LV longitudinal function was diminished (TDI-s 5 [3–11] cm/s; MAPSE 6.5 [2.5–19]mm; TAPSE 12.5 [2–24]mm). LV systolic function (LV-EF<45%) was markedly decreased in 19 patients. Plasma levels of troponin T (0.05 [0.01–0.23]µg/L) and NT-proBNP (4318 [205–16597]ng/L) were elevated. 99mTc-DPD heart retention was 7.8 [2.4–11.0]% and correlated with MAPSE (ρ=−0.716; p=0.0018), TAPSE (ρ=−0.491; p<0.05), and IVS (ρ=0.556; p=0.0153). Heart-to-body ratio correlated with MAPSE (ρ=−0.771; p=0.0018), IVS (ρ=0.603; p=0.0086). Twelve patients died during follow-up of 27.4 [0.1–106.2]months. Exclusively 99mTc-DPD heart retention, diastolic dysfunction and in trend MAPSE were associated with patient''s outcome. Interestingly, risk predictors that were well established in patients with AL amyloidosis were not predictive for survival in patients with SSA. Conclusions: This study gave first evidence that 99mTc-DPD HR may be capable to display the extent of cardiac amyloid deposition. Moreover, this study suggested that 99mTc-DPD HR, diastolic dysfunction and in trend MAPSE are associated with poor outcome. Nevertheless, these findings need to be established in a larger prospective trial. [Copyright &y& Elsevier]

Aims Hereditary transthyretin (TTR)-related amyloidosis (ATTR) is mainly considered a neurologic disease. We assessed the phenotypic and genotypic spectra of ATTR in a Caucasian area and evaluated the prevalence, genetic background, and disease profile of cases with an exclusively cardiac phenotype, highlighting possible hints for the differential diagnosis with hypertrophic cardiomyopathy (HCM) and senile systemic amyloidosis (SSA). Methods and results In this Italian multicentre study, 186 patients with ATTR were characterized at presentation. Thirty patients with SSA and 30 age–gender-matched HCM patients were used for comparison. Phenotype was classified as exclusively cardiac (n = 31, 17%), exclusively neurologic (n = 46, 25%), and mixed cardiac/neurologic (n = 109, 58%). Among the eight different mutations responsible for an exclusively cardiac phenotype, Ile68Leu was the most frequent. Five patients with an exclusively cardiac phenotype developed mild abnormalities at neurological examination, but no symptoms during a 36-month follow-up (range: 14–50). Exclusively cardiac phenotype was characterized by male gender, age >65 years, heart failure symptoms, symmetric left ventricular (LV) ‘hypertrophy’, and moderately depressed LV ejection fraction. This profile was similar to SSA, but relatively distinct from HCM. Compared with patients with a mixed phenotype, patients with an exclusively cardiac phenotype showed a more pronounced cardiac involvement on both echocardiogram and electrocardiogram (ECG). Conclusion A clinically relevant subset of Caucasian ATTR patients present with an exclusively cardiac phenotype, mimicking HCM or SSA. Echocardiographic and ECG findings are useful to differentiate ATTR from HCM but not from SSA. The role of liver transplantation in these patients should be reconsidered. [ABSTRACT FROM PUBLISHER]

We describe a rare complication, systemic arterial thromboembolism, seen in two patients with senile systemic amyloidosis (SSA). Case 1 was a 73-year-old man who was tentatively diagnosed as having cardiac amyloidosis. Five months later, he was afflicted by severe left flank pain. CT disclosed renal infarction and then he received endomyocardial biopsy and the transthyretin (TTR) gene analysis, leading to the final diagnosis of SSA. Case 2 was an 88-year-old woman who had been definitively diagnosed as having SSA-related heart failure with atrial fibrillation two years before. She was transferred to the emergency room in our hospital and enhanced CT revealed complete occlusions of the left internal carotid and left vertebral arteries, both subclavian arteries, and the left renal and left internal iliac arteries. Paying much attention to intracardiac thrombosis might be necessary in taking care of SSA patients. [ABSTRACT FROM AUTHOR]

Spinal amyloidosis can occur as a part of systemic amyloidosis or as localized amyloidomas. However, the exact pathogenesis of the spinal amyloidosis remains to be fully understood. Transthyretin (TTR) is an amyloidogenic protein causing two kinds of amyloid diseases. One is senile systemic amyloidosis (SSA), which is caused by wild-type (WT) TTR and primarily affects cardiac functions. The other type is familial amyloidosis, which is mainly induced by mutated TTR. We report here the first case of multifocal spinal TTR amyloidosis derived from WT TTR with radiculomyelopathy and destructive spondylosis. The data and clinical manifestations suggest that the patient may develop SSA. Clinical manifestations of TTR-related amyloidosis may vary more than we previously thought. In spinal amyloidosis, WT TTR is one of the candidate precursor proteins for the disease. [ABSTRACT FROM AUTHOR]

Summary: Transthyretin-derived amyloid deposition is commonly found in intercarpal ligaments of patients with senile systemic amyloidosis. However, the frequency of transthyretin-derived amyloid deposits in ligaments of other tissues remains to be elucidated. This study aimed to determine the frequency of amyloid deposition and the precursor proteins of amyloid found in orthopedic disorders. We studied 111 specimens from patients with carpal tunnel syndrome (flexor tenosynovium specimens), rotator cuff tears (rotator cuff tendon specimens), and lumbar canal stenosis (yellow ligament specimens). To identify amyloid precursor proteins, we used immunohistochemical staining with antibodies that react with transthyretin, immunoglobulin light chain, amyloid A protein, and β 2-microglobulin. By means of Congo red staining, we identified 47 (42.3%) amyloid-positive samples, 39 of which contained transthyretin-derived amyloid (18 flexor tenosynovium specimens, 5 rotator cuff tendon specimens, and 16 yellow ligament specimens). Genetic testing and/or clinical findings suggested that all patients with transthyretin amyloid deposits did not have familial amyloidotic polyneuropathy. The occurrence of amyloid deposition in those tissues depended on age. These results suggest that transthyretin-derived amyloid deposits may occur more frequently in various ligaments and tendons than originally expected. In the future, such amyloid deposits may aid determination of the pathogenesis of ligament and tendon disorders in older patients. [ABSTRACT FROM AUTHOR]

Summary: Wild-type transthyretin is inherently an amyloidogenic protein, but its contribution to the formation of amyloid fibrils remains unclear in familial amyloid polyneuropathy patients. Our aim in this study was to elucidate the ratio of wild-type transthyretin in amyloid deposits in familial amyloid polyneuropathy patients. Abdominal fat amyloid fibrils in 44 familial amyloid polyneuropathy patients with amyloidogenic transthyretin Val30Met who had not undergone liver transplantation were examined. The amyloid fibrils were extracted from abdominal fat tissues and the composition ratios of wild-type and variant transthyretin were analyzed with liquid chromatography tandem mass spectrometry. The amyloid fibrils in abdominal fat tissues were composed of not only variant but also wild-type transthyretin in most patients (mean ratio, 40.7% ± 27.5%). The composition ratios of wild-type transthyretin in patients older than 50 years were significantly higher than those in patients younger than 50 (50.7% ± 26.9% versus 30.7 ± 24.8%). Our results indicate that wild-type transthyretin significantly contributes to the formation of amyloid fibrils in familial amyloid polyneuropathy patients with amyloidogenic transthyretin Val30Met, and its contribution tends to increase in older patients, suggesting that aging may play an important role in wild-type transthyretin-derived amyloid fibril formation in familial amyloid polyneuropathy patients. This is the first report showing the relationship between wild-type transthyretin deposition and aging in familial amyloid polyneuropathy patients. In addition, wild-type transthyretin may be more strongly amyloidogenic than previously considered because it is detectable even in amyloid fibrils isolated from young familial amyloid polyneuropathy patients. [ABSTRACT FROM AUTHOR]

Background: Familial amyloid polyneuropathy is caused by a variant transthyretin, which is a serum protein secreted by the liver. We previously reported that mutated transthyretins were detected in serum samples by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS). The aim of this study was to evaluate the clinical usefulness of SELDI-TOF MS for diagnosis of transthyretin-related amyloidosis.Methods: We used 106 serum samples obtained from patients who were clinically suspected of having amyloidosis between February 2011 and April 2014. SELDI-TOF MS allowed analysis for transthyretin via a 3-h one-step procedure.Results: Of the 106 patients, 51 are transthyretin amyloidosis. Mutated transthyretins were detected in serum samples from 30 of 51 patients with transthyretin amyloidosis. The results of genetic analysis showed that all of those patients had mutations in the transthyretin gene. For all 18 patients with senile systemic amyloidosis of 51 patients with transthyretin amyloidosis, SELDI-TOF MS detected only wild-type transthyretin peaks, not mutated transthyretin peaks.Conclusion: SELDI-TOF MS is a clinically useful tool for diagnosis of transthyretin-related amyloidosis. [ABSTRACT FROM AUTHOR]

Two male patients aged 72 and 77 were found to have transthyretin (TTR) immunoreactive amyloid deposits in their gastrointestinal tracts when they underwent surgery for gastric and sigmoid colon cancer, respectively. They had no cardiac symptoms and there was no mutation in their TTR gene. Amyloid deposits were seen mainly on vascular walls in submucosal layers of the stomach and colon, while the muscularis mucosae, which is invariably affected in familial amyloid polyneuropathy (FAP), was completely free of amyloid deposition. The pattern of TTR-derived amyloid deposition in the gastrointestinal tract in SSA and in FAP are quite different. [ABSTRACT FROM AUTHOR]

Serum transthyretin (TTR) levels are reduced in familial amyloidotic polyneuropathy (FAP). A single study of patients with senile systemic amyloidosis (SSA) in Sweden found that those individuals also had a significantly lower mean serum TTR concentration than age- and gender-matched controls. To determine if the same phenomenon prevailed in an ethnically more heterogeneous population, we compared the serum TTR levels, as determined by ELISA, in 45 documented SSA patients with congestive heart failure, 20 AL patients with congestive heart failure and population controls. Serum TTR concentrations in the controls were influenced in a statistically significant manner by age, gender and ethnicity. Although it is unlikely that such differences are clinically relevant, they must be considered when assessing the meaning of serum TTR concentrations in any clinically defined population. The serum concentrations in patients with SSA did not differ from age, gender and ethnically matched controls or from a group of AL patients with significant clinical cardiac involvement. We also compared TTR concentrations in 12 African-Americans carrying the TTR V122I allele with those in 826 African-Americans who were homozygous wild type at the TTR locus. The TTR V122I carriers had significantly lower serum TTR concentrations than appropriate controls even though the majority of such individuals had not reached the age of clinical or anatomic risk, i.e. over 60. Thus, as in carriers of other TTR mutations the serum TTR level is lower than normal, despite having a much later appearance of clinical disease. [ABSTRACT FROM AUTHOR]

Background. Senile systemic amyloidosis (SSA) is characterized by deposition of wild-type transthyretin (TTR)-based amyloid in parenchymal organs in elderly individuals. Previously, no population-based studies have been performed on SSA. Methods. Here we have studied the prevalence and risk factors for SSA in a Finnish autopsied population aged 85 or over, as part of the population-based Vantaa 85+ Autopsy Study (n = 256). The diagnosis of SSA was based on histological examination of myocardial samples stained with Congo red and anti-TTR immunohistochemistry. The genotype frequencies of 20 polymorphisms in 9 genes in subjects with and without SSA were compared. Results. The prevalence of SSA was 25%. SSA was associated with age, myocardial infarctions, the G/G (Val/Val) genotype of the exon 24 polymorphism in the alpha2-macroglobulin (α2M), and the H2 haplotype of the tau gene (P-values 0.002, 0.004, 0.042, and 0.016). Conclusion. This population-based study shows that SSA is very common in old individuals, affecting one-quarter of people aged over 85 years. Myocardial infarctions and variation in the genes for α2M and tau may be associated with SSA. [ABSTRACT FROM AUTHOR]

Abstract: Background: The literature is unclear as to the frequency and degree of vascular involvement among the various types of cardiac amyloidosis, specifically the senile type. Methods: We analyzed the intramyocardial vascular involvement, both qualitatively and quantitatively, in 18 patients with autopsy-proven cardiac amyloidosis [11 with primary amyloidosis (AL) and 7 with senile systemic amyloidosis (SSA)]. Results: AL patients (10/11) showed focally transmural vascular involvement by amyloid with thickening of the wall and impingement on the lumens. In SSA patients (6/7), the amyloid deposition was concentrated largely in the adventitia and external media. Histomorphometric analysis revealed that all patients with AL, SSA, and heart failure without amyloidosis had greater luminal areas than normal controls. In addition, the median of the ratio of subendocardial to subepicardial vascular luminal areas was 0.59 in AL patients, 1.17 in SSA patients, 0.94 in heart failure without amyloidosis patients, and 0.89 in normal controls (P=.034). Conclusions: This study shows that the degree of vascular involvement and wall thickening with subsequent impingement on the lumen is much greater in AL than in SSA. All patients with heart failure, with and without amyloidosis, displayed greater luminal areas than normal controls. Moreover, a twofold dilatation of the vessels in the subepicardium compared to those in the subendocardium was noted only in patients with AL. This may be due to transmural vascular involvement by amyloid in these patients, which concomitantly decreases the transmural ventricular perfusion pressure, leading to compensatory expansion of the subepicardial vessels. [Copyright &y& Elsevier]

Senile systemic amyloidosis (SSA) and cerebral amyloid angiopathy (CAA) are amyloid disorders, which typically manifest with old age. The aim of our study was to examine the possible association of these disorders in very old Finns. We performed a prospective, population-based post mortem study and used histological and immunohistochemical staining methods to verify the presence of these types of amyloid. All 63 subjects (59% of the 107 individuals 95 years of age or more, who died during the 10-year follow-up study), 53 women and 10 men), had been neurologically examined. The prevalence of SSA and its association with CAA, dementia, and neuropathologically verified AD was analyzed. Overall SSA occurred in 23 (37%) and CAA in 28 (44%) of the 63 subjects. At clinical examination 41 individuals (65%) were demented; 24 (38%) had Alzheimer's disease. SSA showed no association with the presence of CAA (P = 0.45), clinical dementia (P = 0.09), or Alzheimer's disease (P = 0.21), or sex (P = 0.53). Our prospective population based study shows that SSA and CAA are frequent in very old Finns, but they do not associate. [ABSTRACT FROM AUTHOR]

Background: Cardiac amyloidosis had been considered to be an incurable disease; however, new disease-modifying therapeutic approaches have succeeded in ameliorating the disease. Therefore, early and precise diagnosis based on the amyloid precursor protein is extremely important. Objective: To determine the prevalence rates of systemic amyloidoses underlying cardiac amyloidosis. Methods: The types of amyloidosis in 53 consecutive patients with endomyocardial biopsy-proven cardiac amyloidosis were analyzed by Congo red and immunohistochemical staining. If staining for TTR was positive, direct DNA sequencing of the entire TTR gene was performed. Results: ATTR amyloidosis was the most common (32/53 patients, 60.4%). The ATTR amyloidosis subtypes were senile systemic amyloidosis (SSA) 11, familial ATTR 10, and genotype unknown 11. AL amyloidosis was the next most frequent (19/53, 35.8%). Conclusions: ATTR amyloidosis, especially SSA, might be much more common than previously thought. With the development of new drugs targeting the ATTR amyloidosis, major efforts should be made to increase awareness of senile systemic amyloidosis among cardiologists. [ABSTRACT FROM AUTHOR]

Amyloid deposits in the heart derived from transthyretin are commonly seen at autopsy in elderly patients. Massive deposition, causing senile systemic amyloidosis (SSA), is considered to be relatively uncommon and reported series suggest that SSA is considerably less common than amyloid light-chain (AL) amyloidosis. This article reviews the autopsy prevalence of transthyretin-derived cardiac amyloid, addresses whether there is definitive evidence for regional or ethnic differences and argues that the reported prevalence of SSA significantly underrepresents the true prevalence of the disease which may be as common, or commoner, than AL amyloidosis. [ABSTRACT FROM AUTHOR]

The article presents a study which examined the pathological signs of senile systemic amyloidosis in an aged Savannah monkey (Cercopithecus aethiops) with tenosynovial degeneration. The subject was positively tested with severe cardiac fibrosis and tenosynovial degeneration of the elbow and knee joints including transthyretin (TTR) as stated in the immunohistochemical results. It states that congestive heart failure accompanied by arrhythmia and myocardial infarcts are significant signs representing end stage heart failure resembling its human counterpart.