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International Journal of Molecular... Mar 2024Peripheral and autonomic neuropathy are common disease manifestations in systemic amyloidosis. The neurofilament light chain (NfL), a neuron-specific biomarker, is... (Review)
Review
Peripheral and autonomic neuropathy are common disease manifestations in systemic amyloidosis. The neurofilament light chain (NfL), a neuron-specific biomarker, is released into the blood and cerebrospinal fluid after neuronal damage. There is a need for an early and sensitive blood biomarker for polyneuropathy, and this systematic review provides an overview on the value of NfL in the early detection of neuropathy, central nervous system involvement, the monitoring of neuropathy progression, and treatment effects in systemic amyloidosis. A literature search in PubMed, Embase, and Web of Science was performed on 14 February 2024 for studies investigating NfL levels in patients with systemic amyloidosis and transthyretin gene-variant (v) carriers. Only studies containing original data were included. Included were thirteen full-text articles and five abstracts describing 1604 participants: 298 controls and 1306 v carriers or patients with or without polyneuropathy. Patients with polyneuropathy demonstrated higher NfL levels compared to healthy controls and asymptomatic carriers. Disease onset was marked by rising NfL levels. Following the initiation of transthyretin gene-silencer treatment, NfL levels decreased and remained stable over an extended period. NfL is not an outcome biomarker, but an early and sensitive disease-process biomarker for neuropathy in systemic amyloidosis. Therefore, NfL has the potential to be used for the early detection of neuropathy, monitoring treatment effects, and monitoring disease progression in patients with systemic amyloidosis.
Topics: Humans; Prealbumin; Intermediate Filaments; Immunoglobulin Light-chain Amyloidosis; Amyloidosis; Polyneuropathies; Biomarkers
PubMed: 38612579
DOI: 10.3390/ijms25073770 -
International Journal of Cardiology May 2024Cardiac amyloidosis is increasingly recognized as a significant contributor to cardiovascular morbidity and mortality. With the emergence of novel therapies, there is a... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Cardiac amyloidosis is increasingly recognized as a significant contributor to cardiovascular morbidity and mortality. With the emergence of novel therapies, there is a growing interest in prognostication of patients with cardiac amyloidosis using cardiac magnetic resonance imaging (CMR). In this systematic review and meta-analysis, we aimed to examine the prognostic significance of myocardial native T1 and T2, and extracellular volume (ECV).
METHODS
Observational cohort studies or single arms of clinical trials were eligible. MEDLINE, EMBASE and CENTRAL were systematically searched from their respective dates of inception to January 2023. No exclusions were made based on date of publication, study outcomes, or study language. The study populations composed of adult patients (≥18 years old) with amyloid cardiomyopathy. All studies included the use of CMR with and without intravenous gadolinium contrast administration to assess myocardial native T1 mapping, T2 mapping, and ECV in association with the pre-specified primary outcome of all-cause mortality. Data were extracted from eligible primary studies by two independent reviewers and pooled via the inverse variance method using random effects models for meta-analysis.
RESULTS
A total of 3852 citations were reviewed. A final nine studies including a total of 955 patients (mean age 65 ± 10 years old, 32% female, mean left ventricular ejection fraction (LVEF) 59 ± 12% and 24% had NYHA class III or IV symptoms) with cardiac amyloidosis [light chain amyloidosis (AL) 50%, transthyretin amyloidosis (ATTR) 49%, other 1%] were eligible for inclusion and suitable for data extraction. All included studies were single centered (seven with 1.5 T MRI scanners, two with 3.0 T MRI scanners) and non-randomized in design, with follow-up spanning from 8 to 64 months (median follow-up = 25 months); 320 patients died during follow-up, rendering a weighted mortality rate of 33% across studies. Compared with patients with AL amyloid, patients with ATTR amyloid had significantly higher mean left ventricular mass index (LVMi) (102 ± 34 g/m vs 127 ± 37 g/m, p = 0.02). N-terminal pro-brain natriuretic peptide (NT-proBNP), troponin T levels, mean native T1 values, ECV and T2 values did not differ between patients with ATTR amyloid and AL amyloid (all p > 0.25). Overall, the hazard ratios for mortality were 1.33 (95% CI = [1.10, 1.60]; p = 0.003; I = 29%) for every 60 ms higher T1 time, 1.16 (95% CI = [1.09, 1.23], p < 0.0001; I = 76%) for every 3% higher ECV, and 5.23 (95% CI = [2.27, 12.02]; p < 0.0001; I = 0%) for myocardial-to-skeletal T2 ratio below the mean (vs above the mean).
CONCLUSION
Higher native T1 time and ECV, and lower myocardial to skeletal T2 ratio, on CMR are associated with worse mortality in patients with cardiac amyloidosis. Therefore, tissue mapping using CMR may offer a useful non-invasive technique to monitor disease progression and determine prognosis in patients with cardiac amyloidosis.
Topics: Adult; Humans; Female; Middle Aged; Aged; Adolescent; Male; Cardiomyopathies; Stroke Volume; Ventricular Function, Left; Magnetic Resonance Imaging; Myocardium; Amyloid Neuropathies, Familial; Disease Progression; Magnetic Resonance Imaging, Cine; Predictive Value of Tests; Contrast Media; Observational Studies as Topic
PubMed: 38382853
DOI: 10.1016/j.ijcard.2024.131892 -
ESC Heart Failure Apr 2024The prevalence of transthyretin-associated amyloidosis cardiomyopathy (ATTR-CM) has grown because of newer non-invasive diagnosis tools. Detecting the presence of... (Review)
Review
The prevalence of transthyretin-associated amyloidosis cardiomyopathy (ATTR-CM) has grown because of newer non-invasive diagnosis tools. Detecting the presence of extra-cardiac ATTR manifestations such as musculoskeletal pathologies considered 'red flags', when there is minimal or non-cardiac clinical involvement is primordial to carry out an early diagnosis. The aim of this systematic review is to examine the prevalence of musculoskeletal, ATTR-deposition-related co-morbidities in patients already diagnosed with ATTR-CM, specifically carpal tunnel syndrome, ruptured biceps tendon, spinal stenosis, and trigger finger. We performed a systematic review using PRISMA guidelines. Inclusion criteria were all studies in English and Spanish language and participants had to be patients diagnosed with ATTR-CM, by any diagnostic method, with the musculoskeletal co-morbidities subject of this review. The quality of the studies was based on the Risk of Bias Tool. This systematic review included 22 studies for final analysis. Carpal tunnel syndrome is reported in 21 studies, brachial biceps tendon rupture is reported in three, and spinal stenosis in eight studies. No articles that accomplished all the inclusion criteria for trigger finger were found. Regarding to the quality of the studies, all of them were categorized as being of high and moderate quality. The frequent association between ATTR-CM and carpal tunnel syndrome, ruptured biceps tendon, and lumbar spinal is confirmed, and the onset of these co-morbidities usually precedes the diagnosis of by years. This association defines them as red flags that should be search proactively due to the current treatment possibilities and the severity of the presentation of cardiac amyloidosis.
Topics: Humans; Prealbumin; Spinal Stenosis; Carpal Tunnel Syndrome; Trigger Finger Disorder; Amyloid Neuropathies, Familial; Cardiomyopathies; Morbidity
PubMed: 38130034
DOI: 10.1002/ehf2.14622 -
Orphanet Journal of Rare Diseases Sep 2022Hereditary transthyretin amyloidosis (hATTR) is a progressive and fatal disease with heterogenous clinical presentations, limited diagnosis and poor prognosis. This...
BACKGROUND
Hereditary transthyretin amyloidosis (hATTR) is a progressive and fatal disease with heterogenous clinical presentations, limited diagnosis and poor prognosis. This retrospective analysis study aimed to report the genotypes and phenotypes of herediary transthyretin amyloidosis (hATTR) in Chinese through a systematic review of published literature.
METHODS
The systematic review included structured searches of peer-reviewed literature published from 2007 to 2020 of following online reference databases: PubMed, Web of Science and the literature database in China. Extracted data included sample size, personal information (sex, age, natural course, family history), mutation type, clinical milestones and reason of death.
RESULTS
We described 126 Chinese patients with hereditary transthyretin amyloidosis identified through a systematic review of 30 studies. The most common genotype in the Chinese population was Gly83Arg (25, 19.8%), which most likely presented visual and neurological abnormalities without reported death. The second and third most common genotypes were Val30Met (20, 15.9%) and Val30Ala (10, 7.9%). Peripheral neurological manifestations (91, 72%) were dominant in 126 patients. The followed manifestation was autonomic neurological abnormalities (73, 58%). Half of the cases were reported to have visual disorders, and nearly one-third of the cases presented cardiac abnormalities. Among all 126 reported patients, 46.03% were classified as neurological type, 30.16% as mixed type and only 2.38% as cardiac type. In addition. Chinese patients were mostly early onset, with age of onset at 41.8 (SD: 8.9) years, and the median time from onset to death was 7.5 [IQR: 5.3] years. Patients with cardiac involvement had a shorter survival duration (log Rank (Mantel-Cox), χ = 26.885, P < 0.001).
CONCLUSIONS
This study focused on 126 Chinese hATTR patients obtained from a literature review. A total of 26 kinds of TTR mutations were found and the most common one was Gly83Arg. As for phenotype, 46.03% were classified as neurological type, 30.16% as mixed type and only 2.38% as cardiac type. Chinese hATTR patients were mostly early onset (AO 41.8 years), and the median time from onset to death was 7.5 years.
Topics: Amyloid Neuropathies, Familial; Humans; Phenotype; Prealbumin; Retrospective Studies
PubMed: 36056432
DOI: 10.1186/s13023-022-02481-9 -
European Journal of Heart Failure Sep 2022Systematic evidence on the prevalence and clinical outcome of transthyretin amyloidosis (ATTR) is missing. We explored: (i) the prevalence of cardiac amyloidosis in... (Meta-Analysis)
Meta-Analysis
AIM
Systematic evidence on the prevalence and clinical outcome of transthyretin amyloidosis (ATTR) is missing. We explored: (i) the prevalence of cardiac amyloidosis in various patient subgroups, (ii) survival estimates for ATTR subtypes, and (iii) the effects of novel therapeutics on the natural course of disease.
METHODS AND RESULTS
A systematic review of literature published in MEDLINE before 31 December 2021 was performed for the prevalence of cardiac amyloidosis and all-cause mortality of ATTR patients. Extracted data included sample size, age, sex, and all-cause mortality at 1, 2, and 5 years. Subgroup analyses were performed for ATTR subtype, that is, wild-type ATTR (wtATTR) versus hereditary ATTR (hATTR), hATTR genotypes, and treatment subgroups. We identified a total of 62 studies (n = 277 882 individuals) reporting the prevalence of cardiac amyloidosis, which was high among patients with a hypertrophic cardiomyopathy phenotype, heart failure with preserved ejection fraction, and the elderly with aortic stenosis. Data on ATTR mortality were extracted from 95 studies (n = 18 238 ATTR patients). Patients with wtATTR were older (p = 7 × 10 ) and more frequently male (p = 5 × 10 ) versus hATTR. The 2-year survival of ATTR was 73.3% (95% confidence interval [CI] 70.9-75.7); for non-subtyped ATTR 70.4% (95% CI 66.9-73.9), for wtATTR 76.0% (95% CI 73.0-78.9]) and for hATTR 77.2% (95% CI 74.0-80.4); in meta-regression analysis, wtATTR was associated with higher survival after adjusting for confounders. There was an interaction between survival and hATTR genotypes (p = 10 , Val30Met having the lowest and Val122Ile/Thr60Ala the highest mortality). ATTR 2-year survival was higher on tafamidis/patisiran compared to natural disease course (79.9%, 95% CI 74.4-85.3 vs. 72.4%, 95% CI 69.8-74.9, p < 0.05).
CONCLUSIONS
We report the prevalence of ATTR in various population subgroups and provide survival estimates for the natural course of disease and the effects of novel therapeutics. Important gaps in worldwide epidemiology research in ATTR were identified.
Topics: Amyloid Neuropathies, Familial; Cardiomyopathies; Heart Failure; Humans; Male; Prevalence
PubMed: 35730461
DOI: 10.1002/ejhf.2589 -
ESC Heart Failure Jun 2022Wild-type transthyretin amyloid cardiomyopathy (ATTRwt CM) is a more common disease than previously thought. Awareness of ATTRwt CM and its diagnosis has been challenged... (Review)
Review
Wild-type transthyretin amyloid cardiomyopathy (ATTRwt CM) is a more common disease than previously thought. Awareness of ATTRwt CM and its diagnosis has been challenged by its unspecific and widely distributed clinical manifestations and traditionally invasive diagnostic tools. Recent advances in echocardiography and cardiac magnetic resonance (CMR), non-invasive diagnosis by bone scintigraphy, and the development of disease-modifying treatments have resulted in an increased interest, reflected in multiple publications especially during the last decade. To get an overview of the scientific knowledge and gaps related to patient entry, suspicion, diagnosis, and systematic screening of ATTRwt CM, we developed a framework to systematically map the available evidence of (i) when to suspect ATTRwt CM in a patient, (ii) how to diagnose the disease, and (iii) which at-risk populations to screen for ATTRwt CM. Articles published between 2010 and August 2021 containing part of or a full diagnostic pathway for ATTRwt CM were included. From these articles, data for patient entry, suspicion, diagnosis, and screening were extracted, as were key study design and results from the original studies referred to. A total of 50 articles met the inclusion criteria. Of these, five were position statements from academic societies, while one was a clinical guideline. Three articles discussed the importance of primary care providers in terms of patient entry, while the remaining articles had the cardiovascular setting as point of departure. The most frequently mentioned suspicion criteria were ventricular wall thickening (44/50), carpal tunnel syndrome (42/50), and late gadolinium enhancement on CMR (43/50). Diagnostic pathways varied slightly, but most included bone scintigraphy, exclusion of light-chain amyloidosis, and the possibility of doing a biopsy. Systematic screening was mentioned in 16 articles, 10 of which suggested specific at-risk populations for screening. The European Society of Cardiology recommends to screen patients with a wall thickness ≥12 mm and heart failure, aortic stenosis, or red flag symptoms, especially if they are >65 years. The underlying evidence was generally good for diagnosis, while significant gaps were identified for the relevance and mutual ranking of the different suspicion criteria and for systematic screening. Conclusively, patient entry was neglected in the reviewed literature. While multiple red flags were described, high-quality prospective studies designed to evaluate their suitability as suspicion criteria were lacking. An upcoming task lies in defining and evaluating at-risk populations for screening. All are steps needed to promote early detection and diagnosis of ATTRwt CM, a prerequisite for timely treatment.
Topics: Amyloid Neuropathies, Familial; Cardiomyopathies; Contrast Media; Gadolinium; Humans; Prealbumin; Prospective Studies
PubMed: 35343098
DOI: 10.1002/ehf2.13884 -
Circulation. Genomic and Precision... Oct 2021The p.Val142Ile variant, predominantly found among people of African descent, is the most common cause of variant transthyretin amyloidosis and carriers predominantly...
BACKGROUND
The p.Val142Ile variant, predominantly found among people of African descent, is the most common cause of variant transthyretin amyloidosis and carriers predominantly develop a cardiomyopathy (variant transthyretin amyloidosis cardiomyopathy) phenotype. Yet, there are conflicting data on the prevalence and outcomes of p.Val142Ile variant carriers.
METHODS
We performed a systematic review of the prevalence and outcomes of p.Val142Ile variant transthyretin amyloidosis cardiomyopathy among subjects of African descent. We found 62 relevant articles after searching the MEDLINE databases from 1980 to 2020 that reported data for ≈150 000 subjects.
RESULTS
The reported worldwide prevalence of the p.Val142Ile variant is 0.3% to 1.6% in the general population. Among people of African descent, the reported prevalence from all studies ranges from 1.1% to 9.8%, but for studies with >1000 subjects, it is 3% to 3.5%. The prevalence of the p.Val142Ile variant in a region is dependent on the reported percentage of subjects who are of African descent in that region. p.Val142Ile variant transthyretin amyloidosis cardiomyopathy typically presents in the seventh to eighth decade of life and the majority of cases reported were male, with 25% to 38% diagnosed with atrial fibrillation. It was associated with a longitudinally worse quality of life and a lower adjusted survival compared with other types of transthyretin amyloidosis cardiomyopathy.
CONCLUSIONS
The p.Val142Ile variant is the most common variant of the transthyretin gene with most carriers being of African descent. The true penetrance is unknown but the p.Val142Ile variant is associated with increased rates of incident heart failure and portends a lower overall survival. Increased awareness could lead to earlier diagnosis and improved heart failure outcomes among those of African descent, which is of increasing importance given the advent of novel therapeutics for this disease.
Topics: Amino Acid Substitution; Amyloid Neuropathies, Familial; Cardiomyopathies; Female; Humans; Male; Mutation, Missense; Prealbumin; Prevalence; Risk Factors; Sex Factors
PubMed: 34461737
DOI: 10.1161/CIRCGEN.121.003356 -
European Journal of Clinical... Dec 2021Transthyretin-related cardiac amyloidosis (TTR-CA) is thought to be particularly common in specific at-risk conditions, including aortic stenosis (AS), heart failure...
BACKGROUND
Transthyretin-related cardiac amyloidosis (TTR-CA) is thought to be particularly common in specific at-risk conditions, including aortic stenosis (AS), heart failure with preserved ejection fraction (HFpEF), carpal tunnel syndrome (CTS) and left ventricular hypertrophy or hypertrophic cardiomyopathy (LVH/HCM).
METHODS
We performed a systematic revision of the literature, including only prospective studies performing TTR-CA screening with bone scintigraphy in the above-mentioned conditions. Assessment of other forms of CA was also evaluated. For selected items, pooled estimates of proportions or means were obtained using a meta-analytic approach.
RESULTS
Nine studies (3 AS, 2 HFpEF, 2 CTS and 2 LVH/HCM) accounting for 1375 screened patients were included. One hundred fifty-six (11.3%) TTR-CA patients were identified (11.4% in AS, 14.8% in HFpEF, 2.6% in CTS and 12.9% in LVH/HCM). Exclusion of other forms of CA and use of genetic testing was overall puzzled. Age at TTR-CA recognition was significantly older than that of the overall screened population in AS (86 vs. 83 years, p = .04), LVH/HCM (75 vs. 63, p < .01) and CTS (82 vs. 71), but not in HFpEF (83 vs. 79, p = .35). In terms of comorbidities, hypertension, diabetes and atrial fibrillation were highly prevalent in TTR-CA-diagnosed patients, as well as in those with an implanted pacemaker.
CONCLUSIONS
Screening with bone scintigraphy found an 11-15% TTR-CA prevalence in patients with AS, HFpEF and LVH/HCM. AS and HFpEF patients were typically older than 80 years at TTR-CA diagnosis and frequently accompanied by comorbidities. Several studies showed limitations in the application of recommended TTR-CA diagnostic algorithm, which should be addressed in future prospective studies.
Topics: Amyloid Neuropathies, Familial; Amyloidosis; Aortic Valve Stenosis; Cardiomyopathies; Cardiomyopathy, Hypertrophic; Carpal Tunnel Syndrome; Heart Failure; Humans; Hypertrophy, Left Ventricular; Radionuclide Imaging; Stroke Volume
PubMed: 34390490
DOI: 10.1111/eci.13665 -
Revista Da Associacao Medica Brasileira... Jan 2021To review the literature and to report a clinical case with initial suspicion of pure neural leprosy and final diagnosis of amyloid neuropathy.
OBJECTIVE
To review the literature and to report a clinical case with initial suspicion of pure neural leprosy and final diagnosis of amyloid neuropathy.
METHODS
The study was conducted in two stages. In stage one, a systematic literature review was carried out, with searches performed in the PubMed, Medline, and Lilacs databases, as well as in the leprosy sectoral library of the Virtual Health Library, using the following descriptors: neuritic leprosy, pure neural leprosy, primary neural leprosy, pure neuritic leprosy, amyloid polyneuropathy, amyloid neuropathies, and amyloid polyneuropathy. The search was carried out on May 28, 2020. Clinical trials, cohort studies, cross-sectional studies, clinical cases, and case studies published in Portuguese, English or Spanish between 2010 and 2020 were included. Stage two reports a case with initial suspicion of pure neural leprosy. Laboratory tests, electroneuromyography, ultrasound, and biopsy of the sural nerve were requested.
RESULTS
Twenty-three scientific texts were included. No publications were found that contained both topics together. The challenging diagnosis of pure neural leprosy and the possibility of using auxiliary resources in diagnosis were the most emphasized themes in the studies. In the clinical case, the patient's electroneuromyography showed sensitive and motor polyneuropathy of the lower limbs, which was predominantly sensory and axonal, symmetrical, of moderate intensity, and the mixed type (axonal-demyelinating). Ultrasonography of the sural nerve revealed changes in the contour of the deep fibular nerves; biopsy of the sural nerve showed an accumulation of amorphous eosinophilic material in the nerve path, and Congo red stain showed apple-green birefringence of the deposit under polarized light. The final diagnosis was amyloid neuropathy.
CONCLUSIONS
The final clinical diagnosis was amyloid neuropathy. The diagnosis of pure neural leprosy in endemic areas in Brasil is still a challenge for the health system.
Topics: Amyloid Neuropathies; Brazil; Cross-Sectional Studies; Humans; Leprosy; Leprosy, Tuberculoid
PubMed: 34161469
DOI: 10.1590/1806-9282.67.01.20200422 -
BMC Neurology Feb 2021We aimed to compare neuropathic progression rate between hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) and other peripheral neuropathies, including... (Meta-Analysis)
Meta-Analysis
BACKGROUND
We aimed to compare neuropathic progression rate between hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) and other peripheral neuropathies, including diabetic peripheral neuropathy (DPN) and Charcot-Marie-Tooth disease (CMT).
METHODS
Literature searches identified studies reporting neuropathic progression, measured by Neuropathy Impairment Score (NIS) or NIS-Lower Limbs (NIS-LL). Our study also included unpublished data from a clinical registry of patients who were diagnosed with different peripheral neuropathies and seen at the Oregon Health & Science University (OHSU) during 2016-2020. Meta-analysis and meta-regression models examined and compared annual progression rates, calculated from extracted data, between studies of ATTRv-PN and other peripheral neuropathies.
RESULTS
Data were synthesized from 15 studies in which NIS and/or NIS-LL total scores were assessed at least twice, with ≥12 weeks between assessments, among untreated patients with ATTRv-PN or other peripheral neuropathies. Meta-analysis models yielded that the annual progression rate in NIS total scores was significantly different from zero for studies in ATTRv-PN and CMT (11.77 and 1.41; both P < 0.001), but not DPN (- 1.96; P = 0.147). Meta-regression models showed significantly faster annual progression in studies in ATTRv-PN, which statistically exceeded that in other peripheral neuropathies by 12.45 points/year for NIS, and 6.96 for NIS-LL (both P < 0.001).
CONCLUSIONS
Peripheral nervous function deteriorates more rapidly in patients with ATTRv-PN than for other peripheral neuropathies. These findings may improve understanding of the natural history of neuropathy in ATTRv-PN, facilitate early diagnosis, and guide the development of assessment tools and therapies specifically targeting neuropathic progression in this debilitating disease.
Topics: Amyloid Neuropathies, Familial; Disease Progression; Female; Humans; Male; Middle Aged; Polyneuropathies; Registries
PubMed: 33579211
DOI: 10.1186/s12883-021-02094-y