Edited by: Dr. Juan González Moreno - Hospital Universitario, Spain. Dra. Inés Losada López - Hospital Universitario, Spain
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"Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Actualización de las recomendaciones para el diagnóstico y tratamiento de la amiloidosis por transtiretina variante (ATTRv)" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1074 "Ancho" => 1386 "Tamanyo" => 91000 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Treatment choice in patients with ATTRv-PN.</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">ATTRv-PN: hereditary transthyretin amyloidosis with polyneuropathy.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Introduction</span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">General description</span><p id="par0055" class="elsevierStylePara elsevierViewall">Transthyretin variant amyloidosis (ATTRv) is an autosomal dominantly inherited disease caused by pathogenic mutations in the predominantly hepatically expressed gene <span class="elsevierStyleItalic">TTR</span>, which encodes transthyretin (TTR). In affected subjects, changes in the primary structure of the TTR tetramer, whose function is the transport of thyroxine and retinol, lead to its dissociation into monomers. These form amyloid fibrils that accumulate in the extracellular space, causing damage to a range of tissues, mainly cardiac tissue and the peripheral nervous system.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">The signs and symptoms are heterogeneous and depend on the genetic variant, the age of onset or even the geographical region, making diagnosis and follow-up difficult. The Val30Met (p.Val50Met) variant is the most common and responsible for the high rate of ATTRv amyloidosis in endemic areas.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Definitions and nomenclature</span><p id="par0065" class="elsevierStylePara elsevierViewall">The nomenclature is governed by recommendations made by the International Society of Amyloidosis (ISA), updated in 2022.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Amyloidosis</span><p id="par0070" class="elsevierStylePara elsevierViewall">A heterogeneous group of systemic diseases associated with the deposition of abnormal proteins folded in the form of amyloid fibrils. The systemic nature is a defining requirement.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Amyloid. Amyloid fibril</span><p id="par0075" class="elsevierStylePara elsevierViewall">Amyloid is an extracellular deposition of a fibrillar protein with specific staining properties. The amyloid fibril is the key component of the deposition. It associates with the serum amyloid P component (SAP), heparan sulphate proteoglycan (HSPG) and various apolipoproteins, to define the amyloid signature.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Basic nomenclature</span><p id="par0080" class="elsevierStylePara elsevierViewall">Amyloid fibril is referred to as protein A. It is followed by a suffix referring to the protein responsible for each subtype of amyloidosis. In TTR amyloidosis, the amyloidogenic protein is referred to as “ATTR” and the disease is referred to as “ATTR amyloidosis”.</p><p id="par0085" class="elsevierStylePara elsevierViewall">Hereditary amyloidosis is more accurate than familial amyloidosis. It is appropriate to add the “v” for variant (ATTRv) rather than the “m” for mutation. Genomic sequencing is preferred to protein sequencing. In the second case, three-letter or one-letter codes are accepted. Additional details on nomenclature are provided in Appendix <a class="elsevierStyleCrossRef" href="#sec0310">B</a> Supplementary material.</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Clinical phenotypes</span><p id="par0090" class="elsevierStylePara elsevierViewall">The phenotypic spectrum is wide due to the diversity of mutations and geographical origins. There are unidentified factors that influence the phenotype, as there are differences in age of onset and severity in patients with the same mutation. In addition, late-onset disease may be different from early-onset disease.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> There are four main phenotypes: Early-onset Val30Met (< 50 years), late-onset Val30Met (> 50 years), mixed phenotype without Val30Met and cardiac phenotype without Val30Met<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> (Appendix <a class="elsevierStyleCrossRef" href="#sec0310">B</a> Table S1). This categorisation is important in order to choose the most appropriate tools for patient management and follow-up.</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Diagnosis</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Onset symptoms</span><p id="par0095" class="elsevierStylePara elsevierViewall">The onset of ATTRv amyloidosis usually occurs after the age of 30. Dysautonomia symptoms such as gastric and intestinal motility disorders, orthostatism and palpitations, sweating disorders, neurogenic bladder or erectile dysfunction may be the onset of early forms of the disease. Significant weight losses suggest rapidly progressive and severe onset. Neuropathic foot pain and dysaesthesia mark the onset of sensory involvement. Carpal tunnel syndrome is not uncommon as an onset symptom, especially in males.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> From a cardiological point of view, the symptoms are predominantly right heart failure with peripheral congestion. Specific conduction system disorders may be the initial key to diagnosis. Onset with ocular symptoms or proteinuria is rare.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Clinical staging</span><p id="par0100" class="elsevierStylePara elsevierViewall">The Coutinho and PND scores are the most widely used for clinical staging and mainly consider ambulatory capacity. Although they correlate well with disease severity, they do not adequately assess other organ-specific manifestations. The Gillmore score categorises cardiological manifestations to provide a prognostic index, and its stages correlate with the likelihood of survival (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Genotyping</span><p id="par0105" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">TTR</span> gene has a causal role in ATTRv<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> amyloidosis. Every patient with a histological or non-invasive diagnosis of ATTR amyloidosis is a candidate for genetic testing. If ATTRv amyloidosis is suspected, the procedure is required. There are more than 140 variants in <span class="elsevierStyleItalic">TTR</span>. Val30Met is the most common. The genotype determines the symptomatology, which may be neurological, cardiological or a combination of both (Appendix <a class="elsevierStyleCrossRef" href="#sec0310">B</a> Table S2). Additional details on genotyping and variant distribution are provided in Appendix <a class="elsevierStyleCrossRef" href="#sec0310">B</a> Supplementary material.</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Neurodiagnostic tools</span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Electroneurographic and electromyographic studies</span><p id="par0110" class="elsevierStylePara elsevierViewall">Electrophysiological studies should include nerve conduction studies or electroneurogram (ENG) and electromyogram (EMG). ENG and EMG are useful for assessing the thicker fibres. They are used for diagnosis and follow-up and can identify the type of neuropathy (motor, sensory or mixed) and the anatomical pattern (axonal or demyelinating) but cannot confirm or exclude small fibre neuropathy (SFN). Large fibre neuropathy is more common in late-onset patients, in whom bilateral carpal tunnel syndrome may be associated. Even if the ENG is normal, it is useful for monitoring action potential amplitudes, whose drops of more than 50% are considered relevant. The most commonly used nerves are the ulnar and fibular nerves for motor potentials, and the ulnar and sural for sensory potentials.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Methods of SFN detection</span><p id="par0115" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Skin biopsy.</span> It is the gold standard for the diagnosis of SFN and the quantitative assessment of ATTRv amyloidosis. Assesses intraepidermal fibre density (IEFD). Neuropathy associated with ATTRv amyloidosis is associated with a significant reduction in IEFD. There is a negative correlation between amyloid load and IEFD.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Quantitative sensory test</span> (QST). Determines the threshold for thermal and vibration stimuli but does not differentiate whether the response to the stimulus is due to neuropathy or to a central nervous system disorder.</p><p id="par0125" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Sudoscan.</span> It is based on the fact that the electrochemical conductance of the skin changes according to the innervation of the sweat glands. It is useful during follow-up, although it may be normal in late onset cases. Helps differentiate ATTRv amyloidosis from chronic inflammatory demyelinating polyneuropathy (CIDP).<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">SFN diagnostic process</span><p id="par0130" class="elsevierStylePara elsevierViewall">The definitive diagnosis is based on the combination of compatible clinical symptoms and changes in at least one skin biopsy or QST of the foot. It is advisable to include a test that assesses the autonomic system, such as Sudoscan®. Also, in asymptomatic subjects, changes in at least two tests should be demonstrated to provide diagnostic confidence.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Cardiac diagnostic tools</span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Endomyocardial biopsy</span><p id="par0135" class="elsevierStylePara elsevierViewall">The presence of amyloid in an endomyocardial biopsy (EMB) confirms the diagnosis of cardiac amyloidosis with a sensitivity of almost 100%. The procedure carries a risk of complications, such as perforation or damage to the tricuspid valve, although this is low (∼1–2%) in experienced centres. Therefore, it is usually reserved only for patients in whom the diagnosis cannot be made non-invasively or in whom the differential diagnosis is not clear by these methods. The sample can be taken from any of the ventricles.</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Extracardiac biopsy</span><p id="par0140" class="elsevierStylePara elsevierViewall">The diagnosis of cardiac amyloidosis can be established in the presence of amyloid in extracardiac organs together with criteria of cardiac involvement by transthoracic echocardiography (TTE) or cardiac magnetic resonance imaging (CMR) (Appendix <a class="elsevierStyleCrossRef" href="#sec0310">B</a> Table S3), although the yield of extracardiac biopsies is variable according to centres and location.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Mass spectrometry</span><p id="par0145" class="elsevierStylePara elsevierViewall">It is considered the gold standard technique to determine the subtype of cardiac amyloidosis in borderline or double-positive immunohistochemistry cases.</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Electrocardiogram</span><p id="par0150" class="elsevierStylePara elsevierViewall">Electrocardiographic abnormalities are the norm in subjects with ATTRv. The most common electrocardiographic pattern is pseudoinfarction. Atrial fibrillation or conduction disorders such as atrioventricular block<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> are also common.</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Echocardiogram</span><p id="par0155" class="elsevierStylePara elsevierViewall">Although there may be no changes in the early stages, it is the cornerstone of the initial suspicion of amyloid cardiomyopathy (Appendix <a class="elsevierStyleCrossRef" href="#sec0310">B</a>, Table S3). Initial features are usually diastolic dysfunction, biatrial enlargement, thickening of the interatrial septum, mild pericardial effusion, mottled myocardium or thickening of the atrioventricular valves, causing valvular insufficiency of varying degrees. The left ventricle is usually not dilated, although the presence of at least moderate biventricular hypertrophy in the absence of arterial hypertension or severe valvular heart disease is the most characteristic parameter. In addition to concentric ventricular hypertrophy, asymmetric hypertrophy is commonly observed. In advanced stages there may be a restrictive pattern, with elevated filling pressures (E/eʹ > 15) and low eʹ velocities by tissue Doppler in the mitral and tricuspid annuli.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">Systolic function is normal or mildly reduced and may progress to systolic dysfunction. The global longitudinal strain has great diagnostic utility, detecting abnormalities in nearly 100% of cases, with reduced values in basal and mid-segments, even with preserved systolic function. In addition, as the values are preserved in apical segments, a “bull’s eye” pattern is obtained (cherry on-top) which allows differential diagnosis with other causes of ventricular hypertrophy.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Magnetic resonance imaging</span><p id="par0165" class="elsevierStylePara elsevierViewall">It provides a high-resolution structural image as well as the ability to characterise tissue (Appendix <a class="elsevierStyleCrossRef" href="#sec0310">B</a> Table S3). In cardiac amyloidosis, the intrinsic myocardial signal can be measured by balanced T1-/T2 sequences, T1 mapping (pre- and/or post-contrast), extracellular volume and late enhancement. These markers are pathognomonic in histological confirmation of cardiac amyloidosis but are not specific for amyloidosis. CMR is limited in patients with advanced renal insufficiency due to contraindications to the use of contrast, in patients with atrial fibrillation (AF), and in those with incompatible devices or limited ability to perform repeated breathing.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> CMR patterns suggestive of amyloidosis are described in Appendix <a class="elsevierStyleCrossRef" href="#sec0310">B</a> Supplementary material.</p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Cardiac scintigraphy</span><p id="par0170" class="elsevierStylePara elsevierViewall">Bisphosphonate bone scintigraphy is a mainstay of non-invasive diagnosis of ATTRv amyloidosis. However, more than one in five patients with immunoglobulin light chain amyloidosis may have grades 2 and 3 of 99Tc-DPD uptake, so only grades 2 and 3 in the absence of a monoclonal component allow the diagnosis of ATTR amyloidosis to be confirmed.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Appendix <a class="elsevierStyleCrossRef" href="#sec0310">B</a> Supplementary material provides details about the interpretation of the method.</p></span></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Other tools</span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Biopsy</span><p id="par0175" class="elsevierStylePara elsevierViewall">In regions of endemic ATTRv amyloidosis, no confirmatory biopsy is required for symptomatic individuals with compatible genetic variants. In all other cases, the pathologist should always consider ATTRv amyloidosis in the differential diagnosis of any new amyloidosis.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Archival biopsies may be useful. If absent or negative, amyloid may be detected in nerve and muscle biopsies (ATTRv amyloidosis is neuropathic in most cases). Subcutaneous fat, salivary gland or rectal biopsies may be taken to avoid morbidity. Biopsies of the carpal tunnel retinaculum are becoming increasingly common. It should be recalled that there are cardiac forms whose tissue distribution is similar to that of ATTR <span class="elsevierStyleItalic">wild-type</span> (wt) amyloidosis. Finally, vitreous amyloidosis can be confirmed on vitrectomy specimens. Appendix <a class="elsevierStyleCrossRef" href="#sec0310">B</a> Table S4 lists the biopsies that can be used to assess systemic amyloidosis.</p></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Ophthalmological studies</span><p id="par0180" class="elsevierStylePara elsevierViewall">TTR is widely distributed in many ocular tissues. To assess ocular involvement, an ophthalmological examination should include visual acuity measurement, biomicroscopy with pupillary examination, corneal confocal microscopy, anterior chamber and fundus examinations, tonometry and, where appropriate, visual field testing.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p></span><span id="sec0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Renal function</span><p id="par0185" class="elsevierStylePara elsevierViewall">Renal involvement is uncommon in the early stages, but it is advisable to perform renal function tests before starting therapy, as renal insufficiency or proteinuria may alter prognosis and response to treatment.</p></span><span id="sec0140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Nutritional status</span><p id="par0190" class="elsevierStylePara elsevierViewall">Nutritional status should be assessed by determining body mass index, body fat distribution and biochemical variables. Weight loss is common in ATTRv amyloidosis and, although it can lead to co-morbidities, it responds well to specific treatments.</p></span></span><span id="sec0145" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Disease onset criteria</span><p id="par0195" class="elsevierStylePara elsevierViewall">There is no single biological marker that identifies when a carrier is no longer asymptomatic. Appendix <a class="elsevierStyleCrossRef" href="#sec0310">B</a> describes some supplementary material that may, in the future, prove useful in determining the onset of the disease. Onset is considered to occur when there is at least one disease-defining symptom or sign, or one sign probably related to the disease associated with one or two abnormal tests (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>, Appendix <a class="elsevierStyleCrossRef" href="#sec0310">B</a> Fig. S1).<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0150" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Differential diagnosis</span><span id="sec0155" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Polyneuropathic involvement</span><p id="par0200" class="elsevierStylePara elsevierViewall">The biggest challenge is the patient from a non-endemic area with sporadic, late-onset, length-dependent sensory or sensorimotor axonal polyneuropathy, as the electrophysiological features may be similar to other polyneuropathies and initial screening should be performed. In addition, some comorbidities may coexist with ATTRv amyloidosis. <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> summarises the keys to differential diagnosis. The most common error occurs with CIDP, as there are patients with ATTRv amyloidosis and nerve conduction velocities (NCVs) in the demyelinating range. However, in ATTRv amyloidosis the decrease in NCVs is proportional to the axonal loss and the reduction in the amplitudes of the compound muscle action potential. Lack of response to treatment would also lead to a diagnosis of ATTRv amyloidosis.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0205" class="elsevierStylePara elsevierViewall">Paraproteinaemic neuropathies show clinical and electrophysiological similarities and multisystem involvement. Due to the possible coexistence of a monoclonal gammopathy of undetermined significance, haematological determination, scintigraphy to assess cardiac uptake of bone tracers, or VEGF levels may be required.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p></span><span id="sec0160" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Cardiological involvement</span><p id="par0210" class="elsevierStylePara elsevierViewall">In the presence of left ventricular hypertrophy, phenocopies of hypertrophic cardiomyopathy should be ruled out: primary amyloidosis, ATTRwt amyloidosis, Fabry disease, mitochondrial neuromuscular diseases and glycogenosis. We should have a high index of suspicion for amyloid disease in a patient with heart failure with preserved ejection fraction and the presence of certain criteria such as bilateral carpal tunnel syndrome, spinal stenosis, orthostatic hypotension, pseudoinfarction pattern, peripheral neuropathy or changes in bowel habits (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p></span></span></span><span id="sec0165" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Tratamiento</span><span id="sec0170" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Treatment of neurological and mixed phenotypes</span><p id="par0215" class="elsevierStylePara elsevierViewall">The therapeutic approach in patients with ATTRv amyloidosis and a mixed phenotype is similar to that adopted for an exclusively neurological phenotype. Treatment is determined by the stage according to the Coutinho score (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>) and by factors such as the severity of the neuropathy at onset, the patient’s preferences or the risk of thrombocytopenia. Treatment is only available for stages I or II. Patients in stage III are treated symptomatically and/or palliatively (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><span id="sec0175" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0175">Stage I</span><p id="par0220" class="elsevierStylePara elsevierViewall">There are four drugs with an approved indication for this stage. Tafamidis, at a dose of 20 mg/day, is a stabiliser of the TTR tetramer, slowing its dissociation into monomers, and was the first drug approved for this indication.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> Inotersen, patisiran and the recently approved vutrisiran are inhibitors of liver TTR synthesis. The former is an antisense oligonucleotide, while patisiran and vutrisiran are small interfering ribonucleic acids (siRNAs).<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21–23</span></a> Appendix <a class="elsevierStyleCrossRef" href="#sec0310">B</a> Supplementary material describes dosages, routes of administration and other specifications for the four drugs.</p></span><span id="sec0180" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0180">Choosing the first line of treatment</span><p id="par0225" class="elsevierStylePara elsevierViewall">There is no clinical evidence to prioritise the use of tafamidis, inotersen, patisiran or vutrisiran over the others. The decision is based on the physician's experience, local protocols and patient preferences. Due to its oral dosing, safety profile and use experience, tafamidis is generally the first choice, especially in cases of early diagnosis. It should be remembered that in the case of a mixed phenotype (with cardiac involvement), the dose of tafamidis chosen should be the one approved for the cardiac phenotype, i.e. 61 mg.</p><span id="sec0185" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0185">Liver transplant</span><p id="par0230" class="elsevierStylePara elsevierViewall">The advent of new drugs has relegated transplantation to a secondary role in the therapeutic algorithm. Its indication is limited to the patient's choice, to situations requiring another transplant or to resistance to pharmacological treatment.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> Patisiran has demonstrated safety and efficacy in patients undergoing liver transplantation.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a></p></span><span id="sec0190" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0190">Heart transplant</span><p id="par0235" class="elsevierStylePara elsevierViewall">It can be considered in patients with advanced heart failure and no contraindications to it.</p></span></span><span id="sec0195" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0195">Stage II</span><span id="sec0200" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0200">Liver TTR synthesis inhibitors</span><p id="par0240" class="elsevierStylePara elsevierViewall">First-line treatment is reduced to inhibitors of liver TTR synthesis: inotersen, patisiran or vutrisiran. The considerations and details described for these drugs in Stage I should be reiterated.</p></span><span id="sec0205" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0205">Transplant</span><p id="par0245" class="elsevierStylePara elsevierViewall">In case of therapeutic failure with siRNA, liver transplantation could be considered, as well as cardiac or renal transplantation, in situations of advanced heart failure or severe renal impairment, respectively.</p></span></span></span><span id="sec0210" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0210">Cardiac phenotype treatment</span><p id="par0250" class="elsevierStylePara elsevierViewall">A distinction should be made between specific treatment and cardiac supportive care covering the various cardiac manifestations of the disease.</p><span id="sec0215" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0215">Specific treatment</span><span id="sec0220" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0220">Tafamidis</span><p id="par0255" class="elsevierStylePara elsevierViewall">Tafamidis is the first and only disease-modifying therapy approved for the treatment of cardiac TTR amyloidosis. The ATTR-ACT study (see Appendix <a class="elsevierStyleCrossRef" href="#sec0310">B</a> Supplementary material) demonstrated the usefulness of tafamidis in patients with cardiac TTR amyloidosis, with survival benefits after follow-ups of up to 58 months.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a></p></span></span><span id="sec0225" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0225">Maintenance treatment</span><span id="sec0230" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0230">Heart failure</span><p id="par0260" class="elsevierStylePara elsevierViewall">It is the main manifestation of cardiac amyloidosis. The mainstay of treatment is loop diuretics, which could be combined with low doses of aldosterone antagonists. However, caution should be exercised due to the restrictive pathophysiology of heart disease and possible dysautonomia. Excessive diuretics may lead to hypotension and clinical worsening. Water restriction (1.5 litres/day), salt intake restriction (< 2 g/day) and educational measures, such as daily weight control, are also essential.</p><p id="par0265" class="elsevierStylePara elsevierViewall">There is no evidence to support the use of angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin receptor blockers (ARBs), neprilysin inhibitors or beta-blockers. In fact, they may condition a worsening precipitating hypotension and low cardiac output. Clinical experience suggests that discontinuing these therapeutic groups is beneficial.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> Beta-blocker de-escalation should be considered in the presence of symptomatic hypotension, low heart rates or conduction disturbances. On the other hand, non-dihydropyridine calcium channel blockers are contraindicated, having been associated with cardiogenic shock, atrioventricular block and systolic dysfunction.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a></p><p id="par0270" class="elsevierStylePara elsevierViewall">In advanced HF, ventricular assist devices are often not suitable options. Heart transplantation may be an option for patients with predominantly cardiac involvement, as is the case for carriers of the Val142Ile variant. Studies have documented post-transplant survival comparable to that of patients transplanted for other types of heart disease.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a></p></span><span id="sec0235" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0235">Atrial fibrillation</span><p id="par0275" class="elsevierStylePara elsevierViewall">No differences in survival have been observed in patients with ATTR amyloidosis with or without AF.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> The strategy between heart rate and rhythm control should be individualised. Digoxin may be considered for heart rate control, but at low doses and with close monitoring. If beta-blockers are chosen, the dose should also be as low as possible. Non-dihydropyridine calcium antagonists are contraindicated because of their potential binding to amyloid fibrils, with the consequent risk of arterial hypotension and syncope.</p><p id="par0280" class="elsevierStylePara elsevierViewall">Rhythm control is most effective in early stages of the disease. Amiodarone is the most commonly used antiarrhythmic agent in cardiac amyloidosis. Atrioventricular node ablation plus pacemaker implantation is sometimes the option. As the disease progresses and the left atrium becomes dilated, the likelihood of maintaining sinus rhythm falls, so we would opt for a rate-control strategy.</p><p id="par0285" class="elsevierStylePara elsevierViewall">Electrical cardioversion (ECV) is a risky procedure due to the high rate of intracardiac thrombus formation, so transoesophageal echocardiography is always recommended prior to the procedure. The rate of complications, such as transient atrioventricular block, stroke or ventricular tachycardia/fibrillation, after ECV is also higher than that experienced by patients with other heart diseases.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Finally, there are no robust studies to support the appropriateness of pulmonary vein ablation in cardiac amyloidosis.</p></span><span id="sec0240" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0240">Thromboembolism</span><p id="par0290" class="elsevierStylePara elsevierViewall">Patients with cardiac amyloidosis are at high risk of thromboembolism. All patients with cardiac involvement due to ATTRv amyloidosis and AF should be anticoagulated, regardless of the CHA2DS2-VASC score. No differences have been observed in the choice of anticoagulant between vitamin K antagonists and direct oral anticoagulants, although there are no prospective studies.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p></span><span id="sec0245" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0245">Conduction disorders</span><p id="par0295" class="elsevierStylePara elsevierViewall">The approach follows current guidelines for pacemaker implantation indications. Cardiac resynchronisation therapy (CRT) should also follow the usual indications in heart failure, especially if a high pacing rate is expected.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p></span><span id="sec0250" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0250">Ventricular arrhythmias</span><p id="par0300" class="elsevierStylePara elsevierViewall">Implantable cardioverter-defibrillators should be considered in secondary prevention. There are no definitive guidelines on when and for whom to use them in primary prevention.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p></span></span></span><span id="sec0255" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0255">Symptomatic treatment</span><p id="par0305" class="elsevierStylePara elsevierViewall">Except for some subtleties, it does not differ from that used in other entities with similar symptoms.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> There is little evidence collected specifically for ATTRv amyloidosis, so guidelines for the treatment of diabetic neuropathy and primary amyloidosis have been extrapolated. Appendix <a class="elsevierStyleCrossRef" href="#sec0310">B</a> Table S5 sets out the treatment options, although some points should be clarified. Attention should be paid to the possible side effects associated with neuropathic pain medications, which could worsen manifestations of the disease itself, especially dysautonomia symptoms. For disruptive pain, basic analgesics and non-steroidal anti-inflammatory drugs (NSAIDs) are recommended, with opioids being discouraged. Proteinuria should be treated with ACE inhibitors, which are required in advanced stages of renal replacement therapy, preferably haemodialysis, or in renal transplantation. In addition to possible pharmacological support, diarrhoea requires a correct nutritional approach and correction of water and electrolyte deficiencies. Options for dyspareunia attributable to vaginal dryness would be, in this order, hyaluronic acid lubricating gels and topical oestrogens. It is also important to point out that the response to vitrectomy is modest, with recurrences being observed, which is why retinal laser photocoagulation has been proposed, as this tissue is the producer of ocular amyloid. Finally, the need for re-interventions after glaucoma surgery by trabeculectomy and insertion of drainage devices is also not uncommon.</p></span><span id="sec0260" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0260">Other treatments/experimental treatments</span><p id="par0310" class="elsevierStylePara elsevierViewall">Appendix <a class="elsevierStyleCrossRef" href="#sec0310">B</a> Supplementary material lists a number of drugs and procedures, many of which are in clinical trials, that could expand the battery of therapeutic strategies for the different stages of ATTRv amyloidosis in the short and medium term.</p></span></span><span id="sec0265" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0265">Follow-up</span><span id="sec0270" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0270">Asymptomatic carrier follow-up</span><p id="par0315" class="elsevierStylePara elsevierViewall">To determine when to start follow-up of asymptomatic TTR mutation carriers, the predicted age of disease onset (PADO) should be determined, which depends on the typical age of disease onset with the corresponding mutation and the age of disease onset in relatives, in order to start follow-up at least 10 years earlier. However, the onset of the index case relatives could be much earlier, so that follow-up could be initiated even at the diagnosis of carrier status.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0320" class="elsevierStylePara elsevierViewall">The frequency of monitoring should be annual, and closer surveillance should be maintained as PADO nears or with the onset of symptoms. A complete and thorough system-based history taking is important, and patients should be instructed in the early recognition of symptoms. Ancillary examinations on an annual or biannual basis are desirable (Appendix <a class="elsevierStyleCrossRef" href="#sec0310">B</a> Table S6).<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p></span><span id="sec0275" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0275">Follow-up of the patient in treatment</span><p id="par0325" class="elsevierStylePara elsevierViewall">Carried out by a multidisciplinary team in specialised centres, every 3 to 6 months. The patient should be provided with questionnaires to assess disability and quality of life (QoL) and to perform standardised neurological and cardiological assessments. Ophthalmological assessment can be performed annually. Appendix <a class="elsevierStyleCrossRef" href="#sec0310">B</a> Table S7 summarises the procedures to be carried out.</p></span><span id="sec0280" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0280">Criteria for clinical progression and therapeutic failure</span><p id="par0330" class="elsevierStylePara elsevierViewall">Regular monitoring of all possible manifestations of the disease is essential to adjust treatment, delay clinical deterioration and maintain QoL. There is no consensus on the appropriate tools to determine disease progression.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> It must be based on a combination of clinical manifestations and self-reported symptoms (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>). In terms of criteria for heart disease progression, a recent expert consensus selected 11 variables, grouped into three domains: clinical and functional, biomarkers and imaging, and echocardiography. There should be significant changes in at least one marker in each domain in order for progression to be considered.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a></p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0335" class="elsevierStylePara elsevierViewall">The patient should be involved in his or her follow-up, offering him or her the various therapeutic alternatives available.</p></span></span><span id="sec0285" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0285">Funding</span><p id="par0340" class="elsevierStylePara elsevierViewall">The meetings and the medical writing service have been funded by <span class="elsevierStyleGrantSponsor" id="gs0005">Sobi</span>. The content of the manuscript has been entirely decided by the authors.</p></span><span id="sec0290" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0290">Ethical considerations</span><p id="par0345" class="elsevierStylePara elsevierViewall">Not applicable, as the current work does not include patient data.</p></span><span id="sec0295" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0295">Authors’ contribution</span><p id="par0350" class="elsevierStylePara elsevierViewall">All authors have approved the final version of the manuscript.</p></span><span id="sec0300" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0300">Conflict of interest</span><p id="par0355" class="elsevierStylePara elsevierViewall">JGM has disclosed that he has received lecture and consultancy fees from <span class="elsevierStyleGrantSponsor" id="gs0010">Pfizer</span>, <span class="elsevierStyleGrantSponsor" id="gs0015">Alnylam</span> and <span class="elsevierStyleGrantSponsor" id="gs0020">Akcea</span>. LG has disclosed that he has received lecture fees and consultancy fees from Pfizer, Alnylam, Akcea and <span class="elsevierStyleGrantSponsor" id="gs0025">Grunenthal</span>. EGL has received lecture fees from Pfizer and Alnylam; he has received consultancy fees from Pfizer and <span class="elsevierStyleGrantSponsor" id="gs0030">Proclara</span>. IC reports as a principal investigator and consultant to Alnylam Pharmaceuticals, Pfizer Inc. and IONIS Pharmaceuticals.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "sec0005" "titulo" => "Introduction" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0010" "titulo" => "General description" ] 1 => array:3 [ "identificador" => "sec0015" "titulo" => "Definitions and nomenclature" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Amyloidosis" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Amyloid. 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array:2 [ "identificador" => "sec0085" "titulo" => "Endomyocardial biopsy" ] 1 => array:2 [ "identificador" => "sec0090" "titulo" => "Extracardiac biopsy" ] 2 => array:2 [ "identificador" => "sec0095" "titulo" => "Mass spectrometry" ] 3 => array:2 [ "identificador" => "sec0100" "titulo" => "Electrocardiogram" ] 4 => array:2 [ "identificador" => "sec0105" "titulo" => "Echocardiogram" ] 5 => array:2 [ "identificador" => "sec0110" "titulo" => "Magnetic resonance imaging" ] 6 => array:2 [ "identificador" => "sec0115" "titulo" => "Cardiac scintigraphy" ] ] ] 5 => array:3 [ "identificador" => "sec0120" "titulo" => "Other tools" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0125" "titulo" => "Biopsy" ] 1 => array:2 [ "identificador" => "sec0130" "titulo" => "Ophthalmological studies" ] 2 => array:2 [ "identificador" => "sec0135" "titulo" => "Renal function" ] 3 => array:2 [ "identificador" => "sec0140" "titulo" => "Nutritional status" ] ] ] 6 => array:2 [ "identificador" => "sec0145" "titulo" => "Disease onset criteria" ] 7 => array:3 [ "identificador" => "sec0150" "titulo" => "Differential diagnosis" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0155" "titulo" => "Polyneuropathic involvement" ] 1 => array:2 [ "identificador" => "sec0160" "titulo" => "Cardiological involvement" ] ] ] ] ] 2 => array:3 [ "identificador" => "sec0165" "titulo" => "Tratamiento" "secciones" => array:4 [ 0 => array:3 [ "identificador" => "sec0170" "titulo" => "Treatment of neurological and mixed phenotypes" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0175" "titulo" => "Stage I" ] 1 => array:3 [ "identificador" => "sec0180" "titulo" => "Choosing the first line of treatment" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0185" "titulo" => "Liver transplant" ] 1 => array:2 [ "identificador" => "sec0190" "titulo" => "Heart transplant" ] ] ] 2 => array:3 [ "identificador" => "sec0195" "titulo" => "Stage II" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0200" "titulo" => "Liver TTR synthesis inhibitors" ] 1 => array:2 [ "identificador" => "sec0205" "titulo" => "Transplant" ] ] ] ] ] 1 => array:3 [ "identificador" => "sec0210" "titulo" => "Cardiac phenotype treatment" "secciones" => array:2 [ 0 => array:3 [ "identificador" => "sec0215" "titulo" => "Specific treatment" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0220" "titulo" => "Tafamidis" ] ] ] 1 => array:3 [ "identificador" => "sec0225" "titulo" => "Maintenance treatment" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0230" "titulo" => "Heart failure" ] 1 => array:2 [ "identificador" => "sec0235" "titulo" => "Atrial fibrillation" ] 2 => array:2 [ "identificador" => "sec0240" "titulo" => "Thromboembolism" ] 3 => array:2 [ "identificador" => "sec0245" "titulo" => "Conduction disorders" ] 4 => array:2 [ "identificador" => "sec0250" "titulo" => "Ventricular arrhythmias" ] ] ] ] ] 2 => array:2 [ "identificador" => "sec0255" "titulo" => "Symptomatic treatment" ] 3 => array:2 [ "identificador" => "sec0260" "titulo" => "Other treatments/experimental treatments" ] ] ] 3 => array:3 [ "identificador" => "sec0265" "titulo" => "Follow-up" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0270" "titulo" => "Asymptomatic carrier follow-up" ] 1 => array:2 [ "identificador" => "sec0275" "titulo" => "Follow-up of the patient in treatment" ] 2 => array:2 [ "identificador" => "sec0280" "titulo" => "Criteria for clinical progression and therapeutic failure" ] ] ] 4 => array:2 [ "identificador" => "sec0285" "titulo" => "Funding" ] 5 => array:2 [ "identificador" => "sec0290" "titulo" => "Ethical considerations" ] 6 => array:2 [ "identificador" => "sec0295" "titulo" => "Authors’ contribution" ] 7 => array:2 [ "identificador" => "sec0300" "titulo" => "Conflict of interest" ] 8 => array:2 [ "identificador" => "xack776502" "titulo" => "Acknowledgements" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2023-09-27" "fechaAceptado" => "2024-04-22" "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:2 [ 0 => array:4 [ "apendice" => "<p id="par0365" class="elsevierStylePara elsevierViewall">Roberto Barriales-Villa. Familial Heart Disease Unit, Complexo Hospitalario Universitario de A Coruña (CHUAC-CIBERCV), Instituto de Investigación Biomédica de A Coruña (INIBIC), A Coruña. Spain.</p> <p id="par0370" class="elsevierStylePara elsevierViewall">Catarina Falcão de Campos. Serviço de Neurologia, Departamento de Neurociências, Hospital de Santa Maria CHULN and Lisboa, Centro de Estudos Egas Moniz, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.</p> <p id="par0375" class="elsevierStylePara elsevierViewall">Márcio Neves Cardoso. Unidade Corino de Andrade, Departamento de Neurociências, Centro Hospitalar do Porto, Porto, Portugal.</p> <p id="par0380" class="elsevierStylePara elsevierViewall">Carlos Casasnovas. Neuromuscular Unit, Neurology Department, Hospital Universitari de Bellvitge, IDIBELL and CIBERER, l'Hospitalet de Llobregat, Barcelona, Spain.</p> <p id="par0385" class="elsevierStylePara elsevierViewall">Julián Fernández-Martín. Internal Medicine Department, Hospital Alvaro Cunqueiro, Vigo, Pontevedra, Spain.</p> <p id="par0390" class="elsevierStylePara elsevierViewall">Raúl Juntas Morales. Neuromuscular Diseases Unit, Hospital Universitari Vall d'Hebron, Barcelona, Spain.</p> <p id="par0395" class="elsevierStylePara elsevierViewall">Inés Losada López. Internal Medicine Service, Hospital Son Llàtzer. Institute for Health Research Illes Balears (idISBA). Palma de Mallorca, Spain.</p> <p id="par0400" class="elsevierStylePara elsevierViewall">Laura Martínez-Vicente. Neurology Department, Hospital Universitario Clínico San Carlos, Madrid, Spain.</p> <p id="par0405" class="elsevierStylePara elsevierViewall">Francisco Muñoz-Beamud. Internal Medicine Department, Hospital Universitario Juan Ramón Jiménez, Huelva, Spain.</p> <p id="par0410" class="elsevierStylePara elsevierViewall">Luis F. Quintana. Nephrology Department, Hospital Clínic, Barcelona, University of Barcelona, IDIBAPS, Barcelona, Spain.</p> <p id="par0415" class="elsevierStylePara elsevierViewall">Teresa Sevilla. Neurology Service, Hospital Universitari i Politècnic La Fe / IISLAFE, University of Valencia, CIBERER (ERN EURO-NMD), Valencia, Spain.</p>" "etiqueta" => "Appendix A" "titulo" => "A-ATTR Working Group" "identificador" => "sec0305" ] 1 => array:4 [ "apendice" => "<p id="par0425" class="elsevierStylePara elsevierViewall">The following is Supplementary data to this article:<elsevierMultimedia ident="upi0005"></elsevierMultimedia></p>" "etiqueta" => "Appendix B" "titulo" => "Supplementary data" "identificador" => "sec0315" ] ] ] ] "multimedia" => array:6 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1074 "Ancho" => 1386 "Tamanyo" => 91000 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Treatment choice in patients with ATTRv-PN.</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">ATTRv-PN: hereditary transthyretin amyloidosis with polyneuropathy.</p>" ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">ATTRv: hereditary transthyretin amyloidosis; n.a.: not applicable; NT-proBNP: N-terminal proB natriuretic peptide; FAP: Familial Amyloidotic Polyneuropathy score; PND: modified PolyNeuropathy Disability score; eGFR: estimated glomerular filtration rate.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Symptoms \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Score</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Sensory-motor impairment</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Coutinho<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PND<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Asymptomatic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Sensory disturbances, normal gait \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">II<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">I \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Sensory disturbances, altered gait without requiring support \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">II<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">II \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Gait requiring support \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">III<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IIIA \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Gait requiring two supports \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">III<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IIIB \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Wheelchair-bound or bedridden \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IIII<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">e</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IV \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Cardiac involvement</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gillmore<a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">f</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>NT-proBNP ≤ 3,000 ng/l<a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">g</span></a>; eGFR ≥ 45 ml/min<a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">g</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">I<a class="elsevierStyleCrossRef" href="#tblfn0040"><span class="elsevierStyleSup">h</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Neither Gillmore I nor Gillmore III \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">II<a class="elsevierStyleCrossRef" href="#tblfn0045"><span class="elsevierStyleSup">i</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>NT-proBNP > 3,000 ng/l<a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">g</span></a>; eGFR < 45 ml/min<a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">g</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">III<a class="elsevierStyleCrossRef" href="#tblfn0050"><span class="elsevierStyleSup">j</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3668123.png" ] ] ] "notaPie" => array:10 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Also called the PAF score (Coutinho P et al., Amsterdam: Excerpta Medica; 1980, pp. 88–98).</p>" ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Yamamoto S et al., Am J Transplant. 2007;7:2597–604.</p>" ] 2 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "c" "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Duration: 3 to 9 years in early-onset patients, 2 to 4 years in late-onset patients.</p>" ] 3 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "d" "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Duration: 2 to 8 years in early-onset patients, 2 to 3 years in late-onset patients.</p>" ] 4 => array:3 [ "identificador" => "tblfn0025" "etiqueta" => "e" "nota" => "<p class="elsevierStyleNotepara" id="npar0025">Duration: 1 to 5 years in early-onset patients, 1 to 2 years in late-onset patients.</p>" ] 5 => array:3 [ "identificador" => "tblfn0030" "etiqueta" => "f" "nota" => "<p class="elsevierStyleNotepara" id="npar0030">Gillmore JD et al., Eur Heart J. 2018;39:2799–806.</p>" ] 6 => array:3 [ "identificador" => "tblfn0035" "etiqueta" => "g" "nota" => "<p class="elsevierStyleNotepara" id="npar0035">At diagnosis. Estimated survival times on the Gillmore score:</p>" ] 7 => array:3 [ "identificador" => "tblfn0040" "etiqueta" => "h" "nota" => "<p class="elsevierStyleNotepara" id="npar0040">over 6 years;</p>" ] 8 => array:3 [ "identificador" => "tblfn0045" "etiqueta" => "i" "nota" => "<p class="elsevierStyleNotepara" id="npar0045">about 4 years;</p>" ] 9 => array:3 [ "identificador" => "tblfn0050" "etiqueta" => "j" "nota" => "<p class="elsevierStyleNotepara" id="npar0050">about 2 years.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Staging scores for ATTRv amyloidosis according to sensory-motor or cardiac involvement.</p>" ] ] 2 => array:9 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Source: adapted from Conceição et al., Amyloid 2019;26:3–9." "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0015" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">ATTRv: hereditary transthyretin amyloidosis.</p><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">In neurophysiological tests such as Sudoscan, the pathological result must be repeated to be considered significant. In early-onset patients, a reduction in the sensory potentials of the sural and median nerves precedes the clinical onset.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Definitely related \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Probably related \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Symptoms</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Neurological \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Spontaneous painBurning painAcute painSunburn-like painParoxysmal painEvoked painAllodyniaHypoesthesiaSuperficial proprioceptive \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Non-painful sensationsParesthesiasRestless legs syndrome \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Autonomic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Constipation alternating with diarrhoea <span class="elsevierStyleItalic">(de novo)</span>Orthostatic syncopeUnintentional weight lossSexual dysfunction \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Early satietyEpisodic diarrhoeaDizziness \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Cardiac \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dyspnoea on exertion and at restOrthopnoeaFatigueSyncope \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PalpitationsLeg oedemaDizziness \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Signs</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Neurological \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Small fibre involvementPainful hypoesthesia (pinprick)Hypoaesthesia to temperatureAllodyniaHyperalgesiaLarge fibre involvementHypoaesthesia to superficial touchDecreased vibration sensitivityDecrease in proprioceptive sensitivityAbsence of hamstring reflexesMuscle atrophy and/or weaknessBilateral carpal tunnel syndromeHyperalgesiaDistribution consistent with peripheral neuropathy</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Autonomic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Orthostatic hypotension</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Cardiacs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Signs of right heart failureLower limb oedemaElevated jugular venous pressureSigns of left heart failureLung oedemaAtrial arrhythmias, AF/<span class="elsevierStyleItalic">flutter</span>Sino-atrial blockAtrioventricular blockIncreased wall thickness of the left and right ventriclesGlobal strain abnormalities on echocardiographyCardiac uptake in bone scintigraphyAbnormal gadolinium kinetics and transmural or subendocardial late enhancement on magnetic resonance imaging</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Ocular \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vitreous opacities associated with progressive visual lossGlaucoma</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3668125.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Relationship of symptoms to diagnosis of symptomatic disease in ATTRv.</p>" ] ] 3 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0020" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">AF: atrial fibrillation; ATTRv: inherited transthyretin amyloidosis; AV: atrioventricular; CIDP: chronic inflammatory demyelinating polyradiculopathy; HF: heart failure; HF-PEF: heart failure with preserved ejection fraction; NGS: next generation sequencing; SPECT: single-photon emission tomography; VEGF: vascular endothelial growth factor.</p><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Cardiac involvement in ATTRv is determined by the genetic variant involved, being more common in carriers of Val142Ile, Thr80Ala, Leu131Met and Ile88Leu, whereas Val50Met with late involvement, Ser97Tyr, Glu109Gln and Gly67Glu are associated with mixed, cardiac or neurological phenotypes.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Differential diagnosis \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Keys \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Neuropathies</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>CIDP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">● Detailed analysis of electrophysiological findings● Lack of response to treatment \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Paraproteinemic amyloidosis (AL, POEMS syndrome) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">● Monoclonal band in serum and urine● Haematological assessment● Bone tracer scintigraphy● VEGF levels \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Diabetic neuropathy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">● Less motor impairment● Poor glycaemic control \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Toxic, infectious or deficiency neuropathies \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">● Epidemiological history● Pre-screening for neuropathies \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Charcot-Marie-Tooth disease \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">● Minimal sensory deficit● No autonomic involvement \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Fabry disease \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">● Angiokeratomas● Stroke● Alpha-galactosidase deficiency \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Cardiopathies</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Hypertrophic cardiomyopathy<a class="elsevierStyleCrossRef" href="#tblfn0055"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">● Family tree of at least three generations● Distinct type of inheritance in mitochondrial diseases (matrilineal inheritance)● NGS genetic study for analysis of sarcomeric genes and major phenocopies (<span class="elsevierStyleItalic">TTR</span>, <span class="elsevierStyleItalic">GLA</span>, <span class="elsevierStyleItalic">PRKAG2</span>, etc.)● Family history of hypertrophic cardiomyopathy with neurological involvement● Absence of features typical of other storage and/or neuromuscular diseases \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>HF-PEF with > 12 mm ventricular thickness<a class="elsevierStyleCrossRef" href="#tblfn0060"><span class="elsevierStyleSup">b</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">● Cardiac scintigraphy: planar and SPECT imaging to distinguish activity in the myocardial blood pool activity● Absence of monoclonal component \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>AF/flutter atrial palpitations or syncope due to AV blocks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">● Rule out associated ventricular hypertrophy and <span class="elsevierStyleItalic">red flags</span> typical of the disease when no other reasons for these arrhythmias are found \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3668124.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0055" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0055">Cardiac hypertrophy caused by storage diseases such as glycogenosis, Fabry disease, mitochondrial or neuromuscular diseases.</p>" ] 1 => array:3 [ "identificador" => "tblfn0060" "etiqueta" => "b" "nota" => "<p class="elsevierStyleNotepara" id="npar0060">Compatible with arterial hypertension, restrictive cardiomyopathy and other entities.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Keys to the differential diagnosis of ATTRv amyloidosis versus other neurological and cardiac pathologies.</p>" ] ] 4 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0025" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">6mWT: 6-meter walk test; CMAP: compound muscle action potential; DPD: 99mTc-3,3-diphosphono-1,2-propanedicarboxylic acid; ECG: electrocardiogram; ECHO: echocardiogram; ESC: electrochemical skin conductance; GFR: glomerular filtration rate; mBMI: modified body mass index; NCS: nerve conduction studies; NIS: Neuropathy Impairment Score; NT-proBNP: N-terminal proB natriuretic peptide; PND: modified PolyNeuropathy Disability score; SNAP: sensory nerve action potential; TnI: troponin I.</p><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">It is important to ensure that the tools used in clinical trials are able to establish baseline values, provide reproducible measurements and do not quickly show a ‘floor’ or ‘ceiling’ effect.</p>" "tablatextoimagen" => array:2 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Clinical follow-up</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Field of examination \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Frequency (months) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Determinations \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Disease progression \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neurological (clinical) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NIS total PND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Increase > 10 points/year Increase <span class="elsevierStyleItalic">vs.</span> baseline \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neurological (neurophysiology) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Nerve conduction studies:Σ. NCS - CMAP (ulnar + peroneal) + SNAP (ulnar + sural) Sudoscan:Σ ESC - (ESC feet + ESC hands) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Decrease > 50% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Laboratory (cardiac and renal biomarkers) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Proteinuria Albuminuria/microalbuminuria NT-proBNP TnI GFR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">De novo proteinuria in nephrotic range (> 3,5 g/day, especially albumin Decreasing GFR > 50% <span class="elsevierStyleItalic">vs.</span> baseline \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cardiac \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ECG/Holter ECHO Scintigraphy with DPD6mWT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Conduction abnormalities/<span class="elsevierStyleItalic">de novo</span> arrhythmias Restrictive transmitral filling pattern De novo DPD uptakeDecrease ≥25% in distance covered \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ocular \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Intraocular pressure Classification of vitreous opacities Corneal fibre length in confocal microscopy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Intraocular pressure increase > 20% and/or 5 mmHg Stage progression (irrespective of time) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3668122.png" ] ] 1 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Self-reported symptoms</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Symptoms \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Disease progression \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Autonomic</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">De novo</span> or worsening, refractory to symptomatic therapy \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">•</span><p id="par0005" class="elsevierStylePara elsevierViewall">Orthostatic intolerance</p></li></ul> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">•</span><p id="par0010" class="elsevierStylePara elsevierViewall">Genitourinary dysfunction</p></li></ul> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">•</span><p id="par0015" class="elsevierStylePara elsevierViewall">Sexual dysfunction</p></li></ul> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Gastrointestinal</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Decrease in BMIm > 20%. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">•</span><p id="par0025" class="elsevierStylePara elsevierViewall">Diarrhoea/constipation</p></li></ul> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">•</span><p id="par0030" class="elsevierStylePara elsevierViewall">Nausea/Vomiting</p></li></ul> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><ul class="elsevierStyleList" id="lis0035"><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">•</span><p id="par0035" class="elsevierStylePara elsevierViewall">mBMI</p></li></ul> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Somatic neuropathy</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">An increase in negative sensory symptoms (> 1 level) and/or a change in the neuropathy score (PND) or in the stage of the disease is observed. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><ul class="elsevierStyleList" id="lis0045"><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">•</span><p id="par0045" class="elsevierStylePara elsevierViewall">Negative sensory symptoms (anaesthesia; ataxia)</p></li></ul> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><ul class="elsevierStyleList" id="lis0050"><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">•</span><p id="par0050" class="elsevierStylePara elsevierViewall">Motor impairment</p></li></ul> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Ocular manifestations</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">De novo symptoms or worsening, refractory to symptomatic therapy \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Cardiac manifestations</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">De novo symptoms or worsening, refractory to symptomatic therapy \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3668126.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Longitudinal clinical determinations and patient-reported symptoms to assess disease progression.</p>" ] ] 5 => array:5 [ "identificador" => "upi0005" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => false "mostrarDisplay" => true "Ecomponente" => array:2 [ "fichero" => "mmc1.doc" "ficheroTamanyo" => 145408 ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:31 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Y. 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