ABSTRACT
Abstract Introduction: Hereditary transthyretin amyloidosis (ATTRv) is a severe autosomal dominant systemic disease. It affects the peripheral and autonomic nervous systems, heart, kidneys, and eyes. Amyloid deposition has been demonstrated in the glomerular and tubulointerstitial compartments of the kidney. Therefore, urinary acidification disorders such as renal tubular acidosis (RTA) may be early manifestations of renal involvement in this population. Objective: To evaluate the prevalence of RTA in individuals with ATTRv. Methods: We included symptomatic and asymptomatic individuals with TTR mutation, older than 18 years, GFR >45 mL/min/1.73m2, without systemic metabolic acidosis. Urinary acidification protocol was performed with furosemide and fludrocortisone after 12 h of water deprivation (water deprivation test - WDT) and measurements of urine ammonium ( UNH 4 +) and titratable acidity (UTA). Proximal RTA (pRTA) was diagnosed when FEHCO3>10%. Incomplete form distal RTA (dRTA) was diagnosed if UpH>5.3. Results: We selected 49 individuals with a mean age of 40 (35.5-56.5) years, 63% of which were female, 84% were Caucasian, and mean GFR was 85.5 ± 20.5 mL/min/1.73m2. 94% had the genetic variant Val50Met and 57% were symptomatic. The prevalence of pRTA was 2% and of dRTA was 16.3%. In the subgroup with dRTA, there was no significant increase in excretion of UNH 4 + and UTA. We observed a good correlation between UpH by potentiometry and UpH dipstick. A UpH<5.5 on the dipstick had 100% sensitivity and negative predictive value to exclude dRTA. Conclusion: A high prevalence of RTA was found in individuals with TTR mutations. The UpH dipstick after WDT had good accuracy for screening for dRTA. Further studies are needed to evaluate the impact of early diagnosis and treatment of RTA in this population.
Resumo Introdução: A amiloidose hereditária por transtirretina (ATTRv) é uma doença sistêmica autossômica dominante grave. Afeta os sistemas nervoso periférico e autônomo, coração, rins e olhos. A deposição de amiloide foi demonstrada nos compartimentos glomerular e tubulointersticial do rim. Portanto, distúrbios de acidificação urinária, como acidose tubular renal (ATR), podem ser manifestações precoces de envolvimento renal nessa população. Objetivo: Avaliar a prevalência de ATR em indivíduos com ATTRv. Métodos: Incluímos indivíduos sintomáticos e assintomáticos com mutação na TTR, maiores de 18 anos, TFG >45 mL/min/1,73m2, sem acidose metabólica sistêmica. Realizou-se protocolo de acidificação urinária com furosemida e fludrocortisona após 12 horas de privação hídrica (teste de restrição hídrica - TRH) e medições de amônia urinária ( uNH 4 +) e acidez titulável (uTA) na urina. ATR proximal (ATRp) foi diagnosticada quando FEHCO3>10%. ATR distal (ATRd) de forma incompleta foi diagnosticada se pHu>5,3. Resultados: Selecionamos 49 indivíduos com idade média de 40 (35,5-56,5) anos, 63% mulheres, 84% caucasianos e TFG média de 85,5 ± 20,5 mL/min/1,73m2. 94% apresentaram a variante genética Val50Met; 57% eram sintomáticos. A prevalência de ATRp foi 2% e a de ATRd foi 16,3%. No subgrupo com ATRd, não houve aumento significativo na excreção de uNH 4 + e uTA. Observamos uma boa correlação entre pHU por potenciometria e pHU por fita reagente. Um pHU<5,5 na fita reagente apresentou 100% de sensibilidade e valor preditivo negativo para excluir a ATRd. ConclusÃO: Uma alta prevalência de ATR foi encontrada em indivíduos com mutações na TTR. O pHU por fita reagente após TRH teve boa precisão para triagem de ATRd. São necessários mais estudos para avaliar o impacto do diagnóstico e tratamento precoces da ATR nessa população.
ABSTRACT
Method: Use the PICO format to generate a series of questions, focusing on the specificity and sensitivity of the amyloidosis diagnostic test. PubMed searches were conducted in English and Spanish from July to August 2019. The level of evidence and recommendation are based on the GRADE system (http://www.gradeworkinggroup.org/index.htm). The recommendations are graded according to their direction (for or against) and strength (strong and weak). Finally, it is recommended to use GLIA tools to evaluate the obstacles and facilitators in implementation. Suggested explanation A strong suggestion indicates a high degree of trust in support or opposition to the intervention. When defining a strong recommendation, this guide uses the "recommended" language. The weaker recommendations indicate that the outcome of the intervention (favorable or unfavorable) is doubtful. In this case, if a weak recommendation is defined, the "recommendation" language is used. How to use these guidelines: Recommendations must be explained within the scope of special care in validated diagnostic studies conducted by specially trained doctors. It is not assumed to change the coexistence conditions of the disease process. Presumably, the attending physician has a high degree of suspicion of amyloidosis. It assumes that diagnostic research is conducted by well-trained doctors using a validated standardized method. This guide is intended for health care professionals and those involved in health care policies to help ensure that the necessary agreements have been reached to provide appropriate care. Summary of recommendations For patients with suspected amyloidosis, it is recommended: Measured value of creatinine be used as a preliminary assessment for the diagnosis of renal involvement in patients with suspected renal amyloidosis. 24-hour proteinuria be measured and characterized to diagnose renal involvement in patients with suspected renal amyloidosis. Immunohistochemical staining of skin biopsy for patients genetically diagnosed with ATTR, for early diagnosis of neuropathy. The signs or symptoms of these patients suggest the presence of fine fiber neuropathy. Skin biopsy and immunohistochemical staining for early diagnosis of neuropathy. These patients show signs or symptoms suggesting fine fiber neuropathy. Conduct nerve conduction studies on motor and sensory fibers to diagnose total fiber neuropathy in patients who are diagnosed or suspected of having amyloidosis. Test (Sudoscan) is recommended for the early diagnosis of peripheral autonomic neuropathy (even in asymptomatic patients) in patients with suspected autonomic neuropathy due to amyloidosis. Ewing's standard to measure heart rate variability to diagnose autonomic hypofunction in patients with autonomic neuropathy suspected of having amyloidosis. Measure orthostatic hypotension to diagnose early autonomic hypotension for patients with amyloidosis or systemic amyloidosis suspected of autonomic neuropathy. It is suggested: QST test to diagnose neuropathy early for patients genetically diagnosed with ATTR, if they show signs or symptoms suggesting fine fiber neuropathy Measure alkaline phosphatase to initially assess liver involvement in patients with amyloidosis.
Métodos: Se generó un listado de preguntas con el formato PICO centradas en la especificidad y sensibilidad de las pruebas diagnósticas en amiloidosis. Se realizó la búsqueda en PubMed durante julio-agosto del 2019, en inglés y español. Los niveles de evidencia y los grados de recomendación se basan en el sistema GRADE (http://www.gradeworkinggroup.org/index.htm). Las recomendaciones se graduaron según su dirección (a favor o en contra) y según fuerza (fuertes y débiles). Las recomendaciones finales fueron evaluadas con la herramienta GLIA para barreras y facilitadores en la implementación de éstas. Interpretación de recomendaciones: Las recomendaciones fuertes indican alta confianza, ya sea a favor o en contra, de una intervención. En esta guía se utiliza el lenguaje "se recomienda" cuando se define una recomendación fuerte. Las recomendaciones débiles indican que los resultados para una intervención, favorable o desfavorable, son dudosos. En este caso, se utiliza el lenguaje "se sugiere", cuando se define una recomendación débil.Cómo utilizar estas pautas: Las recomendaciones deben ser interpretadas en el contexto de la atención especializada, con estudios diagnósticos validados y realizados por médicos entrenados. Se asume que el médico tratante tiene alto nivel de sospecha de amiloidosis. No asume condiciones coexistentes que modifican el curso de la enfermedad. Asume que los estudios diagnósticos son realizados por médicos entrenados con métodos validados y estandarizados. Esta guía es relevante para los profesionales de la salud y los involucrados en las políticas sanitarias, para ayudar a asegurar que existan los acuerdos necesarios para brindar la atención adecuada. Resumen de recomendaciones En pacientes con sospecha de amiloidosis se recomienda: Medición de la creatinina como evaluación inicial para el diagnóstico del compromiso renal en el paciente con sospecha de amiloidosis renal. Medición y caracterización de la proteinuria de 24 hs para el diagnóstico de compromiso renal en pacientes con sospecha de amiloidosis renal. Biopsia de piel con tinción inmunohistoquímica para el diagnóstico precoz de neuropatía en pacientes con diagnóstico genético de ATTR, que presenten signos o síntomas sugestivos de neuropatía de fibra fina. Biopsia de piel con tinción inmunohistoquímica para el diagnóstico precoz de neuropatía en pacientes con sospecha de amiloidosis, que presenten signos o síntomas sugestivos de neuropatía de fibra fina. Estudios de conducción nerviosa evaluando fibras motoras y sensitivas para el diagnóstico de neuropatía de fibras gruesas en pacientes con diagnóstico o sospecha de amiloidosis. Prueba de QST para el diagnóstico precoz de neuropatía en pacientes con diagnóstico genético de ATTR, que presenten signos o síntomas sugestivos de neuropatía de fibras finas. Test de cuantificación sudorípara (Sudoscan) para diagnóstico precoz de neuropatía autonómica periférica (incluso en asintomáticos) en pacientes con sospecha de neuropatía autonómica por amiloidosis. Medición de la variabilidad de la frecuencia cardiaca con criterios de Ewing para el diagnóstico de disautonomía en pacientes con sospecha de neuropatía autonómica por amiloidosis. Medición de hipotensión ortostática con técnica adecuadamente estandarizada para el diagnóstico precoz de compromiso autonómico en el paciente con sospecha de neuropatía autonómica por amiloidosis o diagnóstico de amiloidosis sistémica Se sugiere: Prueba de QST para el diagnóstico precoz de neuropatía en pacientes con amiloidosis o sospecha de amiloidosis, que presenten signos o síntomas sugestivos de neuropatía de fibras finas. Medición de fosfatasa alcalina para evaluación inicial del compromiso hepático en el paciente con amiloidosis.
Subject(s)
Amyloidosis , Autonomic Nervous System Diseases , Peripheral Nervous System Diseases , Humans , Amyloidosis/diagnosis , Amyloidosis/pathology , Peripheral Nervous System Diseases/diagnosis , Peripheral Nervous System Diseases/pathology , Proteinuria/pathology , Skin/pathology , Practice Guidelines as TopicABSTRACT
Method: Use the PICO format to generate a series of questions, focusing on the specificity and sensitivity of the amyloidosis diagnostic test. PubMed searches were conducted in English and Spanish from July to August 2019. The level of evidence and recommendation are based on the GRADE system (http://www.gradeworkinggroup.org/index.htm). The recommendations are graded according to their direction (for or against) and strength (strong and weak). Finally, it is recommended to use GLIA tools to evaluate the obstacles and facilitators in implementation. Suggested explanation: A strong suggestion indicates a high degree of trust in support or opposition to the intervention. When defining a strong recommendation, this guide uses the "recommended" language. The weaker recommendations indicate that the outcome of the intervention (favorable or unfavorable) is doubtful. In this case, if a weak recommendation is defined, the "recommendation" language is used. How to use these guidelines: Recommendations must be explained within the scope of special care in validated diagnostic studies conducted by specially trained doctors. Presumably, the attending physician has a high degree of suspicion of amyloidosis. It assumes that diagnostic research is conducted by well-trained doctors using a validated standardized method. This guide is intended for health care professionals and those involved in health care policies to help ensure that the necessary agreements have been reached to provide appropriate care. Summary of recommendations: For patients with suspected amyloidosis, it is recommended: Electrocardiogram be used as a preliminary assessment for all patients with amyloidosis. Doppler echocardiography conventional be used as the initial image of the first choice for cardiac amyloidosis in patients diagnosed with suspected heart involvement due to amyloidosis. Echocardiographic strain diagnosis for patients with amyloidosis prompted by conventional echocardiography or uncertain. Cardiac magnetic resonance imaging (MRI) be used for the diagnosis of cardiac amyloidosis in patients with previous studies suggesting or uncertain amyloidosis. T1 mapping technology for cardiac MRI to diagnose myocardial amyloidosis as an alternative to MRI, for patients with kidney failure or contraindication to other studies Cardiac MRI examination with T1 localization technique for patients who have previously studied amyloidosis, and measure the extracellular volume and quantify the degree of cardiac involvement in order to diagnose and measure the cardiac involvement caused by amyloidosis. It is suggested: Cardiac MRI with T1 mapping technique and extracellular volume measurement for the early diagnosis of amyloidosis in patients with previous studies suggestive of amyloidosis. Measurement of type B-type natriuretic peptide measurement be used for screening and diagnosis of cardiac amyloidosis. Pyrophosphate scintigraphy to make a preliminary diagnosis of patients with suspected cardiac amyloidosis, so as to distinguish ATTR (positive) from other patients.
Métodos: Se generó un listado de preguntas con el formato PICO centradas en la especificidad y sensibilidad de las pruebas diagnósticas en amiloidosis. Se realizó la búsqueda en PubMed durante julio-agosto del 2019, en inglés y español. Los niveles de evidencia y los grados de recomendación se basan en el sistema GRADE (http://www.gradeworkinggroup.org/index.htm). Las recomendaciones se graduaron según su dirección (a favor o en contra) y según fuerza (fuertes y débiles). Las recomendaciones finales fueron evaluadas con la herramienta GLIA para barreras y facilitadores en la implementación de éstas. : Interpretación de recomendaciones: Las recomendaciones fuertes indican alta confianza, ya sea a favor o en contra, de una intervención. En esta guía se utiliza el lenguaje "se recomienda" cuando se define una recomendación fuerte. Las recomendaciones débiles indican que los resultados para una intervención, favorable o desfavorable, son dudosos. En este caso, se utiliza el lenguaje "se sugiere", cuando se define una recomendación débil. Cómo utilizar estas pautas: Las recomendaciones deben ser interpretadas en el contexto de la atención especializada, con estudios diagnósticos validados y realizados por médicos entrenados. Se asume que el médico tratante tiene alto nivel de sospecha de amiloidosis. No asume condiciones coexistentes que modifican el curso de la enfermedad. Asume que los estudios diagnósticos son realizados por médicos entrenados con métodos validados y estandarizados. Esta guía es relevante para los profesionales de la salud y los involucrados en las políticas sanitarias, para ayudar a asegurar que existan los acuerdos necesarios para brindar la atención adecuada. Resumen de recomendaciones: En pacientes con sospecha de amiloidosis, se recomienda realizar: Un electrocardiograma como evaluación inicial a todo paciente con amiloidosis. Ecocardiograma Doppler convencional como imagen inicial de elección para el diagnóstico de amiloidosis cardíaca en pacientes con sospecha de compromiso cardíaco por amiloidosis. Ecocardiograma con deformación (strain) para el diagnóstico de amiloidosis cardíaca en pacientes con un ecocardiograma convencional sugestivo o indeterminado de amiloidosis. Resonancia magnética cardíaca (RMC) con gadolinio para el diagnóstico de amiloidosis cardíaca en pacientes con estudios previos sugestivos o indeterminados de amiloidosis. RMC con técnica de mapeo T1 para el diagnóstico de amiloidosis cardíaca en pacientes con estudios previos sugestivos de amiloidosis y disfunción renal o contraindicación para recibir gadolinio, como alternativa a la RMC con gadolinio. RMC con técnica de mapeo T1, medición de volumen extracelular y la cuantificación de la extensión del compromiso cardíaco para el diagnóstico y medición del compromiso cardíaco por amiloidosis en pacientes con estudios previos sugestivos de amiloidosis. Se sugiere realizar: RMC con técnica de mapeo T1 y medición del volumen extracelular para el diagnóstico precoz por amiloidosis en pacientes con estudios previos sugestivos de amiloidosis. Medición de péptido natriurético tipo B para el rastreo y diagnóstico de amiloidosis cardíaca. Centellograma con pirofosfato para el diagnóstico inicial de pacientes con sospecha de amiloidosis cardíaca, diferenciando ATTR (positiva) del resto.
Subject(s)
Amyloidosis , Cardiomyopathies , Amyloidosis/diagnostic imaging , Amyloidosis/pathology , Cardiomyopathies/diagnostic imaging , Cardiomyopathies/pathology , Echocardiography , Humans , Magnetic Resonance Imaging , Myocardium , Practice Guidelines as TopicABSTRACT
Currently, there is growing evidence in the literature warning of misdiagnosis involving amyloidosis and chronic inflammatory demyelinating polyneuropathy (CIDP). Although inducing clinical manifestations outside the peripheral nervous system, light chain and transthyretin amyloidosis may initially present with peripheral neuropathy, which can be indistinguishable from CIDP, leading to a delay in the correct diagnosis. Besides, the precise identification of the amyloid subtype is often challenging. This case report exemplifies clinical and laboratory pitfalls in diagnosing amyloidosis and subtyping amyloid, exposing the patient to potentially harmful procedures.
ABSTRACT
Currently, there is growing evidence in the literature warning of misdiagnosis involving amyloidosis and chronic inflammatory demyelinating polyneuropathy (CIDP). Although inducing clinical manifestations outside the peripheral nervous system, light chain and transthyretin amyloidosis may initially present with peripheral neuropathy, which can be indistinguishable from CIDP, leading to a delay in the correct diagnosis. Besides, the precise identification of the amyloid subtype is often challenging. This case report exemplifies clinical and laboratory pitfalls in diagnosing amyloidosis and subtyping amyloid, exposing the patient to potentially harmful procedures.
Subject(s)
Humans , Male , Aged , Amyloidosis, Familial/complications , Paraproteinemias , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/complications , Diagnostic Errors , Immunoglobulin Light-chain Amyloidosis/complicationsSubject(s)
Humans , Amyloid Neuropathies, Familial/genetics , Phenotype , Syncope/etiology , Prealbumin/genetics , MutationABSTRACT
Abstract Background: Amyloidosis is a disease caused by deposits of insoluble fibrils in extracellular spaces. The most common type of familial amyloidosis is mediated by mutation of transthyretin, especially Val30Met. Symptoms and ejection fraction decrease may occur in cardiac amyloidosis only in case of poor prognosis. Myocardial strain detected by two-dimensional speckle tracking echocardiography can indicate changes in myocardial function at early stages of the disease. Objective: To determine the accuracy of left ventricular longitudinal strain by two-dimensional speckle tracking echocardiography in patients with familial amyloidosis caused by Val30Met transthyretin mutation. Methods: Eighteen consecutive patients, carriers of transthyretin mutation, were evaluated by two-dimensional speckle tracking echocardiography, by which myocardial strain curves were obtained, following the American Society of Echocardiography recommendations. Results: Patients were divided into three groups: 1- Val30Met with cardiac amyloidosis; 2-Val30Met with extracardiac amyloidosis; 3 - Val30Met without evidence of disease. As the three groups were compared by the Mann-Whitney test, we found a statistically significant difference between groups 1 and 2 in the mean longitudinal tension (p=0.01), mean basal longitudinal strain (p=0.014); in mean longitudinal tension and mean longitudinal strain between groups 1 and 3 (p=0.005); and in the ratio of longitudinal strain of apical septum segment to longitudinal strain of basal septum (p=0.041) between groups 2 and 3. Conclusion: Left ventricular longitudinal strain detected by two-dimensional speckle tracking echocardiography is able to diagnose left ventricular dysfunction in early stages of familial amyloidosis caused by transthyretin Val30Met mutation.
Resumo Fundamento: A amiloidose é uma doença de depósito de fibrilas insolúveis nos espaços intercelulares. A forma mais comum de amiloidose familiar é mediada por mutação da transtirretina, sendo a Val30Met a mutação mais frequente. A amiloidose cardíaca só causa sintomas e queda da fração de ejeção em fases tardias quando o prognóstico é pobre. A deformação miocárdica obtida com speckle tracking bidimensional pode detectar alterações da função miocárdica em estágios precoces da doença. Objetivos: Determinar a acurácia da deformação longitudinal do ventrículo esquerdo obtida com speckle tracking bidimensional em um grupo de pacientes com amiloidose familial por mutação da transtirretina Val30Met. Métodos: Foram examinados 18 pacientes consecutivos com a mutação da transtirretina com speckle tracking bidimensional obtendo curvas de deformação miocárdica segundo normas da American Society of Echocardiography. Resultados: Os pacientes foram divididos em três grupos: 1- Val30Met com amiloidose cardíaca; 2- Val30Met com amiloidose extra-cardíaca; 3- Val30Met sem doença aparente. Ao compararmos os três grupos com o teste de Mann-Whitney encontramos diferença estatística significativa entre os grupos 1 e 2 na tensão longitudinal média (p=0,01), deformação longitudinal basal média (p=0,014); entre os grupos 1 e 3 na tensão longitudinal média (p=0,005), deformação longitudinal média (p=0,002); entre os grupos 2 e 3 na relação de deformação longitudinal do septo apical/deformação longitudinal do septo basal (p=0,041). Conclusão: A deformação longitudinal do ventrículo esquerdo obtida com speckle tracking bidimensional é capaz de diagnosticar disfunção do ventrículo esquerdo em fases precoces da amiloidose familial por mutação Val30Met da transtirretina.