¿Qué hay de nuevo en el diagnóstico de amiloidosis? / What is new in diagnosis of amyloidosis?

La amiloidosis siempre ha representado un desafío diagnóstico. En el año 2020, el Grupo de Estudio de Amiloidosis (GEA), confeccionó la Guía de Práctica Clínica para el Diagnóstico de Amiloidosis. Nuevas líneas de investigación se han desarrollado posteriormente. Esta revisión narrativa tiene como intención explorar el estado del arte en el diagnóstico de la amiloidosis. En pacientes con amiloidosis se recomienda la tipificación de la proteína mediante espectrometría de masa, técnica de difícil ejecución por requerir de microdisectores láser para la preparación de la muestra. Algunas publicaciones recientes proponen otros métodos para obtener la muestra de amiloide que se va a analizar, permitiendo prescindir de la microdisección. Por otra parte, en pacientes con Amiloidosis ATTR confirmada, la recomendación de secuenciar el gen amiloidogénico se encontraba destinada a los casos sospechosos de ATTR hereditaria (ATTRv,), pero actualmente esta se ha extendido a todos los pacientes sin importar la edad. En lo que respecta a los estudios complementarios orientados al diagnóstico de compromiso cardíaco, se ha propuesto el uso de la inteligencia artificial para su interpretación, permitiendo la detección temprana de la enfermedad y el correcto diagnóstico diferencial. Para el diagnóstico de neuropatía, las últimas publicaciones proponen el uso de la cadena ligera de neurofilamento sérica, que también podría resultar un indicador útil para seguimiento. Finalmente, con referencia a la amiloidosis AL, la comunidad científica se encuentra interesada en definir qué características determinan el carácter amiloidogénico de las cadenas livianas. La N-glicosilación de dichas proteínas impresiona ser uno de los determinantes en cuestión. (AU)

Amyloidosis has always represented a diagnostic challenge. In 2020, the Amyloidosis Study Group (ASG) developed the "Clinical Practice Guideline for the Diagnosis of Amyloidosis". New lines of research have subsequently emerged. This narrative review aims to explore the state of the art in the diagnosis of amyloidosis diagnosis. In patients with amyloidosis, protein typing by mass spectrometry is recommended, a technique hard to perform because it requires laser microdissection for sample preparation. Recent publications propose other methods to obtain the amyloid sample to be analyzed, making it possible to dispense with microdissection. On the other hand, in patients with confirmed TTR amyloidosis (aTTR), the recommendation to sequence the amyloidogenic gene was intended for suspected cases of hereditary aTTR but has now been extended to all patients regardless of age. (AU)

Trasplante cardíaco y autólogo de células progenitoras hematopoyéticas en pacientes con amiloidosis AL / Cardiac and autologous stem cell transplantation hematopoietic in patients with AL amyloidosis

Resumen Objetivo: Describir la evolución de las cadenas livianas libres séricas (CLL) en el período comprendido entre el trasplante cardíaco ortotópico (TCO) y el trasplante de células progenitoras hematopoyéticas (TCPH), la respuesta hematológica al año tras el TCPH y el tratamiento quimioterápico e inmunosupresor en pacientes con amiloidosis AL. Método: Serie de casos de pacientes consecutivos con diagnóstico de amiloidosis AL que recibieron TCO seguido de TCPH del Registro Institucional de Amiloidosis del Hospital Italiano de Buenos Aires, entre enero de 2010 y noviembre de 2021. Se reportaron los valores de CLL entre trasplantes y al año del TCPH. Las variables cuantitativas se describieron como mediana e intervalo intercuartil, y las variables categóricas como frecuencias absolutas y relativas. Resultados: De 106 pacientes con amiloidosis AL, seis tuvieron TCO seguido de TCPH. La mediana de edad fue de 55 años. La mayoría eran hombres (n = 5). En el período entre trasplantes, la CLL involucrada disminuyó en dos pacientes y se mantuvo estable en tres. Todos lograron la remisión hematológica completa al año del TCPH. Un solo paciente presentó recaída en el órgano sólido trasplantado. Tacrolimus, micofenolato de mofetilo y corticoides fue el esquema inmunosupresor utilizado después del TCO. Conclusiones: El TCO representa una opción de tratamiento en pacientes con falla cardíaca grave por amiloidosis, permitiendo luego un tratamiento intensivo con quimioterapia de inducción y TCPH. Si bien faltan estudios, la terapia inmunosupresora después del TCO podría tener algún efecto sobre las células plasmáticas clonales.

Abstract Objective: To describe the evolution of serum free light chains (FLC) in the period between orthotopic heart transplantation (OHT) and autologous stem cell transplantation (ASCT), the hematological response one year after ASCT and chemotherapy and immunosuppressive treatment in patients with AL amyloidosis. Method: Case series of consecutive patients diagnosed with AL amyloidosis who received OHT followed by ASCT from the Institutional Registry of Amyloidosis of the Italian Hospital of Buenos Aires, between January 2010 and November 2021. FLC values between transplants and at year post ASCT. Quantitative variables were described with their median and interquartile range. Categorical variables as absolute and relative frequencies. Results: Of 106 patients with AL amyloidosis, 6 had an OHT followed by ASCT. The median age was 55 years. Most were men (n = 5). In the period between transplants, the involved CLL decreased in two patients and remained stable in three. All achieved complete hematologic remission 1 year after ASCT. A single patient presented relapse in the transplanted solid organ. Tacrolimus, mycophenolate mofetil, and corticosteroids were the immunosuppressive regimen used after OHT. Conclusions: OHT represents a treatment option in patients with severe heart failure due to amyloidosis, allowing later intensive treatment with induction chemotherapy and ASCT. Although studies are lacking, immunosuppressive therapy after OHT might have some effect on clonal plasma cells.

Clinical characterization and outcomes of a cohort of colombian patients with AL Amyloidosis

Background: Amyloid light chain (AL) amyloidosis is characterized by amyloid fibril deposition derived from monoclonal immunoglobulin light chains, resulting in multiorgan dysfunction. Limited data exist on the clinical features of AL amyloidosis. Objective: This study aims to describe the clinical characteristics, treatments, and outcomes in Colombian patients with AL amyloidosis. Methods: A retrospective descriptive study was conducted at three high-complexity centers in Medellín, Colombia. Adults with AL amyloidosis diagnosed between 2012 and 2022 were included. Clinical, laboratory, histological, treatment, and survival data were analyzed. Results: The study included 63 patients. Renal involvement was most prevalent (66%), followed by cardiac involvement (61%). Multiorgan involvement occurred in 61% of patients. Amyloid deposition was most commonly detected in renal biopsy (40%). Bortezomib-based therapy was used in 68%, and 23.8% received high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HDCT-ASCT). Hematological response was observed in 95% of patients with available data. Cardiac and renal organ responses were 15% and 14%, respectively. Median overall survival was 45.1 months (95% CI: 22.2-63.8). In multivariate analysis, cardiac involvement was significantly associated with inferior overall survival (HR 3.27; 95% CI: 1.23-8.73; p=0.018), HDCT-ASCT had a non-significant trend towards improved overall survival (HR 0.25; 95% CI: 0.06-1.09; p=0.065). Conclusions: In this study of Colombian patients with AL amyloidosis, renal involvement was more frequent than cardiac involvement. Overall survival and multiorgan involvement were consistent with data from other regions of the world. Multivariate analysis identified cardiac involvement and HDCT-AHCT as possible prognostic factors.

Antecedentes: La amiloidosis por amiloide de cadenas ligeras (AL) se caracteriza por el depósito de fibrillas amiloides derivadas de cadenas ligeras de inmunoglobulinas monoclonales, lo que resulta en disfunción multiorgánica. Existen datos limitados sobre las características clínicas de la amiloidosis AL. Objetivo: Este estudio tiene como objetivo describir las características clínicas, tratamientos y desenlaces en pacientes colombianos con amiloidosis AL. Métodos: Se llevó a cabo un estudio descriptivo retrospectivo en tres centros de alta complejidad en Medellín, Colombia. Se incluyeron adultos con diagnóstico de amiloidosis AL entre 2012 y 2022. Se analizaron datos clínicos, de laboratorio, histológicos, de tratamiento y de supervivencia. Resultados: El estudio incluyó 63 pacientes. La afectación renal fue más prevalente (66%), seguida de la afectación cardíaca (61%). El 61% de los pacientes presentaron afectación multiorgánica. El depósito amiloide se detectó con mayor frecuencia en la biopsia renal (40%). El tratamiento basado en bortezomib se utilizó en el 68%, y el 23.8% recibió altas dosis de quimioterapia con trasplante autólogo de progenitores hematopoyéticos (ADQT-TAPH). Se observó respuesta hematológica en el 95% de los pacientes con datos disponibles. La respuesta de órgano cardíaca y renal fue del 15% y 14%, respectivamente. La mediana de la supervivencia global fue de 45.1 meses (IC del 95%: 22.2-63.8). En el análisis multivariado, la afectación cardíaca se asoció significativamente con una supervivencia global inferior (HR 3.27; IC del 95%: 1.23-8.73; p=0.018), ADQT-TAPH mostró una tendencia no significativa hacia una mejora en la supervivencia global (HR 0.25; IC 95%: 0.06-1.09; p=0.065). Conclusiones: En este estudio de pacientes colombianos con amiloidosis AL, la afectación renal fue más frecuente que la afectación cardíaca. La supervivencia global y la afectación multiorgánica fueron consistentes con datos de otras regiones del mundo. El análisis multivariado identificó la afectación cardíaca y ADQT-TAPH como posibles factores pronósticos.

Amiloidose pulmonar com apresentação traqueobrônquica: relato de caso clínico / Pulmonary amyloidosis with tracheobronchial presentation: clinical case report

Introdução: Amiloidose é o termo utilizado para designar doenças que fazem deposição extracelular de proteínas fibrilares patológicas em órgãos e tecidos, podendo ser sistêmica ou restrita a um único órgão. As manifestações clínicas são diversas, como cardiomiopatia, falência renal, esplenomegalia, problemas intestinais, neuropatias, problemas pulmonares, entre outros. Objetivo: relatar um caso clínico de paciente com amiloidose traqueobrônquica. Metodologia: revisão de bibliografias em comparação ao relato de caso, o qual foi descrito a partir de dados retirados do prontuário e de exames complementares da paciente. Caso clínico: paciente do sexo feminino, 70 anos, procurou assistência médica por dorsalgia, apresentando também chiado, tosse seca, dispneia paroxística noturna e ortopneia. Realizou-se investigação diagnóstica durante a internação, na qual biópsia da mucosa traqueobrônquica e coleta de lavado alveolar foram positivos para o teste Vermelho Congo, o que confirmou o diagnóstico de amiloidose. A paciente, então, foi encaminhada para terapia de ablação a laser. Conclusão: portanto, diante de um paciente com quadro clínico inespecífico e suspeita diagnóstica principal de amiloidose pulmonar, é imprescindível investigar e descartar diagnósticos diferenciais como neoplasia ou discrasia de células plasmáticas. Para isso, é necessário que haja alta precisão na análise dos exames de imagem, de modo a sugerir esse diagnóstico, o qual deve ser confirmado através da fibrobroncoscopia com biópsia de tecido brônquico, que através da coloração Vermelho do Congo, evidenciará presença de substância amorfa e birrefringente, compatível com substância amiloide [au]

Introduction: Amyloidosis is the term used to describe diseases that cause extracellular deposition of pathological fibrillar proteins in organs and tissues, which can be systemic or restricted to a single organ. The clinical manifestations are diverse, such as cardiomyopathy, renal failure, splenomegaly, intestinal problems, neuropathies, lung problems, among others. Objective: to report a clinical case of a patient with pulmonary amioloidosis. Methodology: review of bibliographies in comparison to the case report, which was described based on data taken from the patient's record and complementary exams. Clinical case: a seventy-year-old female patient sought medical assistance because of back pain, also presenting wheezing, dry cough, paroxysmal nocturnal dyspnea and orthopnea. Diagnostic investigation was carried out during hospitalization, in which biopsy of the tracheobronchial mucosa and collection of alveolar lavage were positive for the Congo Red test,wich confirmed the amyloidosis diagnosis. The patient was then referred for laser ablation therapy.Conclusion: hence, in a patient with a nonspecific clinical presentation and main diagnostic suspicion of pulmonary amyloidosis, it is essential to investigate and rule out differential diagnoses such as malignancy or plasma cell dyscrasia. Therefore, it is necessary to use high precision in the analysis of image exams in order to suggest this diagnosis, which should be confirmed through fibrobronchoscopy with bronchial tissue biopsy, that through the Congo Red dye, will show the presence of amorphous and birefringent substance, compatible with amyloid substance [au]

Amiloidosis cardiaca secundaria a macroglobulinemia de Waldenström / Cardiac amyloidosis secondary to Waldenström macroglobulinemia

Introducción: La macroglobulinemia de Waldenström constituye una neoplasia hematológica del grupo de las gammapatías monoclonales, que incluye síntomas sistémicos y relacionados al incremento de la paraproteína M. Objetivo: Describir un caso de amiloidosis cardiaca asociada a macroglobulinemia. Caso clínico: Paciente masculino que fue admitido por astenia, disfonía, y durante su evolución desarrolló disnea progresiva, insuficiencia cardiaca y efusión pleural. Adicionalmente, la ecocardiografía mostró patrón granular miocárdico, y la biopsia pleural resultó positiva para la tinción rojo congo. Posteriormente, recibió tratamiento con bortezomib, dexametasona y rituximab con evolución favorable. Conclusiones: En esta enfermedad el diagnóstico temprano es una ventaja importante para la supervivencia. Es por esa razón, que su manejo es paliativo de las manifestaciones cardiacas. El presente caso pone en manifiesto un reto diagnóstico, en el cual se deben tomar en cuenta las etiologías menos frecuentes de insuficiencia cardiaca(AU)

Introduction: Waldenström's macroglobulinemia is a hematological neoplasm belonging to the group of monoclonal gammopathies, which includes systemic symptoms and those related to an increase in M paraprotein. Objective: To describe a case of cardiac amyloidosis associated with macroglobulinemia. Clinical case: Male patient who was admitted for asthenia, dysphonia, and who, during his evolution, developed progressive dyspnea, heart failure and pleural effusion. Additionally, echocardiography showed myocardial granular pattern, while pleural biopsy was positive for Congo red staining. Subsequently, he received treatment with bortezomib, dexamethasone and rituximab, with favorable evolution. Conclusions: In this disease, early diagnosis is an important advantage for survival. Therefore, its management is palliative of cardiac manifestations. The present case shows a diagnostic challenge, in which the less frequent etiologies of heart failure must be taken into account(AU)

Amiloidosis AL y mieloma múltiple: macroglosia como primera manifestación de una combinación infrecuente / AL amyloidosis and multiple myeloma: macroglossia as first manifestation of a rare combination

El diagnóstico diferencial de la macroglosia es amplio y puede estar en el contexto de una patología localizada o una enfermedad sistémica. Dentro de las enfermedades sistémicas que se manifiestan con macroglosia se describe la amiloidosis, caracterizada por un depósito irreversible de una proteína amorfa y fibrilar El compromiso de esta patología en el territorio de cabeza y cuello es infrecuente y su depósito en la lengua corresponde a menos del 9% de los casos. Se presenta el caso de un paciente que consultó por dolor en hemilengua derecha, disfagia y baja de peso. Se estudió inicialmente con exámenes de laboratorio y nasofibroscopía, sin hallazgos concluyentes. Dado persistencia de síntomas se realizó resonancia nuclear magnética (RM) que mostraba signos sugerentes de enfermedad de depósito, confirmándose mediante estudios histopatológicos una amiloidosis sistémica secundaria. El paciente fue derivado a hematología para completar estudio e iniciar el tratamiento. La amiloidosis sistémica es un diagnóstico infrecuente, que debe ser considerado por su mal pronóstico vital. El diagnóstico en etapas iniciales puede mejorar sustancialmente la sobrevida y calidad de vida de aquellos que padecen la enfermedad. Por lo anterior, es necesario completar un estudio acabado de la patología, apoyándose en métodos no invasivos como la RM.

The differential diagnosis of macroglossia is broad, and it may be present in the context of a localized pathology or a systemic disease. One of the systemic diseases that present macroglossia is amyloidosis, which is characterized by an irreversible deposit of an amorphous and fibrillar protein. The manifestation of this pathology in head and neck territory is infrequent, and its deposit in the tongue represents less than 9% of all types of amyloidosis. We present the case of a patient, who consulted with pain in the tongue, dysphagia, and weight loss. He was initially studied with laboratory tests and a nasofibroscopy with no conclusive findings. Given the persistence of symptoms, magnetic resonance imaging (MRI) was performed, showing signs of an infiltrative disease, which was confirmed as secondary systemic amyloidosis through histopathological studies. Given the above, the patient was referred to hematology to start treatment. Systemic amyloidosis is an uncommon diagnosis that should be suspected since it implies a poor vital prognosis. Moreover, an early diagnosis can substantially improve the survival rate and quality of life of those who suffer this disease. Therefore, a comprehensive study of this condition is needed, complementing with non-invasive methods such as MRI.

De Novo Light Chain Deposition Disease in Long-term Survived Renal Allograft / 대한신장학회지

Light chain deposition disease (LCDD) is characterized by the deposition of abnormal immunoglobulin light chains in many organs, including kidney. It is usually associated with multiple myeloma or other lymphoproliferative disorders. Myeloma usually occurs in old age and may develop after renal transplantation thus being categorized as posttransplant lymphoproliferative disease (PTLD). Renal LCDD usually presents with variable degree of proteinuria and renal insufficiency. The diagnosis of LCDD depends on histologic findings with detection of monoclonal immunoglobulin light chain. Histologically, it is characterized by nodular glomerulosclerosis. We report the first case of de novo LCDD associated with myeloma after renal transplantation in Korea. With advancing renal transplantation and increasing old aged renal recipients, myeloma or LCDD should be included in the differential diagnoses of renal recipient patients with deteriorating renal function.

Clinical features and survival analysis of light-chain amyloidosis associated renal disease / 中国医师进修杂志

Objective To analyze the clinical pathology features of light-chain amyloidosis associated renal disease,and investigate the survival influential factors. Method From January 1998 to March 2009,25 patients with light-chain amyloidosis associated renal disease were reviewed and followed up.Results Of the 25 patients with light-chain amyloidosis associated renal disease,median age was 57(37-69) years old and lamda light-chain predominated (88% ,22/25). Heavy proteinuria and nephrotic syndrome with peripheral edema were typical clinical presentations. Renal biopsy showed that amyloid deposition of light-chain amyloidosis associated renal disease involved the glomeruh mostly, with mesangial area widening. Median survival of all patients was 24.4 months after diagnosis. The estimated 1,2,3 year survival rate was (65 ± 10 )%, (46 ± 12 )% and (15 ± 12 )% respectively. There was significant difference in median survival between the two groups (24.7 months in the group of 14 patients with isolated kidney affected,16.4 months in the group of 11 patients with kidney and other organs involved,P = 0.03). By univariate analysis, kidney associated with other organs amyloidosis and renal dysfunction were relevant to prognosis (P ＜ 0.05) and heart involvement was probably relevant (P = 0.06),whereas sex,age,plasma cell ratio,serum albumin level and hemoglobin level had no relation(P＞ 0.05 ). Multivariate analysis revealed that renal dysfunction at the time of diagnosis was a significant and independent prognostic factor for survival (P ＜0.05). Conclusions Renal dysfunction at the time of diagnosis is the best predictor of survival. The presence of amyloidosis in organs other than the kidney, such as advanced cardiac amyloidosis, predicts a poor survival.

Analysis of Immunoglobulin lambda Light Chain Repertoire in Systemic Lupus Erythematosus

BACKGROUND: Immunoglobulin (Ig) light chain repertoire has been implicated as a critical determinant in regulation of autoreactive B cells and production of pathogenic anti-DNA antibodies in systemic lupus erythematosus (SLE). We analyzed the impact of Ig lambda chain repertoire on development of autoimmunity in patients with SLE. METHODS: We obtained genomic DNA from individual peripheral CD19+ B cells of 3 untreated active SLE patients, and amplified Vlambda rearrangements from each single cell by polymerase chain reaction. RESULTS: A total number of 208 VlambdaJlambda rearrangements were analyzed. Analyzed sequences included 158 productive rearrangements and 50 nonproductive rearrangements. The differences in Vlambda gene usage in the productive and nonproductive repertoire of SLE patients were found compared to the non-autoimmune individuals. Vlambda gene, 9A was significantly overrepresented in nonproducative repertoire of SLE patients (P=0.016). In the productive repertoire, Vlambda genes, 3L and 1E were found more often in the SLE patients (P=0.001, P=0.043). When the productive and the nonproductive repertoires were compared, 9A was found significantly less in the productive repertoire in the SLE patients (P=0.000). There were no significant differences in the Jlambda gene usage between SLE patients and non-autoimmune individuals, but Jlambda2/3 gene was the most frequently used in SLE, whereas Jlambda7 gene was the most frequently used in the normal subjects. In the productive SLE Vlambda repertoire, 9.4% of the total sequences employed identical CDR3. It was particularly striking to find 7 identical versions of the 1G-Jlambda2/3 VlambdaJlambda rearrangements from one patient and 3 of the same sequence from another patient. Notably, identical Vlambda junctions in the SLE patients utilized significantly more homologous joining compared to Vlambda junctions of the normal adults (P=0.044). CONCLUSION: These data demonstrate regulation of lambda light chain expression in the SLE patients by selection of unique Vlambda genes. Also, biased selection and clonal expansion of particular Vlambda rearrangements are apparent in the SLE lambda repertoire.

Expressions of light chain immunoglobulins kappa and lambda in multiple primary malignant tumors in senile patients / 解放军医学杂志

Objective To investigate the abnormal expressions of light chain immunoglobulins kappa (Ig?) and lambda ( Ig?) in multiple primary malignant tumors (MPMT) in elderly patients. Methods The expressions of Ig? and Ig? in specimens obtained from multiple malignant tumors in 21 elderly patients were investigated. Immunohistochemical staining was performed with mouse antihuman Ig? and Ig? monoclonal antibodies. Among 21 patients with multiple primary malignant tumors, the first tumor which occurred in the digestive tract was detected in 20 patients. In 17 patients first and second tumors were found to occur in the digestive tract. In 21 patients with MPMT the relationship between the expressions of light chain immunogloblin and survival time was analyzed. Results Positive staining of Ig? and/or Ig? in specimens from the first and/or second tumor tissues was found in 16 patients(76 2%). Statistic analysis showed that there was close relationship between the expression of Ig? and that of Ig? in the tissues from double tumors ( P