scholarly journals Multiorgan involvement by amyloid light chain amyloidosis

2019 ◽  
Vol 47 (4) ◽  
pp. 1778-1786 ◽  
Author(s):  
Guoliang Li ◽  
Dan Han ◽  
Suhua Wei ◽  
Huaiyu Wang ◽  
Limei Chen
Keyword(s):  
Light Chain ◽  
Amyloid Fibrils ◽  
Normal Structure ◽  
Al Amyloidosis ◽  
Initial Symptom ◽  
Close Monitoring ◽  
Clinical Complexity ◽  
Amyloid Light Chain ◽  
Low Incidence ◽  
Chemotherapy Strategy

Amyloid light chain (AL) amyloidosis is a protein conformational disease. AL amyloidosis results from aggregation of misfolded proteins that are deposited in tissues as amyloid fibrils. Diagnosis of AL amyloidosis can be challenging due to its low incidence and clinical complexity. Therapy requires a risk-adapted approach involving dose reductions and schedule modifications of chemotherapy regimens along with close monitoring of hematologic and organ responses. We herein describe a patient whose condition was diagnosed as systemic AL amyloidosis and presented with splenic rupture as the initial symptom. Congo red staining of the kidney biopsy was positive. The normal structure of the liver and spleen had been replaced by amyloid deposition. The chemotherapy strategy involved a combination of bortezomib, cyclophosphamide, thalidomide, and dexamethasone.

scholarly journals A comparison of immunohistochemistry and mass spectrometry for determining light chain amyloid fibril protein from formalin-fixed renal biopsy tissue in a single Chinese center

2019 ◽  
Author(s):  
Ying Sun ◽  
Jian Sun ◽  
Wei Sun ◽  
Junyi Pang ◽  
Yubing Wen ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Renal Biopsy ◽  
Light Chain ◽  
Protein Identification ◽  
Amyloid Fibrils ◽  
Al Amyloidosis ◽  
Precise Diagnosis ◽  
Ffpe Tissues ◽  
Amyloid Light Chain ◽  
Formalin Fixed

Abstract Background Amyloidosis, a disease caused by abnormal protein deposition in tissues, is classified according to the protein precursor that form amyloid fibrils. Diagnosis of amyloidosis is type-specific as the identification of amyloid protein determines the following treatment. However, around a quarter of amyloidosis cases cannot be accurately subtyped by most commonly used immunohistochemistry (IHC). In order to obtain precise diagnosis, our study is focusing on another protein identification methods, laser microdissection and mass spectrometry (LDMS). Methods 20 cases of Amyloid Light-chain (AL) amyloidosis without further subtype were included. IHC and LDMS were used to detect light chains on formalin-fixed paraffin-embedded (FFPE) tissues from renal biopsy. Results 100% consistence between positive IHC and LDMS results were observed, however, chances of subtyping using LDMS is increased to 94% compared to IHC which is only 76%. Conclusion LDMS is a valuable tool in regard to subtyping amyloidosis.

scholarly journals Dissecting the Molecular Features of Systemic Light Chain (AL) Amyloidosis: Contributions from Proteomics

Medicina ◽  
2021 ◽  
Vol 57 (9) ◽  
pp. 916
Author(s):  
Paola Rognoni ◽  
Giulia Mazzini ◽  
Serena Caminito ◽  
Giovanni Palladini ◽  
Francesca Lavatelli
Keyword(s):  
Light Chain ◽  
Amyloid Fibrils ◽  
Cell Clone ◽  
Experimental Models ◽  
Critical Discussion ◽  
Al Amyloidosis ◽  
Primary Role ◽  
Molecular Features ◽  
Amyloid Light Chain ◽  
Models Of Disease

Amyloidoses are characterized by aggregation of proteins into highly ordered amyloid fibrils, which deposit in the extracellular space of tissues, leading to organ dysfunction. In AL (amyloid light chain) amyloidosis, the most common form in Western countries, the amyloidogenic precursor is a misfolding-prone immunoglobulin light chain (LC), which, in the systemic form, is produced in excess by a plasma cell clone and transported to target organs though blood. Due to the primary role that proteins play in the pathogenesis of amyloidoses, mass spectrometry (MS)-based proteomic studies have gained an established position in the clinical management and research of these diseases. In AL amyloidosis, in particular, proteomics has provided important contributions for characterizing the precursor light chain, the composition of the amyloid deposits and the mechanisms of proteotoxicity in target organ cells and experimental models of disease. This review will provide an overview of the major achievements of proteomic studies in AL amyloidosis, with a presentation of the most recent acquisitions and a critical discussion of open issues and ongoing trends.

scholarly journals Barriers to Small Molecule Drug Discovery for Systemic Amyloidosis

Molecules ◽  
2021 ◽  
Vol 26 (12) ◽  
pp. 3571
Author(s):  
Gareth J. Morgan
Keyword(s):  
Small Molecules ◽  
Light Chain ◽  
Amyloid Fibrils ◽  
Systemic Amyloidosis ◽  
Light Chains ◽  
Al Amyloidosis ◽  
Amyloid Formation ◽  
Amyloid Fibril Formation ◽  
Amyloid Light Chain

Inhibition of amyloid fibril formation could benefit patients with systemic amyloidosis. In this group of diseases, deposition of amyloid fibrils derived from normally soluble proteins leads to progressive tissue damage and organ failure. Amyloid formation is a complex process, where several individual steps could be targeted. Several small molecules have been proposed as inhibitors of amyloid formation. However, the exact mechanism of action for a molecule is often not known, which impedes medicinal chemistry efforts to develop more potent molecules. Furthermore, commonly used assays are prone to artifacts that must be controlled for. Here, potential mechanisms by which small molecules could inhibit aggregation of immunoglobulin light-chain dimers, the precursor proteins for amyloid light-chain (AL) amyloidosis, are studied in assays that recapitulate different aspects of amyloidogenesis in vitro. One molecule reduced unfolding-coupled proteolysis of light chains, but no molecules inhibited aggregation of light chains or disrupted pre-formed amyloid fibrils. This work demonstrates the challenges associated with drug development for amyloidosis, but also highlights the potential to combine therapies that target different aspects of amyloidosis.

scholarly journals Search for AL amyloidosis risk factors using Mendelian randomization

2021 ◽  
Vol 5 (13) ◽  
pp. 2725-2731
Author(s):  
Charlie N. Saunders ◽  
Subhayan Chattopadhyay ◽  
Stefanie Huhn ◽  
Niels Weinhold ◽  
Per Hoffmann ◽  
...  
Keyword(s):  
Risk Factors ◽  
Light Chain ◽  
Amyloid Fibrils ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Tumor Necrosis Factor Receptor ◽  
Al Amyloidosis ◽  
Genome Wide Association Studies ◽  
Significance Level ◽  
Amyloid Light Chain

In amyloid light chain (AL) amyloidosis, amyloid fibrils derived from immunoglobulin light chain are deposited in many organs, interfering with their function. The etiology of AL amyloidosis is poorly understood. Summary data from genome-wide association studies (GWASs) of multiple phenotypes can be exploited by Mendelian randomization (MR) methodology to search for factors influencing AL amyloidosis risk. We performed a 2-sample MR analyzing 72 phenotypes, proxied by 3461 genetic variants, and summary genetic data from a GWAS of 1129 AL amyloidosis cases and 7589 controls. Associations with a Bonferroni-defined significance level were observed for genetically predicted increased monocyte counts (P = 3.8 × 10−4) and the tumor necrosis factor receptor superfamily member 17 (TNFRSF17) gene (P = 3.4 × 10−5). Two other associations with the TNFRSF (members 6 and 19L) reached a nominal significance level. The association between genetically predicted decreased fibrinogen levels may be related to roles of fibrinogen other than blood clotting. be related to its nonhemostatic role. It is plausible that a causal relationship with monocyte concentration could be explained by selection of a light chain–producing clone during progression of monoclonal gammopathy of unknown significance toward AL amyloidosis. Because TNFRSF proteins have key functions in lymphocyte biology, it is entirely plausible that they offer a potential link to AL amyloidosis pathophysiology. Our study provides insight into AL amyloidosis etiology, suggesting high circulating levels of monocytes and TNFRSF proteins as risk factors.

scholarly journals Immunoglobulin Light-Chain Amyloidosis: From Basics to New Developments in Diagnosis, Prognosis and Therapy

2016 ◽  
Vol 135 (3) ◽  
pp. 172-190 ◽  
Author(s):  
Eli Muchtar ◽  
Francis K. Buadi ◽  
Angela Dispenzieri ◽  
Morie A. Gertz
Keyword(s):  
Light Chain ◽  
Plasma Cells ◽  
Treatment Options ◽  
Organ Damage ◽  
Major Effect ◽  
Response To Treatment ◽  
Al Amyloidosis ◽  
Prognostic Effect ◽  
Amyloid Light Chain ◽  
Immunoglobulin Light Chain Amyloidosis

Immunoglobulin amyloid light-chain (AL) amyloidosis is the most common form of systemic amyloidosis, where the culprit amyloidogenic protein is immunoglobulin light chains produced by marrow clonal plasma cells. AL amyloidosis is an infrequent disease, and since presentation is variable and often nonspecific, diagnosis is often delayed. This results in cumulative organ damage and has a negative prognostic effect. AL amyloidosis can also be challenging on the diagnostic level, especially when demonstration of Congo red-positive tissue is not readily obtained. Since as many as 31 known amyloidogenic proteins have been identified to date, determination of the amyloid type is required. While several typing methods are available, mass spectrometry has become the gold standard for amyloid typing. Upon confirming the diagnosis of amyloidosis, a pursuit for organ involvement is essential, with a focus on heart involvement, even in the absence of suggestive symptoms for involvement, as this has both prognostic and treatment implications. Details regarding initial treatment options, including stem cell transplantation, are provided in this review. AL amyloidosis management requires a multidisciplinary approach with careful patient monitoring, as organ impairment has a major effect on morbidity and treatment tolerability until a response to treatment is achieved and recovery emerges.

scholarly journals A case of isolated amyloid light-chain amyloidosis of the radial nerve

2016 ◽  
Vol 125 (3) ◽  
pp. 598-602 ◽  
Author(s):  
Ron Ron Cheng ◽  
Ramin Eskandari ◽  
Cynthia T. Welsh ◽  
Abhay K. Varma
Keyword(s):  
Peripheral Nerve ◽  
Light Chain ◽  
Radial Nerve ◽  
Systemic Disease ◽  
Mass Spectrometry Analysis ◽  
Al Amyloidosis ◽  
Electrodiagnostic Testing ◽  
Nerve Involvement ◽  
Peripheral Nerve Involvement ◽  
Amyloid Light Chain

Peripheral nerve involvement may be the first sign of systemic amyloid light-chain (AL) amyloidosis, a rare disease. Physical examination and electrodiagnostic testing are the mainstays of peripheral neuropathy evaluation at presentation. Sural nerve biopsy is performed in conjunction with serum and urine protein evaluation to differentiate between focal and systemic disease. Systemic disease is treated with a combination of chemotherapy, steroids, and stem cell transplantation. Isolated peripheral nerve disease is extremely rare. The authors here report the case of an 80-year-old woman who presented with progressive right upper-extremity weakness due to right radial neuropathy discovered upon electrodiagnostic testing. Magnetic resonance neurography (MRN) revealed a focal lesion within the right radial nerve. She underwent radial nerve exploration and excision of an intraneural mass consisting of amyloid on histopathology, with mass spectrometry analysis diagnostic for AL amyloidosis. Noninvasive testing and clinical history did not suggest systemic involvement. This unique case of isolated peripheral nerve AL amyloidosis in the absence of signs and symptoms of systemic disease is described, and the literature demonstrating peripheral nerve involvement in AL amyloidosis is reviewed.

Acquired factor X deficiency in patients with amyloid light-chain amyloidosis: incidence, bleeding manifestations, and response to high-dose chemotherapy

Blood ◽  
2001 ◽  
Vol 97 (6) ◽  
pp. 1885-1887 ◽  
Author(s):  
Elie B. Choufani ◽  
Vaishali Sanchorawala ◽  
Timothy Ernst ◽  
Karen Quillen ◽  
Martha Skinner ◽  
...  
Keyword(s):  
Light Chain ◽  
Medical Center ◽  
Bleeding Complications ◽  
Plasma Cell Dyscrasia ◽  
High Dose ◽  
Al Amyloidosis ◽  
Related Factor ◽  
Factor X ◽  
Factor X Deficiency ◽  
Amyloid Light Chain

Acquired deficiency of factor X occurs in patients with systemic amyloid light-chain (AL) amyloidosis, presumably due to adsorption of factor X to amyloid fibrils. Of 368 consecutive patients with systemic AL amyloidosis evaluated at Boston Medical Center, 32 patients (8.7%) had factor X levels below 50% of normal. Eighteen of these patients (56%) had bleeding complications, which were more frequent and severe in the 12 patients below 25% of normal; 2 episodes were fatal. Ten factor X–deficient patients received high-dose melphalan chemotherapy followed by autologous stem cell transplantation. Of 7 patients alive 1 year after treatment, 4 had a complete hematologic response, and all 4 experienced improvement in their factor X levels. One of 2 additional patients with partial hematologic responses had improvement in factor X. Thus, aggressive treatment of the underlying plasma cell dyscrasia in AL amyloidosis can lead to the amelioration of amyloid-related factor X deficiency.

scholarly journals Management of AL amyloidosis in 2020

Blood ◽  
2020 ◽  
Vol 136 (23) ◽  
pp. 2620-2627
Author(s):  
Giovanni Palladini ◽  
Paolo Milani ◽  
Giampaolo Merlini
Keyword(s):  
Monoclonal Gammopathy ◽  
Amyloid Fibrils ◽  
Cell Clone ◽  
Clinical Manifestations ◽  
Standard Of Care ◽  
Organ Involvement ◽  
Al Amyloidosis ◽  
Close Monitoring ◽  
Risk Of Death ◽  
Hematologic Response

Abstract In amyloid light chain (AL) amyloidosis, a small B-cell clone, most commonly a plasma cell clone, produces monoclonal light chains that exert organ toxicity and deposit in tissue in the form of amyloid fibrils. Organ involvement determines the clinical manifestations, but symptoms are usually recognized late. Patients with disease diagnosed at advanced stages, particularly when heart involvement is present, are at high risk of death within a few months. However, symptoms are always preceded by a detectable monoclonal gammopathy and by elevated biomarkers of organ involvement, and hematologists can screen subjects who have known monoclonal gammopathy for amyloid organ dysfunction and damage, allowing for a presymptomatic diagnosis. Discriminating patients with other forms of amyloidosis is difficult but necessary, and tissue typing with adequate technology available at referral centers, is mandatory to confirm AL amyloidosis. Treatment targets the underlying clone and should be risk adapted to rapidly administer the most effective therapy patients can safely tolerate. In approximately one-fifth of patients, autologous stem cell transplantation can be considered up front or after bortezomib-based conditioning. Bortezomib can improve the depth of response after transplantation and is the backbone of treatment of patients who are not eligible for transplantation. The daratumumab+bortezomib combination is emerging as a novel standard of care in AL amyloidosis. Treatment should be aimed at achieving early and profound hematologic response and organ response in the long term. Close monitoring of hematologic response is vital to shifting nonresponders to rescue treatments. Patients with relapsed/refractory disease are generally treated with immune-modulatory drugs, but daratumumab is also an effective option.

Sign in / Sign up

Export Citation Format

Share Document