Light chain amyloidosis needs to be considered in the differential diagnosis of patients with nondiabetic nephrotic range proteinuria, unexplained fatigue or heart failure with preserved ejection fraction, a progressive peripheral neuropathy associated with a monoclonal protein, or atypical multiple myeloma. Screening involves serum and urine immunofixation and an immunoglobulin free light chain assay. Most patients can have the diagnosis established via biopsy of the bone marrow and subcutaneous fat. Visceral organ biopsy is rarely needed. The prognosis is determined by the DFLC, the levels of cardiac biomarkers, troponin and BNP. Therapy includes high-dose chemotherapy; and for patients ineligible for high-dose chemotherapy, bortezomib appears to be the single most active agent. Combinations of bortezomib and the inclusion of monoclonal antibodies are the subject of further studies.

Immunoglobulin light chain amyloidosis

Immunoglobulin light chain amyloidosis (AL amyloidosis) has an incidence of approximately 1 case per 100,000 person-years in Western countries. The rarity of the condition not only poses a challenge for making a prompt diagnosis but also makes evidenced decision making about treatment even more challenging. Physicians caring for patients with AL amyloidosis have been borrowing and customizing the therapies used for patients with multiple myeloma with varying degrees of success. One of the biggest failings in the science of the treatment of AL amyloidosis is the paucity of prospective trials, especially phase 3 trials. Herein, we present an extensive review of the literature with an aim of making recommendations in the context of the best evidence and expert opinion.

https://www.mayoclinicproceedings.org/article/S0025-6196(15)00505-4/pdf

Treatment of Immunoglobulin Light Chain Amyloidosis: Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) Consensus Statement

What do I need to know about immunoglobulin light chain (AL) amyloidosis

Amyloid is an abnormal extracellular fibrillar protein deposit in the tissues. In humans, more than 25 different proteins can adopt a fibrillar conformation in vivo that results in the pathognomonic tinctorial property of amyloid (that is, green birefringence when an affected tissue specimen is stained with Congo red dye and viewed by microscopy under cross-polarized light). Amyloid deposition is associated with disturbance of organ function and causes a wide variety of clinical syndromes that are classified according to the respective fibril protein precursor. Systemic amyloidosis, in which amyloid deposits are widespread and typically accumulate gradually, continues to be fatal and is responsible for about one in 1,500 deaths per year in the UK. Advances in our understanding of the pathogenesis of systemic amyloidosis have resulted in the identification of new therapeutic targets, and several drugs with novel mechanisms of action are currently under development. Meanwhile, an increased awareness of amyloidosis coupled with enhancements to existing diagnostic techniques and therapeutic strategies have already resulted in better outcomes for patients with the disease.

Pathophysiology and treatment of systemic amyloidosis.

Amyloidosis represents a group of diseases in which proteins undergo misfolding to form insoluble fibrils with subsequent tissue deposition. While almost all deposited amyloid fibers share a common nonbranched morphology, the affected end organs, clinical presentation, treatment strategies, and prognosis vary greatly among this group of diseases and are largely dependent on the specific amyloid precursor protein. To date, at least 27 precursor proteins have been identified to result in either local tissue or systemic amyloidosis, with nine of them manifesting in cardiac deposition and resulting in a syndrome termed “cardiac amyloidosis” or “amyloid cardiomyopathy.” Although cardiac amyloidosis has been traditionally considered to be a rare disorder, as clinical appreciation and understanding continues to grow, so too has the prevalence, suggesting that this disease may be greatly underdiagnosed. The most common form of cardiac amyloidosis is associated with circulating amyloidogenic monoclonal immunoglobulin light chain proteins. Other major cardiac amyloidoses result from a misfolding of products of mutated or wild-type transthyretin protein. While the various cardiac amyloidoses share a common functional consequence, namely, an infiltrative cardiomyopathy with restrictive pathophysiology leading to progressive heart failure, the underlying pathophysiology and clinical syndrome varies with each precursor protein. Herein, we aim to provide an up-to-date overview of cardiac amyloidosis from nomenclature to molecular mechanisms and treatment options, with a particular focus on amyloidogenic immunoglobulin light chain protein cardiac amyloidosis.

https://www.physiology.org/doi/pdf/10.1152/ajpheart.00815.2011

Current perspectives on cardiac amyloidosis

Structural alterations within native amyloidogenic immunoglobulin light chains

Glycosaminoglycans promote fibril formation by amyloidogenic immunoglobulin light chains through a transient interaction

Light chain amyloidosis (AL amyloidosis) is a haematological disorder in which a clonal population of B cells expands and secretes enormous amounts of the immunoglobulin light chain protein. These light chains misfold and aggregate into amyloid fibrils, leading to organ dysfunction and death. We have studied the in vitro fibril formation kinetics of two patient-derived immunoglobulin light chain variable domain proteins, designated AL-09 and AL-103, in response to changes in solution conditions. Both proteins are members of the κI O18:O8 germline and therefore are highly similar in sequence, but they presented with different clinical phenotypes. We find that AL-09 forms fibrils more readily and more rapidly than AL-103 in vitro, mirroring the clinical phenotypes of the patients and suggesting a possible connection between the fibril kinetics of the disease protein and the disease progression.

Comparison of amyloid fibril formation by two closely related immunoglobulin light chain variable domains.

Amyloid fibrils are protein aggregates with a characteristic cross-β structure found in association with many human diseases. This chapter begins with a review of some basics of protein biochemistry and the theory of amyloid formation. The rest of the chapter focuses on the biophysical understanding of amyloid formation, touching on the kinetics and thermodynamics of fibril formation, different tools that can be used to probe fibril formation, and current theories on the mechanism of fibril formation. Finally, we discuss current structural approaches for the study of amyloid fibrils and several structural models that have been proposed as a result of these studies.

Douglas J. Martin

Papers

Structural alterations within native amyloidogenic immunoglobulin light chains

Glycosaminoglycans promote fibril formation by amyloidogenic immunoglobulin light chains through a transient interaction

Comparison of amyloid fibril formation by two closely related immunoglobulin light chain variable domains.

Fibril Structure and Fibrillogenesis