Amyloid Typing by Mass Spectrometry in Clinical Practice: a Comprehensive Review of 16,175 Samples

Abstract

Objective: To map the occurrence of amyloid types in a large clinical cohort using mass spectrometry-based shotgun proteomics, an unbiased method that unambiguously identifies all amyloid types in a single assay. Methods: A mass spectrometry-based shotgun proteomics assay was implemented in a central reference laboratory. We documented our experience of typing 16,175 amyloidosis specimens over an 11year period from January 1, 2008, to December 31, 2018. Results: We identified 21 established amyloid types, including AL (n¼9542; 59.0%), ATTR (n¼4600; 28.4%), ALECT2 (n¼511; 3.2%), AA (n¼463; 2.9%), AH (n¼367; 2.3%), AIns (n¼182; 1.2%), KRT5-14 (n¼94; <1%), AFib (n¼71; <1%), AApoAIV (n¼57; <1%), AApoA1 (n¼56; <1%), AANF (n¼47; <1%), Ab2M (n¼38; <1%), ASem1 (n¼34; <1%), AGel (n¼29; <1%), TGFB1 (n¼29; <1%), ALys (n¼15; <1%), AIAPP (n¼13; <1%), AApoCII (n¼11; <1%), APro (n¼8; <1%), AEnf (n¼6; <1%), and ACal (n¼2; <1%). We developed the first comprehensive organ-by-type map showing the relative frequency of 21 amyloid types in 31 different organs, and the first type-by-organ map showing organ tropism of 18 rare types. Using a modified bioinformatics pipeline, we detected amino acid substitutions in cases of hereditary amyloidosis with 100% specificity. Conclusion: Amyloid typing by proteomics, which effectively recognizes all amyloid types in a single assay, optimally supports the diagnosis and treatment of amyloidosis patients in routine clinical practice.

Differences in the characteristics and contemporary cardiac outcomes of patients with light-chain versus transthyretin cardiac amyloidosis

“…Cardiac amyloidosis (CA) is most commonly caused by the extracellular deposition of insoluble amyloid fibrils of either immunoglobulin light chain (AL) or amyloid transthyretin (ATTR) [ 1 ], and is considered to portend a poor prognosis [ 2 ]. This distinctive cardiomyopathy is most frequently categorized as heart failure with preserved ejection fraction (HFpEF), and patients with CA are oftentimes described with advanced heart failure (HF) and significant volume overload [ 3 ].…”

Non‐cardiac biopsy sites with high frequency of transthyretin amyloidosis

“…The clinical characteristics of amyloidoses, a group of clinical syndromes characterized by abnormal deposition of misfolded proteins in organs, 1 are determined by the identity of the deposited protein. Nearly all cardiac amyloidoses result from deposition of monoclonal light chains (AL) or transthyretin (ATTR) 1,2 . However, AL and ATTR cardiac amyloidosis are separate diseases with distinct therapies and clinical courses, so accurate typing of the amyloid deposits is critical for patient care.…”

“…Nearly all cardiac amyloidoses result from deposition of monoclonal light chains (AL) or transthyretin (ATTR). 1,2 However, AL and ATTR cardiac amyloidosis are separate diseases with distinct therapies and clinical courses, so accurate typing of the amyloid deposits is critical for patient care. Recently, technetium-labelled cardiac scintigraphy (99mTc-PYP and 99mTc-DPD) has been shown to be an effective method for detecting ATTR cardiac amyloidosis.…”

The amyloid proteome: a systematic review and proposal of a protein classification system

“…Until now, proteomic evaluation of amyloid has mainly focused on the detection and characterization of the fibril-forming protein itself to determine if a candidate is a diagnostic biomarker or to find novel amyloid fibrilforming proteins. A comprehensive review of LC-MS generated amyloid fibril protein data was recently published by Dasari et al (2020), who evaluated 16,175 amyloidosis cases and described the distribution of amyloidosis types and organ-specific enrichment of amyloid deposits. However, little attention has been paid to the other proteinaceous constituents present in these complexes.…”