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Bone marrow biopsy is common in patients suspected of having systemic AL amyloidosis. However, little is known about the incidence, morphology and clinical phenotype of non-AL amyloid types in bone marrow. We retrospectively identified N = 1469 bone marrow amyloid biopsies typed using a proteomics-based method between 2008–2020. Frequency of amyloid types (N = 1469), distribution of amyloid deposits (N = 139), and clinical phenotypes (N = 355), with particular emphasis on cardiac involvement, were assessed. The amyloid types were: AL (N = 1172; 79.8%), ATTR (N = 240; 16.3%), AH (N = 38; 2.6%), AA (N = 17; 1.2%), and Aβ2M (N = 2; 0.1%). Although there were characteristic morphologic features, including periosteal soft tissue and/or vascular involvement in ATTR, interstitial vascular involvement in AA, and variable anatomic compartment involvement in AL, none were pathognomonic. Most patients with both an M-spike and cardiac involvement had AL amyloid in their BM, but in over 10% the amyloid type was ATTR. Compared to AL patients, ATTR patients had higher stage cardiac amyloidosis and lower overall survival, which was mainly due to advanced cardiac stage. ATTR amyloid is common in bone marrow and its morphologic distribution overlaps with AL. Amyloid typing is critical as over 10% of patients with bone marrow amyloid, cardiac amyloidosis, and an M-spike have ATTR amyloidosis. [ABSTRACT FROM AUTHOR]

Amyloidosis is characterised by extracellular deposition of proteinaceous fibrils, disrupting tissue structure and function. There are at least 36 different types of amyloid, and correct identification of the specific amyloid precursor protein is of paramount importance, as therapy varies dramatically depending on the amyloid type. Iatrogenic amyloidosis is a form of localised amyloidosis, caused by the repetitive injection of protein medications, such as insulin [[2]]. [Extracted from the article]

Aims Prognostication and treatment selection for cardiac amyloidosis requires accurate amyloid typing. The aim of this study was to investigate the utility of histomorphology for predicting type. Methods and results Autopsy cases with cardiac amyloidosis (1998-2010) were typed by the use of mass spectrometry-based proteomics. Deposition patterns were correlated with amyloid type. Among 108 decedents (mean age 75 years; 69% men), 107 had a single type, including transthyretin (ATTR) (60 cases), amyloid light chain (AL) (32 λ; 12 κ), amyloid A (AA) (two), and apolipoprotein AIV (AApoAIV) (one). Interstitial deposition was more extensive in AL amyloidosis cases than in ATTR cases [odds ratio (OR) 6.8, P = 0.0004]. Histomorphological patterns of interstitial deposition were mixed in 61% of AL amyloidosis cases and in 61% of ATTR cases, but diffuse pericellular deposits favoured AL amyloidosis (OR 10.7, P = 0.0001), nodular deposits favoured ATTR (OR 3.1, P = 0.0229), and discrete pericellular deposits tended to partially favour ATTR (OR 1.7, P = 0.1970). Arterial and venous deposits each favoured AL amyloidosis (OR ranging from 9.3 to 192.0, P-value ranging from 0.0022 to <0.0001), and were severe in AL amyloidosis. Endocardial deposits favoured AL amyloidosis (OR 46.3, P < 0.0001) and were also more severe in AL amyloidosis. Conclusions The extent and distribution of cardiac amyloidosis strongly correlate with amyloid type, suggesting fundamental differences in the pathobiology of deposition. The tendency for mixed patterns to occur limits the practicality and accuracy of using histopathology for amyloid typing. [ABSTRACT FROM AUTHOR]

AbstractBackgroundObjectivesMethodsResultsConclusionsCardiac AL and ATTR are potentially fatal cardiomyopathies. Current therapies do not address mechanisms of tissue dysfunction because these remain unknown. Our prior work focused on the amyloid plaque proteome, which may not capture tissue-wide proteomic alterations.To evaluate mechanisms of tissue dysfunction in cardiac AL and ATTR using a full biopsy tissue proteomics approach.We performed proteomics analysis on 76 ATTR and 27 AL diagnostic endomyocardial biopsies.Stage-3 AL patients exhibited increased coagulation, extracellular matrix remodelling (ECM), epithelial-to-mesenchymal transition (EMT), complement activation, hypoxia, and clathrin-mediated endocytosis pathways vs. stages-1/2, with decreased healthy cardiac metabolism. In stages-2 and 3 ATTR, immunoglobulin proteins, complement, and keratinisation pathways were increased compared to stage-1. Unsupervised analyses identified an ATTR group with worse survival characterised by upregulated complement and downregulated metabolic pathways. Compared to ATTR, AL had higher clathrin-mediated endocytosis, mRNA splicing, and ribosomal proteins, while ATTR had higher complement levels.This study identifies known processes dysregulated in heart failure with preserved ejection fraction as well as novel pathways responsible for tissue damage. Our results support an immune-mediated mechanism of tissue toxicity in cardiac amyloidosis, especially among patients with worse outcomes. [ABSTRACT FROM AUTHOR]

Abstract: Background: Proper identification of cardiac amyloid type is essential for patient management, and has historically relied upon immunohistochemical- or immunofluorescence-based methods, often correlated with serum and urine protein electrophoresis (SPEP and UPEP) with immunofixation electrophoresis (IFE), and/or free light chain immunoassay (FLC). The recent implementation of mass spectrometry-based proteomic analysis for clinical amyloid typing allows us to determine the validity of these tests to predict amyloid type. Validity of SPEP/UPEP/IFE and FLC assays in cardiac amyloid prediction was examined. Methods: Retrospective analysis of two tertiary care populations (n=143, 2001–2010), of cardiac biopsy-proven amyloidosis, was performed. Results: Amyloid of transthyretin (ATTR) type was found in 81 (57%) of 143 patients and immunoglobulin light chain amyloid was found in the remaining 62 (43%). SPEP/UPEP/IFE detected a monoclonal gammopathy in 76 individuals, 56 with AL and 20 with ATTR amyloid and was overall a poor predictor of AL amyloid in this patient population: specificity (75%; 95% CI, 65-83%) and positive predictive value (PPV 74%; 95% CI, 63–82%). The FLC assay detected an abnormal kappa/lambda ratio in 61 patients, 53 with AL and 8 with ATTR amyloid and was a better predictor of AL amyloid type in this patient population: specificity (90%, 95% CI, 82–95%) and PPV (87%, 95% CI, 76–93%). Conclusions: ATTR was the predominant amyloid type in this large cohort of endomyocardial biopsies characterized by mass spectrometry. Although FLC performs better than SPEP/UPEP/IFE, the performance of blood and urine studies for monoclonal proteins are not adequate to classify amyloid type. Summary: This large-scale retrospective analysis of cardiac amyloidosis shows that blood and urine monoclonal protein studies are not, by themselves, robust predictors of cardiac amyloid type in patients undergoing endomyocardial biopsy. [Copyright &y& Elsevier]