ATTR- and AFib amyloid - two different types of amyloid in the annular ligament of trigger finger.

INTRODUCTION: Histological examination of tissue specimens obtained during surgical treatment of trigger finger frequently encountered unclassifiable amyloid deposits in the annular ligament. We systematically explored this unknown type by a comprehensive analysis using histology, immunohistochemistry, and quantitative mass spectrometry-based proteomics. METHODS: 205 tissue specimens of annular ligaments were obtained from 172 patients. Each specimen was studied by histology and immunohistochemistry. Tissue specimens obtained from ten patients with histology proven amyloid in annular ligament were analysed by label-free quantitative proteomics. Histological and immunohistochemical findings were correlated with patient demographics. RESULTS: Amyloid was present as band like deposits along the surface of annular ligament, dot like or patchy deposits within the matrix. Immunohistochemistry identified ATTR amyloid in 92 specimens (mostly patchy in the matrix), while the band like deposits of 100 specimens remained unclassifiable. Proteomic profiles identified the unknown amyloid as most likely of fibrinogen origin. The complete cohort was re-examined by immunohistochemistry using a custom-made antibody and confirmed the presence of fibrinogen alpha-chain (FGA) in a hitherto unclassifiable type of amyloid in annular ligament. CONCLUSION: Our study shows that two different types of amyloid affect the annular ligament, ATTR amyloid and AFib amyloid, with distinct demographic patient characteristics and histomorphological deposition patterns.

Quantitative proteome profiling provides evidence of an activation of the complement cascade in ATTR amyloidosis.

Amyloidosis is a disease group caused by pathological aggregation and deposition of peptides in diverse tissue sites. Apart from the fibril protein, amyloid deposits frequently enclose non-fibrillar constituents. In this study, carpal tunnel tissue sections with ATTR amyloid were analysed by quantitative mass spectrometry-based proteomics. Following manual dissection, tissue samples of equal size and with heterogeneous amyloid load were dissected and forwarded to bottom-up proteome analysis and label-free protein profiling. The amyloid-associated proteins showed significant correlations of label-free intensity profiles. A comprehensive list of 83 proteins specifically enriched in amyloid deposits was discovered. In addition to well-known signature proteins (e.g. apolipoprotein E, apolipoprotein A-IV, and vitronectin), 22 members of the complement system, including all seven components of the membrane attack complex could be associated to the disease. These data lend support to the hypothesis that the complement system is activated in ATTR amyloidosis.

[Carpal tunnel syndrome and ATTR-amyloidosis]. / Karpaltunnelsyndrom und ATTR-Amyloidose.

BACKGROUND: Carpal tunnel syndrome is the most common compression syndrome of a peripheral nerve. It mostly affects patients older than 50 years. One cause for a carpal tunnel syndrome is transthyretin (ATTR) amyloid, which deposits in the carpal tunnel tissue. Carpal tunnel syndrome can be the first symptom of ATTR amyloidosis, which in the worst case leads to amyloid cardiomyopathy with the symptoms of heart failure with reduction in quality and time of life. For this article, all histological tissue samples of carpal tunnel tissue, collected from 2010 to 2018, were evaluated according to age and gender of each patient. Evaluation of the ATTR amyloid content in different regions of the carpal tunnel has enabled a recommendation for resection for optimal histological diagnosis. MATERIAL AND METHODS: In the Amyloid Registry Kiel, all cases are archived according to type of amyloid and available tissue. We evaluated 582 resected tissue samples of patients with ATTR amyloid in the carpal tunnel, collected from 2010 to the beginning of 2018. In addition, amyloid load of two different regions of the carpal tunnel (synovial tissue and tissue of the flexor retinaculum) were compared. RESULTS: The majority of resections came from women (53 %). The median age was 78 years for the entire collective, 77 years for men and 79 years for women. Specimens of the flexor retinaculum contained significantly more amyloid (9.66 % amyloid) than specimens of the synovial tissue (2.10 % amyloid). The prevalence of ATTR amyloid in carpal tunnel syndrome is 11.66 %. CONCLUSIONS: Both men and women develop a carpal tunnel syndrome caused by ATTR amyloid. In particular, at the age of over 50 years, amyloid deposits should be considered in the context of the etiological clarification of the carpal tunnel syndrome. Early histological diagnosis is highly relevant to identify the risk of cardiac amyloidosis. For an early and correct diagnosis of ATTR amyloidosis, histological examination of the flexor retinaculum is particularly necessary, and a sample excision should always be obtained and examined histologically.

ATTR amyloid in the carpal tunnel ligament is frequently of wildtype transthyretin origin.

The carpal tunnel ligament often encloses transthyretin-derived (ATTR) amyloid deposits. In this study we tested the hypothesis that ATTR amyloid in the carpal tunnel ligament is most commonly of wildtype origin in a Caucasian population without endemic background of familial amyloid polyneuropathy. All resection specimens from the carpal tunnel ligament were retrieved from the Amyloid Registry of the University of Kiel spanning the period of 2004-2011 and dichotomized into two study groups: the first study group of 25 patients was obtained from diverse referring pathologists. The second group comprised a patient cohort of 73 patients obtained from a single-referring department of pathology. The selection of biopsies was based on the histological identification of amyloid by Congo red staining and polarization microscopy between crossed polars and immunohistochemical classification as ATTR amyloid. A novel anti-TTR-peptide antibody was raised in rabbits using a recombinant peptide (FHEHAEVVFTANDSGPRRYT) spanning residues 87-106 of the TTR protein. Amplification of the TTR exons 1, 2, 3 and 4 was done by a nested polymerase chain reaction approach. Ninety-eight biopsies were available from 98 patients, including 51 women and 47 men. All amyloid deposits showed strong immunoreactions with the novel anti-TTR peptide antibody. In 81 of 98 patients, genomic DNA was available. In 10 (12%) patients non-amyloidogenic TTR gene mutations were found with the following amino acid substitutions: p.G6S (normal allelic variant). A single patient carried a p.G6S and a p.M13I-variant. The remaining patients all showed wildtype sequence of the TTR gene (70 patients). No significant difference was found between the two study groups. ATTR amyloid in the carpal tunnel ligament is commonly of wildtype origin and genetic counseling is not mandatory in these patients.