Effects of sporadic transthyretin amyloidosis frequently on the gallbladder and the correlation between amyloid deposition in the gallbladder and heart: A forensic autopsy‐based histopathological evaluation

Background: Amyloidosis treatment has advanced rapidly along with the discovery of drugs to prevent amyloid deposition. Therefore, it is vital to detect amyloidosis at an early stage. Wild-type transthyretin, which can cause carpal tunnel syndrome, may also cause finger tenosynovitis. However, the correlation between wild-type transthyretin amyloid and finger tenosynovitis is unclear. Here, we investigated pathological and clinical findings for 20 patients with finger tenosynovitis who underwent operation at our hospital to determine the frequency of transthyretin amyloid deposition in idiopathic finger tenosynovitis. Methods: To check for the presence of amyloid deposition, all specimens (tendon synovium tissue or flexor tendon sheath) resected during the operation were stained by the direct fast scarlet method. Amyloid-positive specimens were evaluated by immunohistochemical staining using an anti-transthyretin antibody. Patient characteristics were evaluated with respect to amyloid presence. Results: Thirteen (65%) of 20 finger tenosynovitis cases had amyloid deposition. Nine (69.2%) of the 13 amyloid-positive cases exhibited extensive transthyretin staining and were considered to have transthyretin amyloid. Amyloid deposition was more frequent in men. The mean number of fingers with tenosynovitis was significantly higher in amyloid-positive cases (3.8 fingers) than in amyloid-negative cases (2.0 fingers). Conclusions: Men with multiple finger tenosynovitis tended to have transthyretin amyloid deposition. Our results support that multiple finger tenosynovitis may serve as an initial indication of evaluation for transthyretin amyloidosis.

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Machine learning quantification of amyloid deposits in histological images of ligamentum flavum

10.1101/2021.12.05.21267317 ◽

2021 ◽

Author(s):

Andy Y. Wang ◽

Vaishnavi Sharma ◽

Harleen Saini ◽

Joseph N. Tingen ◽

Alexandra Flores ◽

...

Keyword(s):

Machine Learning ◽

Spinal Stenosis ◽

Ligamentum Flavum ◽

Amyloid Deposition ◽

Future Research ◽

Manual Segmentation ◽

Training Set ◽

Transthyretin Amyloidosis ◽

Amyloid Deposits ◽

Lumbar Spinal

ABSTRACTBackgroundWild-type transthyretin amyloidosis (ATTRwt) is an underdiagnosed and potentially fatal disease. Interestingly, ATTRwt deposits have been found to deposit in the ligamentum flavum (LF) of patients with lumbar spinal stenosis prior to the development of systemic and cardiac amyloidosis. In order to study this phenomenon and its possible relationship with LF thickening and systemic amyloidosis, a precise method of quantifying amyloid deposits in histological slides of LF is critical. However, such a method is currently unavailable. Here, we present a machine learning quantification method with Trainable Weka Segmentation (TWS) to assess amyloid deposition in histological slides of LF.MethodsImages of ligamentum flavum specimens stained with Congo red are obtained from spinal stenosis patients undergoing laminectomies and confirmed to be positive for ATTRwt. Amyloid deposits in these specimens are classified and quantified by TWS through training the algorithm via user-directed annotations on images of LF. TWS can also be automated through exposure to a set of training images with user-directed annotations, and then application to a set of new images without additional annotations. Additional methods of color thresholding and manual segmentation are also used on these images for comparison to TWS.ResultsWe develop the use of TWS in images of LF and demonstrate its potential for automated quantification. TWS is strongly correlated with manual segmentation in the training set of images with user-directed annotations (R = 0.98; p = 0.0033) as well as in the application set of images where TWS was automated (R = 0.94; p = 0.016). Color thresholding was weakly correlated with manual segmentation in the training set of images (R = 0.78; p = 0.12) and in the application set of images (R = 0.65; p = 0.23).ConclusionTWS machine learning closely correlates with the gold standard comparator of manual segmentation and outperforms the color thresholding method. This novel machine learning method to quantify amyloid deposition in histological slides of ligamentum flavum is a precise, objective, accessible, high throughput, and powerful tool that will hopefully pave the way towards future research and clinical applications.

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Unfolding Cardiac Amyloidosis –From Pathophysiology to Cure

Current Medicinal Chemistry ◽

10.2174/0929867325666180104153338 ◽

2019 ◽

Vol 26 (16) ◽

pp. 2865-2878 ◽

Cited By ~ 3

Author(s):

Klemens Ablasser ◽

Nicolas Verheyen ◽

Theresa Glantschnig ◽

Giulio Agnetti ◽

Peter P. Rainer

Keyword(s):

Cardiac Disease ◽

Cardiac Remodeling ◽

Cardiac Amyloidosis ◽

Amyloid Fibrils ◽

Amyloid Deposition ◽

Transthyretin Amyloidosis ◽

Cardiac Amyloid ◽

Amyloidogenic Proteins ◽

Preclinical Trials ◽

Current Therapies

Deposition of amyloidogenic proteins leading to the formation of amyloid fibrils in the myocardium causes cardiac amyloidosis. Although any form of systemic amyloidosis can affect the heart, light-chain (AL) or transthyretin amyloidosis (ATTR) account for the majority of diagnosed cardiac amyloid deposition. The extent of cardiac disease independently predicts mortality. Thus, the reversal of arrest of adverse cardiac remodeling is the target of current therapies. Here, we provide a condensed overview on the pathophysiology of AL and ATTR cardiac amyloidoses and describe treatments that are currently used or investigated in clinical or preclinical trials. We also briefly discuss acquired amyloid deposition in cardiovascular disease other than AL or ATTR.

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Progression of cardiac amyloid deposition in hereditary transthyretin amyloidosis patients after liver transplantation

Amyloid ◽

10.1080/13506120701614032 ◽

2007 ◽

Vol 14 (4) ◽

pp. 277-282 ◽

Cited By ~ 77

Author(s):

Juris J. Liepnieks ◽

Merrill D. Benson

Keyword(s):

Liver Transplantation ◽

Amyloid Deposition ◽

Transthyretin Amyloidosis ◽

Cardiac Amyloid ◽

Hereditary Transthyretin Amyloidosis

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Ocular Involvement in Hereditary Amyloidosis

Genes ◽

10.3390/genes12070955 ◽

2021 ◽

Vol 12 (7) ◽

pp. 955

Author(s):

Angelo Maria Minnella ◽

Roberta Rissotto ◽

Elena Antoniazzi ◽

Marco Di Girolamo ◽

Marco Luigetti ◽

...

Keyword(s):

Local Level ◽

Retinal Pigment ◽

Diagnostic Delay ◽

Amyloid Deposition ◽

Retinal Pigment Epithelial Cells ◽

Ocular Involvement ◽

Transthyretin Amyloidosis ◽

Systemic Involvement ◽

Ocular Manifestations ◽

Eye Involvement

The term amyloidosis describes a group of rare diseases caused by protein conformation abnormalities resulting in extracellular deposition and accumulation of insoluble fibrillar aggregates. So far, 36 amyloid precursor proteins have been identified, and each one is responsible for a specific disease entity. Transthyretin amyloidosis (ATTRv) is one of the most common forms of systemic and ocular amyloidosis, due to the deposition of transthyretin (TTR), which is a transport protein mainly synthesized in the liver but also in the retinal pigment epithelial cells. ATTRv amyloidosis may be misdiagnosed with several other conditions, resulting in a significant diagnostic delay. Gelsolin and keratoepithelin are other proteins that, when mutated, are responsible for a systemic amyloid disease with significant ocular manifestations that not infrequently appear before systemic involvement. The main signs of ocular amyloid deposition are in the cornea, irido-corneal angle and vitreous, causing complications related to vasculopathy and neuropathy at the local level. This review aims at describing the main biochemical, histopathological and clinical features of systemic amyloidosis associated with eye involvement, with particular emphasis on the inherited forms. We discuss currently available treatments, focusing on ocular involvement and specific ophthalmologic management and highlighting the importance of a prompt treatment for the potential sight-threatening complications derived from amyloid deposition in ocular tissues.

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The prostate as a good candidate organ for proving amyloid deposition in non-endemic late onset hereditary transthyretin amyloidosis: Report of two cases

Journal of the Neurological Sciences ◽

10.1016/j.jns.2021.117418 ◽

2021 ◽

pp. 117418

Author(s):

Kentaro Maeda ◽

Yasuaki Kubota ◽

Satoshi Kitagawa ◽

Mitsuharu Ueda ◽

Yukio Ando ◽

...

Keyword(s):

Late Onset ◽

Amyloid Deposition ◽

Transthyretin Amyloidosis ◽

Hereditary Transthyretin Amyloidosis

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Plasmin activity promotes amyloid deposition in a transgenic model of human transthyretin amyloidosis

Nature Communications ◽

10.1038/s41467-021-27416-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Ivana Slamova ◽

Rozita Adib ◽

Stephan Ellmerich ◽

Michal R. Golos ◽

Janet A. Gilbertson ◽

...

Keyword(s):

Amyloid Fibrils ◽

Amyloid Deposition ◽

Amyloid Formation ◽

Plasmin Activity ◽

Transthyretin Amyloidosis ◽

In Vivo Models ◽

Transgenic Expression ◽

Attr Amyloidosis ◽

Amyloid Deposits

AbstractCardiac ATTR amyloidosis, a serious but much under-diagnosed form of cardiomyopathy, is caused by deposition of amyloid fibrils derived from the plasma protein transthyretin (TTR), but its pathogenesis is poorly understood and informative in vivo models have proved elusive. Here we report the generation of a mouse model of cardiac ATTR amyloidosis with transgenic expression of human TTRS52P. The model is characterised by substantial ATTR amyloid deposits in the heart and tongue. The amyloid fibrils contain both full-length human TTR protomers and the residue 49-127 cleavage fragment which are present in ATTR amyloidosis patients. Urokinase-type plasminogen activator (uPA) and plasmin are abundant within the cardiac and lingual amyloid deposits, which contain marked serine protease activity; knockout of α2-antiplasmin, the physiological inhibitor of plasmin, enhances amyloid formation. Together, these findings indicate that cardiac ATTR amyloid deposition involves local uPA-mediated generation of plasmin and cleavage of TTR, consistent with the previously described mechano-enzymatic hypothesis for cardiac ATTR amyloid formation. This experimental model of ATTR cardiomyopathy has potential to allow further investigations of the factors that influence human ATTR amyloid deposition and the development of new treatments.

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Effects of sporadic transthyretin amyloidosis frequently on the gallbladder and the correlation between amyloid deposition in the gallbladder and heart

10.21203/rs.3.rs-397058/v1 ◽

2021 ◽

Author(s):

Shojiro Ichimata ◽

Yukiko Hata ◽

Naoki Nishida

Keyword(s):

Gastrointestinal Tract ◽

Gall Bladder ◽

Cardiac Involvement ◽

Amyloid Deposition ◽

Clinicopathological Features ◽

Common Condition ◽

Transthyretin Amyloidosis ◽

Attr Amyloidosis ◽

Hematoxylin And Eosin ◽

Interstitial Deposition

Abstract The aim of the study is to evaluate the clinicopathological features of cholecystic ATTR deposition in patients with cardiac involvement, investigate the correlation of amyloid deposition severity in the gallbladder and the heart, and compare its prevalence in the gallbladder and other organs. Fifty patients with sporadic ATTR amyloidosis were identified. Of these, we evaluated 15 patients who underwent gallbladder sampling accurately. Among 10 patients (67%) with cholecystic deposition, six exhibited detectable deposition in the hematoxylin and eosin-stained specimens, and all of them displayed obstructive vascular deposition (VD). The severity of gall bladder VD was statistically correlated with that of cardiac VD and atrial interstitial deposition (ID). Additionally, all patients exhibiting cholecystic ID displayed severe ventricular and atrial IDs. In visceral organs excluding the heart, amyloid deposition was commonly observed in the lungs (93%), followed by the gastrointestinal tract (47%‒80%), liver (60%), and periosteal tissues (53%). The involvement of gallbladder was prevalent and comparable to that of the gastrointestinal tract. Moreover, the severity of cholecystic deposition was correlated with that of cardiac deposition. Therefore, pathologists should be aware that sporadic ATTR amyloidosis is a common condition and should not be overlooked.

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