scholarly journals Diagnostic algorithm in transthyretin amyloidosis with cardiomyopathy

2020 ◽  
Vol 26 (2) ◽  
pp. 5-20
Author(s):  
Mariana Gospodinova ◽  
Elena Kinova ◽  
Iana Simova ◽  
Yoto Yotov ◽  
Marina Garcheva ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Early Recognition ◽  
Multimodality Imaging ◽  
Diagnostic Algorithm ◽  
Restrictive Cardiomyopathy ◽  
Wild Type ◽  
Transthyretin Amyloidosis ◽  
Life Threatening ◽  
Timely Treatment ◽  
Centres Of Expertise

Transthyretin cardiac amyloidosis is a restrictive cardiomyopathy ((ATTR-CM), caused by an extracellular deposition of insoluble amyloid fibrils in the myocardium. It is a life threatening disease with life expectancy of 2 to 6 years after diagnosis. There are two types – hereditary and wild type. Recent data reveal that the wild type ATTR-CM is a common cause of heart failure with preserved ejection fraction, especially in elderly men. Hereditary ATTR amyloidosis is not so rare in Bulgaria. Five different mutations have been diagnosed, the most common being p.Glu89Gln, identified in 62 unrelated families with 117 patients and 72 mutation carriers. ATTR-CM diagnosis is often delayed or even missed, however its early recognition has become very important as a new drug, which is a transthyretin stabilizer is now available and other drugs are under development. Updated knowledge about the clinical presentation, diagnostic algorithm, available and future therapeutic options for ATTR-CM are a prerequisite for an early identification, timely treatment and better prognosis of the affected patients. The diagnosis requires a multidisciplinary approach with the participation of experienced specialists, multimodality imaging, well equipped histopathological and genetic laboratories. Establishing centres of expertise could improve the management of the patients with ATTR-CM.

scholarly journals The rheumatology/hematology interface: CAPS and MAS diagnosis and management

Hematology ◽  
2018 ◽  
Vol 2018 (1) ◽  
pp. 313-317 ◽  
Author(s):  
John M. Gansner ◽  
Nancy Berliner
Keyword(s):  
Lupus Erythematosus ◽  
Macrophage Activation ◽  
Early Recognition ◽  
Antiphospholipid Antibody ◽  
Antiphospholipid Antibody Syndrome ◽  
Rheumatologic Disease ◽  
Rheumatologic Diseases ◽  
Life Threatening ◽  
Vessel Thrombosis ◽  
Timely Treatment

Abstract Catastrophic antiphospholipid antibody syndrome (CAPS) and macrophage activation syndrome (MAS) are both life-threatening hematologic disorders that infrequently afflict patients with rheumatologic disease. CAPS is characterized by fulminant multiorgan damage related to small vessel thrombosis in the setting of persistent antiphospholipid antibodies. It can occur in patients with rheumatologic diseases such as systemic lupus erythematosus but can also affect patients who do not have rheumatologic disease. By contrast, the term MAS is applied when patients with rheumatologic disease develop hemophagocytic lymphohistiocytosis (HLH); therefore, patients with MAS have an underlying rheumatologic disease by definition. Similar to CAPS, HLH/MAS can have a fulminant presentation, but the pathogenesis and manifestations are different. In both CAPS and MAS, management generally includes but is not limited to immunosuppression with steroids. Fatalities are relatively common and morbidity is often significant. Early recognition of these disorders and initiation of timely treatment are important. More effective therapies for both syndromes are urgently needed.

scholarly journals Ultrastructure in Transthyretin Amyloidosis: From Pathophysiology to Therapeutic Insights

Biomedicines ◽  
2019 ◽  
Vol 7 (1) ◽  
pp. 11 ◽  
Author(s):  
Haruki Koike ◽  
Masahisa Katsuno
Keyword(s):  
Elderly Population ◽  
Amyloid Fibrils ◽  
Age Of Onset ◽  
Therapeutic Option ◽  
The Elderly ◽  
Organ Damage ◽  
Phase Iii ◽  
Wild Type ◽  
Electron Microscopic ◽  
Transthyretin Amyloidosis

Transthyretin (TTR) amyloidosis is caused by systemic deposition of wild-type or variant amyloidogenic TTR (ATTRwt and ATTRv, respectively). ATTRwt amyloidosis has traditionally been termed senile systemic amyloidosis, while ATTRv amyloidosis has been called familial amyloid polyneuropathy. Although ATTRwt amyloidosis has classically been regarded as one of the causes of cardiomyopathy occurring in the elderly population, recent developments in diagnostic techniques have significantly expanded the concept of this disease. For example, this disease is now considered an important cause of carpal tunnel syndrome in the elderly population. The phenotypes of ATTRv amyloidosis also vary depending on the mutation and age of onset. Peripheral neuropathy usually predominates in patients from the conventional endemic foci, while cardiomyopathy or oculoleptomeningeal involvement may also become major problems in other patients. Electron microscopic studies indicate that the direct impact of amyloid fibrils on surrounding tissues leads to organ damage, whereas accumulating evidence suggests that nonfibrillar TTR, such as oligomeric TTR, is toxic, inducing neurodegeneration. Microangiopathy has been suggested to act as an initial lesion, increasing the leakage of circulating TTR. Regarding treatments, the efficacy of liver transplantation has been established for ATTRv amyloidosis patients, particularly patients with early-onset amyloidosis. Recent phase III clinical trials have shown the efficacy of TTR stabilizers, such as tafamidis and diflunisal, for both ATTRwt and ATTRv amyloidosis patients. In addition, a short interfering RNA (siRNA), patisiran, and an antisense oligonucleotide (ASO), inotersen, have been shown to be effective for ATTRv amyloidosis patients. Given their ability to significantly reduce the production of both wild-type and variant TTR in the liver, these gene-silencing drugs seem to be the optimal therapeutic option for ATTR amyloidosis. Hence, the long-term efficacy and tolerability of novel therapies, particularly siRNA and ASO, must be determined to establish an appropriate treatment program.

scholarly journals Treatment With Tafamidis Slows Disease Progression in Early-Stage Transthyretin Cardiomyopathy

2017 ◽  
Vol 11 ◽  
pp. 117954681773032 ◽  
Author(s):  
Marla B Sultan ◽  
Balarama Gundapaneni ◽  
Jennifer Schumacher ◽  
Jeffrey H Schwartz
Keyword(s):  
Disease Progression ◽  
Amyloid Fibrils ◽  
Early Stage ◽  
Heart Association ◽  
Analysis Data ◽  
Amyloid Formation ◽  
Functional Classification ◽  
Wild Type ◽  
Open Label ◽  
Transthyretin Amyloidosis

Background: Transthyretin cardiomyopathy (TTR-CM) is a progressive, fatal disease caused by the accumulation of misfolded transthyretin (TTR) amyloid fibrils in the heart. Tafamidis is a kinetic stabilizer of TTR that inhibits misfolding and amyloid formation. Methods: In this post hoc analysis, data from an observational study (Transthyretin Amyloidosis Cardiac Study; n = 29) were compared with an open-label study of tafamidis in patients with TTR-CM (Fx1B-201; n = 35). To ensure comparable baseline disease severity, patients with New York Heart Association (NYHA) functional classification ≥III were excluded in this time-to-mortality analysis. Results: Patients with either wild-type or Val122Ile genotypes treated with tafamidis have a significantly longer time to death compared with untreated patients ( P = .0004). Similar results were obtained when limiting the analysis to wild-type patients only, without restricting NYHA functional classification ( P = .0262). Conclusions: These results support earlier conclusions suggesting that tafamidis slows disease progression compared with no treatment outside of standard of care and warrant further investigation. Trial Registration: ClinicalTrials.gov, NCT00694161.

scholarly journals Transthyretin amyloid cardiomyopathy in women: frequency, characteristics, and diagnostic challenges

2020 ◽  
Vol 26 (1) ◽  
pp. 35-45 ◽  
Author(s):  
Marianna Bruno ◽  
Adam Castaño ◽  
Arianna Burton ◽  
Justin L. Grodin
Keyword(s):  
Wall Thickness ◽  
Amyloid Fibrils ◽  
Posterior Wall ◽  
Pooled Analysis ◽  
Left Ventricular ◽  
Wild Type ◽  
Eligibility Criteria ◽  
Posterior Wall Thickness ◽  
Life Threatening ◽  
Amyloid Cardiomyopathy

AbstractTransthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, life-threatening disease characterized by deposition of insoluble amyloid fibrils in the myocardium, resulting in cardiac structural and functional abnormalities and ultimately heart failure. Disease frequency is reportedly lower in women than men, but sex-related differences have not been well established. We conducted a systematic literature review (SLR), based on PRISMA-P guidelines and registered with PROSPERO, to assess whether the epidemiology and clinical presentation of ATTR-CM differ between women and men. MEDLINE, Embase, and Cochrane databases and selected conference proceedings were searched (August 16, 2019) to identify observational and clinical studies reporting sex-specific data for patients with wild-type or hereditary ATTR-CM. Of 193 publications satisfying final eligibility criteria, 69 studies were included in our pooled analysis. Among the 4669 patients with ATTR-CM analyzed, 791 (17%) were women, including 174 (9%), 366 (29%), and 251 (18%) in studies of wild-type, hereditary, and undefined ATTR-CM, respectively. Data available on disease characteristics were limited and very heterogeneous, but trends suggested some cardiac structural/functional differences, i.e., lower interventricular septal and posterior wall thickness and left ventricular (LV) end diastolic diameter, and higher LV ejection fractions, in women versus men across ATTR-CM subtypes. Because LV wall thickness > 12 mm is generally the suggested threshold for ATTR-CM diagnosis in both sexes, smaller cardiac anatomy in women with the disease may lead to underdiagnosis. Additional research and studies are needed to elucidate potential disparities between sexes in ATTR-CM frequency, clinical characteristics, and underlying biological mechanisms. This study was registered within the International Prospective Register of Systematic Reviews (PROSPERO) database of the University of York (CRD42019146995).

scholarly journals Amyloid seeding of transthyretin by ex vivo cardiac fibrils and its inhibition

2018 ◽  
Vol 115 (29) ◽  
pp. E6741-E6750 ◽  
Author(s):  
Lorena Saelices ◽  
Kevin Chung ◽  
Ji H. Lee ◽  
Whitaker Cohn ◽  
Julian P. Whitelegge ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Ex Vivo ◽  
Standard Of Care ◽  
Wild Type ◽  
Current Standard ◽  
Transthyretin Amyloidosis ◽  
Physiological Conditions ◽  
Type Gene ◽  
Amyloid Diseases

Each of the 30 human amyloid diseases is associated with the aggregation of a particular precursor protein into amyloid fibrils. In transthyretin amyloidosis (ATTR), mutant or wild-type forms of the serum carrier protein transthyretin (TTR), synthesized and secreted by the liver, convert to amyloid fibrils deposited in the heart and other organs. The current standard of care for hereditary ATTR is liver transplantation, which replaces the mutantTTRgene with the wild-type gene. However, the procedure is often followed by cardiac deposition of wild-type TTR secreted by the new liver. Here we find that amyloid fibrils extracted from autopsied and explanted hearts of ATTR patients robustly seed wild-type TTR into amyloid fibrils in vitro. Cardiac-derived ATTR seeds can accelerate fibril formation of wild-type and monomeric TTR at acidic pH and under physiological conditions, respectively. We show that this seeding is inhibited by peptides designed to complement structures of TTR fibrils. These inhibitors cap fibril growth, suggesting an approach for halting progression of ATTR.

scholarly journals Modulation of the Mechanisms Driving Transthyretin Amyloidosis

2020 ◽  
Vol 13 ◽  
Author(s):  
Filipa Bezerra ◽  
Maria João Saraiva ◽  
Maria Rosário Almeida
Keyword(s):  
Amyloid Fibrils ◽  
Single Point ◽  
Point Mutations ◽  
Disease Process ◽  
Wild Type ◽  
Transthyretin Amyloidosis ◽  
Natural Ligand ◽  
Single Point Mutations ◽  
Pharmacologic Agents ◽  
Plasma Stabilization

Transthyretin (TTR) amyloidoses are systemic diseases associated with TTR aggregation and extracellular deposition in tissues as amyloid. The most frequent and severe forms of the disease are hereditary and associated with amino acid substitutions in the protein due to single point mutations in the TTR gene (ATTRv amyloidosis). However, the wild type TTR (TTR wt) has an intrinsic amyloidogenic potential that, in particular altered physiologic conditions and aging, leads to TTR aggregation in people over 80 years old being responsible for the non-hereditary ATTRwt amyloidosis. In normal physiologic conditions TTR wt occurs as a tetramer of identical subunits forming a central hydrophobic channel where small molecules can bind as is the case of the natural ligand thyroxine (T4). However, the TTR amyloidogenic variants present decreased stability, and in particular conditions, dissociate into partially misfolded monomers that aggregate and polymerize as amyloid fibrils. Therefore, therapeutic strategies for these amyloidoses may target different steps in the disease process such as decrease of variant TTR (TTRv) in plasma, stabilization of TTR, inhibition of TTR aggregation and polymerization or disruption of the preformed fibrils. While strategies aiming decrease of the mutated TTR involve mainly genetic approaches, either by liver transplant or the more recent technologies using specific oligonucleotides or silencing RNA, the other steps of the amyloidogenic cascade might be impaired by pharmacologic compounds, namely, TTR stabilizers, inhibitors of aggregation and amyloid disruptors. Modulation of different steps involved in the mechanism of ATTR amyloidosis and compounds proposed as pharmacologic agents to treat TTR amyloidosis will be reviewed and discussed.

scholarly journals A case of panitumumab containing chemotherapy causing interstitial lung disease: early recognition and treatment resulting in a good outcome

2019 ◽  
Vol 12 (2) ◽  
pp. bcr-2018-227785 ◽  
Author(s):  
Kamal Naguib Makar Rezkallah ◽  
Adnan Ahmed ◽  
Sabah Patel ◽  
Kelly Kozma
Keyword(s):  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Early Recognition ◽  
Wild Type ◽  
Serious Adverse Event ◽  
Systemic Corticosteroids ◽  
Life Threatening ◽  
Systemic Antibiotics ◽  
New Onset

Panitumumab is a recombinant human IgG2 monoclonal antibody which is used for the treatment of patients with metastatic colorectal cancer (mCRC) with disease progression on or following FOLFIRI (fluoropyrimidine, oxaliplatin and irinotecan) containing chemotherapy regimen. We report a case of an 83-year-old Hispanic man, non-smoker, with KRAS/NRAS wild-type mCRC of the liver who was treated with 9 cycles of FOLFOX4 (fluorouracil, leucovorin and oxaliplatin) and cetuximab. Follow-up abdominal imaging showed progression of CRC, requiring initiation of panitumumab in addition to FOLFIRI. After 2 cycles of this combination chemotherapy, he presented with acute hypoxaemic respiratory failure. Pulmonary imaging showed new onset of interstitial lung disease (ILD). He was treated with systemic corticosteroids with marked improvement of ILD. We aim to highlight the risk of severe life-threatening ILD associated with panitumumab. Early recognition of this serious adverse event helps avoid unnecessary administration of systemic antibiotics and prevent mortality.

scholarly journals Cardiac Amyloidosis: Diagnostic Tools for a Challenging Disease

2021 ◽  
Vol 11 (3) ◽  
pp. 111-121
Author(s):  
Marco Giuseppe Migliaccio ◽  
Franco Iodice ◽  
Marco Di Mauro ◽  
Angela Iannuzzi ◽  
Roberta Pacileo ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Cardiac Tissue ◽  
Diastolic Heart Failure ◽  
Target Therapy ◽  
Clinical Signs ◽  
Restrictive Cardiomyopathy ◽  
Diagnostic Tools ◽  
Transthyretin Amyloidosis ◽  
Amyloid Fibril Formation ◽  
Immunoglobulin Light Chain Amyloidosis

Amyloidosis is a group of diseases in which amyloid fibrils build up in tissues, leading to organ dysfunction. Cardiac involvement is observed in immunoglobulin light chain amyloidosis (AL) and transthyretin amyloidosis (ATTR) and, when it occurs, the prognosis worsens. Cardiac tissue infiltration can lead to restrictive cardiomyopathy with clinical signs of diastolic heart failure, without reduction of ejection fraction (HFpEF). The aim of multiple and less invasive diagnostic tests is to discern peculiar characteristics and reach the diagnosis without performing an invasive endomyocardial biopsy. These diagnostic tools allow early diagnosis, and they are crucial to best benefit from target therapy. In this review article, we describe the mechanism behind amyloid fibril formation, infiltration of tissues, and consequent clinical signs, focusing on the diagnostic tools and the red flags to obtain a diagnosis.

scholarly journals Current Challenges of Cardiac Amyloidosis Awareness Among Romanian Cardiologists

2021 ◽  
Author(s):  
Robert Adam ◽  
Gabriela Neculae ◽  
Claudiu Stan ◽  
Ruxandra Jurcut
Keyword(s):  
Cardiac Amyloidosis ◽  
Online Survey ◽  
Treatment Options ◽  
Delayed Diagnosis ◽  
Diagnostic Algorithm ◽  
Restrictive Cardiomyopathy ◽  
Transthyretin Amyloidosis ◽  
Cardiac Symptom ◽  
Important Challenge ◽  
New Treatment

Cardiac amyloidosis (CA) is a restrictive cardiomyopathy characterized by deposition of amyloid in the myocardium and recent studies revealed it is more frequently seen than we thought. Advances have been made over the last years, but a delayed diagnosis is frequently seen. An online survey was conducted among cardiologists from Romania representing the first assessment of the knowledge of CA among them with 195 cardiologists answering the questionnaire. There was a wide variation in their knowledge regarding CA. Our participants had few experience with CA and reported a significant delay between first cardiac symptom and diagnosis. Around one half of them did not seem familiar with the noninvasive diagnostic algorithm and with the wild-type transthyretin amyloidosis (ATTRwt). Even the participants who are aware of this condition and the available treatment options stated this is a rare disease and there is no disease modifying treatment available for ATTRwt. Awareness among cardiologists is the most important challenge in diagnosing CA. Romanian cardiologists are partially aware of this topic, but there are still gaps in their knowledge. Educational programs can improve screening of patients with a high suspicion for this progressive condition whose evolution has been dramatically changed by the new treatment options.

Effect of Undertriage on the Outcomes of Cancer Patients with Febrile Neutropenia, Sepsis, and Septic Shock

2021 ◽  
pp. 105477382199968
Author(s):  
Anas Alsharawneh
Keyword(s):  
Emergency Department ◽  
Septic Shock ◽  
Length Of Stay ◽  
Febrile Neutropenia ◽  
Cancer Patients ◽  
Emergency Setting ◽  
Extended Length ◽  
Life Threatening ◽  
Sepsis And Septic Shock ◽  
Timely Treatment

Sepsis and neutropenia are considered the primary life-threatening complications of cancer treatment and are the leading cause of hospitalization and death. The objective was to study whether patients with neutropenia, sepsis, and septic shock were identified appropriately at triage and receive timely treatment within the emergency setting. Also, we investigated the effect of undertriage on key treatment outcomes. We conducted a retrospective analysis of all accessible records of admitted adult cancer patients with febrile neutropenia, sepsis, and septic shock. Our results identified that the majority of patients were inappropriately triaged to less urgent triage categories. Patients’ undertriage significantly prolonged multiple emergency timeliness indicators and extended length of stay within the emergency department and hospital. These effects suggest that triage implementation must be objective, consistent, and accurate because of the several influences of the assigned triage scoring on treatment and health outcomes.

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