Biochemistry, Genetics and Molecular Biology › Molecular Biology

Amyloidosis: Diagnosis, Treatment, Outcomes

Works Count: 46657

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Description

This cluster of papers focuses on the molecular mechanisms, diagnosis, treatment, and prognosis of amyloidosis, with a particular emphasis on transthyretin-related cardiac and familial amyloid polyneuropathy. It covers topics such as RNAi therapy, cardiovascular magnetic resonance, and immunoglobulin light chain involvement.

Keywords

Transthyretin; Cardiac Amyloidosis; Light Chain Amyloidosis; RNAi Therapy; Diagnosis; Treatment; Prognosis; Familial Amyloid Polyneuropathy; Immunoglobulin Light Chain; Cardiovascular Magnetic Resonance

Amyloid Deposits and Amyloidosis

1980-06-05

George G. Glenner

SINCE Cohen's review of amyloidosis was published in the Journal in 1967, there have been major advances in our understanding of what was less than a decade ago an untreatable, … SINCE Cohen's review of amyloidosis was published in the Journal in 1967, there have been major advances in our understanding of what was less than a decade ago an untreatable, usually lethal disease complex of unknown nature, cause, and pathogenesis. Much of the mystery about the character of the "waxy, eosinophilic" tissue deposits, which Virchow believed in 1853 to be of polysaccharide composition and consequently designated as "amyloid" (starch-like or cellulose-like) has now yielded to investigations employing a wide variety of chemical and physical techniques. Once it was demonstrated that unique fibrillar components comprised over 90 per cent of amyloid . . .

Acute Phase Proteins with Special Reference to C-Reactive Protein and Related Proteins (Pentaxins) and Serum Amyloid A Protein

1983-01-01

Mark B. Pepys , M L Baltz

Serum reference intervals and diagnostic ranges for free kappa and free lambda immunoglobulin light chains: relative sensitivity for detection of monoclonal light chains.

2002-09-01

Jerry A. Katzmann , Raynell Clark , Roshini S. Abraham +4 more

The detection of monoclonal free light chains (FLCs) is an important diagnostic aid for a variety of monoclonal gammopathies and is especially important in light-chain diseases, such as light-chain myeloma, … The detection of monoclonal free light chains (FLCs) is an important diagnostic aid for a variety of monoclonal gammopathies and is especially important in light-chain diseases, such as light-chain myeloma, primary systemic amyloidosis, and light-chain-deposition disease. These diseases are more prevalent in the elderly, and assays to detect and quantify abnormal amounts of FLCs require reference intervals that include elderly donors.We used an automated immunoassay for FLCs and sera from a population 21-90 years of age. We used the calculated reference and diagnostic intervals to compare FLC results with those obtained by immunofixation (IFE) to detect low concentrations of monoclonal kappa and lambda FLCs in the sera of patients with monoclonal gammopathies.Serum kappa and lambda FLCs increased with population age, with an apparent change for those >80 years. This trend was lost when the FLC concentration was normalized to cystatin C concentration. The ratio of kappa FLC to lambda FLC (FLC K/L) did not exhibit an age-dependent trend. The diagnostic interval for FLC K/L was 0.26-1.65. The 95% reference interval for kappa FLC was 3.3-19.4 mg/L, and that for lambda FLC was 5.7-26.3 mg/L. Detection and quantification of monoclonal FLCs by nephelometry were more sensitive than IFE in serum samples from patients with primary systemic amyloidosis and light-chain-deposition disease.Reference and diagnostic intervals for serum FLCs have been developed for use with a new, automated immunoassay that makes the detection and quantification of monoclonal FLCs easier and more sensitive than with current methods. The serum FLC assay complements IFE and allows quantification of FLCs in light-chain-disease patients who have no detectable serum or urine M-spike.

Apolipoprotein E: A pathological chaperone protein in patients with cerebral and systemic amyloid

1992-02-01

Thomas Wısnıewskı , Blas Frangione

Many biochemically diverse proteins can give rise to amyloid fibrils; however, they are all accompanied by P component and glucosaminoglycans. With antibodies specific to apolipoprotein E (apo E) we used … Many biochemically diverse proteins can give rise to amyloid fibrils; however, they are all accompanied by P component and glucosaminoglycans. With antibodies specific to apolipoprotein E (apo E) we used immunohistochemical techniques to test for the presence of this protein in both cerebral and systemic amyloid. We found apo E immunoreactivity in all tested types of cerebral and systemic amyloid. In amyloid deposits apo E P, component and glucosaminoglycans may be acting as ‘pathological molecular chaperones’. The latter we define as a group of unrelated proteins that induce β-pleated conformation in amyloidogenic polypeptides.

Cerebrospinal fluid analysis: disease-related data patterns and evaluation programs

2001-03-01

Hansotto Reiber , James B. Peter

Amyloid and amyloidosis

1988-01-01

Stephen M. Breathnach

AMYLOIDOSIS: REVIEW OP 236 CASES

1975-07-01

KOBERT A. KYLE , KUWIN D. BAYED

From 1960 through 1972, 236 cases of amyloidosis with histologic proof were found. The amyloidosis was primary (without evidence of preceding or coexisting disease) in 132 cases (group 1) and … From 1960 through 1972, 236 cases of amyloidosis with histologic proof were found. The amyloidosis was primary (without evidence of preceding or coexisting disease) in 132 cases (group 1) and associated with multiple myeloma in 61 (group 2). Secondary amyloidosis appeared in 19 cases (associated with rheumatoid arthritis or osteomyelitis in two-thirds of them). There were 22 patients with amyloid localized to a single organ (bladder, lung, skin, or larynx in more than half of them). Two patients had familial amyloidosis. In group 1 and group 2, the most common presenting symptoms were fatigue, weight loss, edema, dyspnea, light-headedness or syncope, and paresthesias. Symptoms of the carpal-tunnel syndrome were frequent. The liver was palpable in almost 50% of the series, but splenomegaly was an initial finding in less than 10%. Macroglossia was recorded in 26% of group 2 and in 12% of group 1. Enlargement of submandibular structures was noted in about 10% of cases; and purpura, particularly around the eyes, was a significant feature. Substantial numbers of the patients had carpal-tunnel syndrome, nephrotic syndrome, congestive heart failure, sprue, peripheral neuropathy, or orthostatic hypotension. Approximately 50% of patients had renal insufficiency at the time of diagnosis. Proteinuria was found in more than 90%. A monoclonal protein was found in the serum of 49% of group 1 and in 74% of group 2. Monoclonal proteins were found in the urine of 35% and 81%, respectively. Only 12% of patients in group 1 had no monoclonal protein when both serum and urine were analyzed, and all patients of group 2 had a monoclonal protein in the serum or urine when both were analyzed. Lambda light chains were more common than kappa. None of the patients in group 1 had more than 15% plasma cells in the marrow, whereas more than half of group 2 had more than 15% plasma cells. Roentgenograms showed no evidence of skeletal disease in 94% of group 1, but 50% of group 2 had skeletal abnormalities. Rectal biopsy was positive for amyloid in 84% of cases. Kidney, liver, and carpal-tunnel biopsies were positive in 90% or more. Follow-up of all 193 patients in groups 1 and 2 revealed that 80% of group 1 and 97% of group 2 had died. The median survival was 14.7 months in group 1 and 4 months in group 2. Cardiac failure was the most common cause of death, accounting for 30% of the fatalities. We also reclassified all cases by the method of Isobe and Osserman (105), which is based on clinical patterns: pattern I--principal involvement of tongue, heart, gastrointestinal tract, muscle, nerves, skin, and carpal ligaments; pattern II--principal involvement of liver, spleen, kidneys, and adrenals; and mixed pattern I and II. This analysis failed to reveal predictive value in the clinical pattern classification, and did not discern the survival differences between primary amyloidosis (group 1) and amyloidosis with myeloma (group 2). Consequently, for the present we prefer the classification used in this study.

Serum amyloid A, the major vertebrate acute‐phase reactant

1999-10-01

Clarissa Uhlar , Alexander S. Whitehead

The serum amyloid A (SAA) family comprises a number of differentially expressed apolipoproteins, acute‐phase SAAs (A‐SAAs) and constitutive SAAs (C‐SAAs). A‐SAAs are major acute‐phase reactants, the in vivo concentrations of … The serum amyloid A (SAA) family comprises a number of differentially expressed apolipoproteins, acute‐phase SAAs (A‐SAAs) and constitutive SAAs (C‐SAAs). A‐SAAs are major acute‐phase reactants, the in vivo concentrations of which increase by as much as 1000‐fold during inflammation . A‐SAA mRNAs or proteins have been identified in all vertebrates investigated to date and are highly conserved. In contrast, C‐SAAs are induced minimally, if at all, during the acute‐phase response and have only been found in human and mouse. Although the liver is the primary site of synthesis of both A‐SAA and C‐SAA, extrahepatic production has been reported for most family members in most of the mammalian species studied. In vitro , the dramatic induction of A‐SAA mRNA in response to pro‐inflammatory stimuli is due largely to the synergistic effects of cytokine signaling pathways, principally those of the interleukin‐1 and interleukin‐6 type cytokines. This induction can be enhanced by glucocorticoids. Studies of the A‐SAA promoters in several mammalian species have identified a range of transcription factors that are variously involved in defining both cytokine responsiveness and cell specificity. These include NF‐κB, C/EBP, YY1, AP‐2, SAF and Sp1. A‐SAA is also post‐transcriptionally regulated. Although the precise role of A‐SAA in host defense during inflammation has not been defined, many potential clinically important functions have been proposed for individual SAA family members. These include involvement in lipid metabolism/transport, induction of extracellular‐matrix‐degrading enzymes, and chemotactic recruitment of inflammatory cells to sites of inflammation. A‐SAA is potentially involved in the pathogenesis of several chronic inflammatory diseases: it is the precursor of the amyloid A protein deposited in amyloid A amyloidosis, and it has also been implicated in the pathogenesis of atheroscelerosis and rheumatoid arthritis.

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Fibril in senile systemic amyloidosis is derived from normal transthyretin.

1990-04-01

Per Westermark , Knut Sletten , Tomas Johansson +1 more

The amyloid fibril in senile systemic amyloidosis (SSA), like that of familial amyloidotic polyneuropathy, is derived from transthyretin (TTR). SSA, however, is a common disease, affecting to some degree 25% … The amyloid fibril in senile systemic amyloidosis (SSA), like that of familial amyloidotic polyneuropathy, is derived from transthyretin (TTR). SSA, however, is a common disease, affecting to some degree 25% of the population greater than 80 years old. In familial amyloidotic polyneuropathy, the amyloidogenesis has been considered to depend on point mutations leading to TTR variants. We show that the TTR molecule in SSA, on the other hand, has a normal primary structure. Factors other than the primary structure of TTR must therefore be important in the pathogenesis of TTR-derived amyloid.

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Noninvasive Etiologic Diagnosis of Cardiac Amyloidosis Using 99m Tc-3,3-Diphosphono-1,2-Propanodicarboxylic Acid Scintigraphy

2005-08-30

Enrica Perugini , Pier Luigi Guidalotti , Fabrizio Salvi +7 more

Noncontrast T1 Mapping for the Diagnosis of Cardiac Amyloidosis

2013-03-14

Theodoros D. Karamitsos , Stefan K. Piechnik , Sanjay M Banypersad +7 more

Systemic Cardiac Amyloidoses

2009-09-15

Claudio Rapezzi , Giampaolo Merlini , Candida Cristina Quarta +7 more

Background— Most studies of amyloidotic cardiomyopathy consider as a single entity the 3 main systemic cardiac amyloidoses: acquired monoclonal immunoglobulin light-chain (AL); hereditary, mutated transthyretin-related (ATTRm); and wild-type transthyretin-related (ATTRwt). … Background— Most studies of amyloidotic cardiomyopathy consider as a single entity the 3 main systemic cardiac amyloidoses: acquired monoclonal immunoglobulin light-chain (AL); hereditary, mutated transthyretin-related (ATTRm); and wild-type transthyretin-related (ATTRwt). In this study, we compared the diagnostic/clinical profiles of these 3 types of systemic cardiac amyloidosis. Methods and Results— We conducted a longitudinal study of 233 patients with clear-cut diagnosis by type of cardiac amyloidosis (AL, n=157; ATTRm, n=61; ATTRwt, n=15) at 2 large Italian centers providing coordinated amyloidosis diagnosis/management facilities since 1990. Average age at diagnosis was higher in AL than in ATTRm patients; all ATTRwt patients except 1 were elderly men. At diagnosis, mean left ventricular wall thickness was higher in ATTRwt than in ATTRm and AL. Left ventricular ejection fraction was moderately depressed in ATTRwt but not in AL or ATTRm. ATTRm patients less often displayed low QRS voltage (25% versus 60% in AL; P <0.0001) or low voltage-to-mass ratio (1.1±0.5 versus 0.9±0.5; P <0.0001). AL patients appeared to have greater hemodynamic impairment. On multivariate analysis, ATTRm was a strongly favorable predictor of survival, and ATTRwt predicted freedom from major cardiac events. Conclusions— AL, ATTRm, and ATTRwt should be considered 3 different cardiac diseases, probably characterized by different pathophysiological substrates and courses. Awareness of the diversity underlying the cardiac amyloidosis label is important on several levels, ranging from disease classification to diagnosis and clinical management.

Classification of amyloidosis by laser microdissection and mass spectrometry–based proteomic analysis in clinical biopsy specimens

2009-10-02

Julie A. Vrana , Jeffrey D. Gamez , Benjamin J. Madden +3 more

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Misdiagnosis of Hereditary Amyloidosis as AL (Primary) Amyloidosis

2002-06-06

Helen J. Lachmann , David R. Booth , Susanne E. Booth +5 more

Hereditary, autosomal dominant amyloidosis, caused by mutations in the genes encoding transthyretin, fibrinogen A α-chain, lysozyme, or apolipoprotein A-I, is thought to be extremely rare and is not routinely included … Hereditary, autosomal dominant amyloidosis, caused by mutations in the genes encoding transthyretin, fibrinogen A α-chain, lysozyme, or apolipoprotein A-I, is thought to be extremely rare and is not routinely included in the differential diagnosis of systemic amyloidosis unless there is a family history.

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Safety and Efficacy of RNAi Therapy for Transthyretin Amyloidosis

2013-08-28

Teresa Coelho , David Adams , Ana Silva +7 more

Transthyretin amyloidosis is caused by the deposition of hepatocyte-derived transthyretin amyloid in peripheral nerves and the heart. A therapeutic approach mediated by RNA interference (RNAi) could reduce the production of … Transthyretin amyloidosis is caused by the deposition of hepatocyte-derived transthyretin amyloid in peripheral nerves and the heart. A therapeutic approach mediated by RNA interference (RNAi) could reduce the production of transthyretin.

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Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): A consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis

2005-01-01

Morie A. Gertz , Ray Comenzo , Rodney H. Falk +7 more

We undertook this study to develop uniformly accepted criteria for the definition of organ involvement and response for patients on treatment protocols for immunoglobulin light-chain amyloidosis (AL). A consensus panel … We undertook this study to develop uniformly accepted criteria for the definition of organ involvement and response for patients on treatment protocols for immunoglobulin light-chain amyloidosis (AL). A consensus panel was convened comprising 13 specialists actively involved in the treatment of patients with amyloidosis. Institutional criteria were submitted from each, and a consensus was developed defining each organ involved and the criteria for response. Specific criteria have been developed with agreed on definitions of organ and hematologic response as a result of discussions at the 10th International Symposium on Amyloid and Amyloidosis held in Tours, France, April 2004. These criteria now form the working definition of involvement and response for the purposes of future data collection and reporting. We report criteria that centers can now use to define organ involvement and uniform response criteria for reporting outcomes in patients with light-chain AL. Am. J. Hematol. 79:319–328, 2005. © 2005 Wiley-Liss, Inc.

Cardiovascular Magnetic Resonance in Cardiac Amyloidosis

2005-01-04

Alicia M. Maceira , Jayshree Joshi , Sanjay Prasad +7 more

Background— Cardiac amyloidosis can be diagnostically challenging. Cardiovascular magnetic resonance (CMR) can assess abnormal myocardial interstitium. Methods and Results— Late gadolinium enhancement CMR was performed in 30 patients with cardiac … Background— Cardiac amyloidosis can be diagnostically challenging. Cardiovascular magnetic resonance (CMR) can assess abnormal myocardial interstitium. Methods and Results— Late gadolinium enhancement CMR was performed in 30 patients with cardiac amyloidosis. In 22 of these, myocardial gadolinium kinetics with T 1 mapping was compared with that in 16 hypertensive controls. One patient had CMR and autopsy only. Subendocardial T 1 in amyloid patients was shorter than in controls (at 4 minutes: 427±73 versus 579±75 ms; P <0.01), was shorter than subepicardium T 1 for the first 8 minutes ( P ≤0.01), and was correlated with markers of increased myocardial amyloid load, as follows: left ventricular (LV) mass ( r =−0.51, P =0.013); wall thickness ( r =−0.54 to −0.63, P <0.04); interatrial septal thickness ( r =−0.52, P =0.001); and diastolic function ( r =−0.42, P =0.025). Global subendocardial late gadolinium enhancement was found in 20 amyloid patients (69%); these patients had greater LV mass (126±30 versus 93±25 g/m 2 ; P =0.009) than unenhanced patients. Histological quantification showed substantial interstitial expansion with amyloid (30.5%) but only minor fibrosis (1.3%). Amyloid was dominantly subendocardial (42%) compared with midwall (29%) and subepicardium (18%). There was 97% concordance in diagnosis of cardiac amyloid by combining the presence of late gadolinium enhancement and an optimized T 1 threshold (191 ms at 4 minutes) between myocardium and blood. Conclusions— In cardiac amyloidosis, CMR shows a characteristic pattern of global subendocardial late enhancement coupled with abnormal myocardial and blood-pool gadolinium kinetics. The findings agree with the transmural histological distribution of amyloid protein and the cardiac amyloid load and may prove to have value in diagnosis and treatment follow-up.

Primary systemic amyloidosis: clinical and laboratory features in 474 cases.

1995-01-01

Kyle Ra , Gertz Ma

Serum Cardiac Troponins and N-Terminal Pro-Brain Natriuretic Peptide: A Staging System for Primary Systemic Amyloidosis

2004-09-13

Angela Dispenzieri , Morie A. Gertz , Robert A. Kyle +7 more

Primary systemic amyloidosis (AL) is a multisystemic disorder resulting from an underlying plasma cell dyscrasia. There is no formal staging system for AL, making comparisons between studies and treatment centers … Primary systemic amyloidosis (AL) is a multisystemic disorder resulting from an underlying plasma cell dyscrasia. There is no formal staging system for AL, making comparisons between studies and treatment centers difficult. Our group previously identified elevated serum cardiac troponin T (cTnT) as the most powerful predictor of overall survival. Others have reported that N-terminal pro-brain natriuretic peptide (NT-proBNP) is a valuable prognostic marker. We sought to develop a staging system for patients with AL.Two hundred forty-two patients with newly diagnosed AL who were seen at the Mayo Clinic between April 1979 and November 2000, and who had echocardiograms and stored serum samples at presentation were eligible for this retrospective review. NT-proBNP measurements were performed on 242 patients in whom cTnT and cardiac troponin I (cTnI) had been previously run. Two prognostic models were designed using threshold values of NT-proBNP and either cTnT or cTnI (NT-proBNP < 332 ng/L, cTnT < 0.035 microg/L, and cTnI < 0.1 microg/L). Depending on whether NT-proBNP and troponin levels were both low, were high for only one level, or were both high, patients were classified as stage I, II, or III, respectively.Using the cTnT+NT-proBNP model 33%, 30%, and 37% of patients were stages I, II, and III, respectively, with median survivals of 26.4, 10.5, and 3.5 months, respectively. The alternate cTnI+NT-proBNP model predicted median survivals of 27.2, 11.1, and 4.1 months, respectively.Stratification of AL patients into three stages is possible with two readily available and reproducible tests setting the stage for more consistent and reliable cross comparisons of therapeutic outcomes.

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High-Dose Melphalan and Autologous Stem-Cell Transplantation in Patients with AL Amyloidosis: An 8-Year Study

2004-01-20

Martha Skinner , Vaishali Sanchorawala , David C. Seldin +7 more

AL amyloidosis is a fatal disease resulting from tissue deposition of amyloid fibrils derived from monoclonal immunoglobulin light chains. Treatment with oral chemotherapy is minimally effective.To test survival and organ … AL amyloidosis is a fatal disease resulting from tissue deposition of amyloid fibrils derived from monoclonal immunoglobulin light chains. Treatment with oral chemotherapy is minimally effective.To test survival and organ response in a large sample of patients treated with high-dose intravenous melphalan (100 to 200 mg/m2) and autologous blood stem-cell transplantation.8-year longitudinal analysis of clinical effectiveness.University-affiliated specialty referral clinic.701 consecutive new patients with AL amyloidosis.High-dose chemotherapy and autologous stem-cell transplantation for patients who met eligibility requirements based on organ involvement and clinical status.Survival analysis of all patients evaluated and a detailed analysis of treatment outcome in the subgroup that received high-dose melphalan and stem-cell transplantation.Among 701 patients with AL amyloidosis, 394 (56%) were eligible for high-dose melphalan and stem-cell transplantation; 82 did not proceed with treatment because of patient choice or disease progression. Median survival of the 312 patients who initiated treatment was 4.6 years. A complete hematologic response, defined as no evidence of an underlying plasma cell dyscrasia 1 year after treatment, was achieved in 40% of patients and was associated with prolonged survival. Statistically significant improvements occurred in end-organ disease and were greater in patients with a complete hematologic response. Mortality rate within 100 days of treatment with high-dose melphalan and stem-cell transplantation was 13%; patients with cardiomyopathy had the highest mortality rates.Treatment of selected patients with AL amyloidosis by using high-dose melphalan and stem-cell transplantation resulted in hematologic remission, improved 5-year survival, and reversal of amyloid-related disease in a substantial proportion.

New Criteria for Response to Treatment in Immunoglobulin Light Chain Amyloidosis Based on Free Light Chain Measurement and Cardiac Biomarkers: Impact on Survival Outcomes

2012-10-23

Giovanni Palladini , Angela Dispenzieri , Morie A. Gertz +7 more

To identify the criteria for hematologic and cardiac response to treatment in immunoglobulin light chain (AL) amyloidosis based on survival analysis of a large patient population.We gathered for analysis 816 … To identify the criteria for hematologic and cardiac response to treatment in immunoglobulin light chain (AL) amyloidosis based on survival analysis of a large patient population.We gathered for analysis 816 patients with AL amyloidosis from seven referral centers in the European Union and the United States. A different cohort of 374 patients prospectively evaluated at the Pavia Amyloidosis Research and Treatment Center was used for validation. Data was available for all patients before and 3 and/or 6 months after initiation of first-line therapy. The prognostic relevance of different criteria for hematologic and cardiac response was assessed.There was a strong correlation between the extent of reduction of amyloidogenic free light chains (FLCs) and improvement in survival. This allowed the identification of four levels of response: amyloid complete response (normal FLC ratio and negative serum and urine immunofixation), very good partial response (difference between involved and uninvolved FLCs [dFLC] < 40 mg/L), partial response (dFLC decrease > 50%), and no response. Cardiac involvement is the major determinant of survival, and changes in cardiac function after therapy can be reliably assessed using the cardiac biomarker N-terminal natriuretic peptide type B (NT-proBNP). Changes in FLC and NT-proBNP predicted survival as early as 3 months after treatment initiation.This study identifies and validates new criteria for response to first-line treatment in AL amyloidosis, based on their association with survival in large patient populations, and offers surrogate end points for clinical trials.

Diagnosis and Management of the Cardiac Amyloidoses

2005-09-26

Rodney H. Falk

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Guideline of transthyretin-related hereditary amyloidosis for clinicians

2013-01-01

Yukio Ando , Teresa Coelho , John L. Berk +7 more

Transthyretin amyloidosis is a progressive and eventually fatal disease primarily characterized by sensory, motor, and autonomic neuropathy and/or cardiomyopathy. Given its phenotypic unpredictability and variability, transthyretin amyloidosis can be difficult … Transthyretin amyloidosis is a progressive and eventually fatal disease primarily characterized by sensory, motor, and autonomic neuropathy and/or cardiomyopathy. Given its phenotypic unpredictability and variability, transthyretin amyloidosis can be difficult to recognize and manage. Misdiagnosis is common, and patients may wait several years before accurate diagnosis, risking additional significant irreversible deterioration. This article aims to help physicians better understand transthyretin amyloidosis—and, specifically, familial amyloidotic polyneuropathy—so they can recognize and manage the disease more easily and discuss it with their patients. We provide guidance on making a definitive diagnosis, explain methods for disease staging and evaluation of disease progression, and discuss symptom mitigation and treatment strategies, including liver transplant and several pharmacotherapies that have shown promise in clinical trials.

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International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders

2008-11-20

Angela Dispenzieri , Robert A. Kyle , Giampaolo Merlini +7 more

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Tafamidis for transthyretin familial amyloid polyneuropathy

2012-07-27

Teresa Coelho , Luı́s F. Maia , Ana Silva +7 more

To evaluate the efficacy and safety of 18 months of tafamidis treatment in patients with early-stage V30M transthyretin familial amyloid polyneuropathy (TTR-FAP).In this randomized, double-blind trial, patients received tafamidis 20 … To evaluate the efficacy and safety of 18 months of tafamidis treatment in patients with early-stage V30M transthyretin familial amyloid polyneuropathy (TTR-FAP).In this randomized, double-blind trial, patients received tafamidis 20 mg QD or placebo. Coprimary endpoints were the Neuropathy Impairment Score-Lower Limbs (NIS-LL) responder analysis (<2-point worsening) and treatment-group difference in the mean change from baseline in Norfolk Quality of Life-Diabetic Neuropathy total score (TQOL) in the intent-to-treat (ITT) population (n = 125). These endpoints were also evaluated in the efficacy-evaluable (EE; n = 87) population. Secondary endpoints, including changes in neurologic function, nutritional status, and TTR stabilization, were analyzed in the ITT population.There was a higher-than-anticipated liver transplantation dropout rate. No differences were observed between the tafamidis and placebo groups for the coprimary endpoints, NIS-LL responder analysis (45.3% vs 29.5% responders; p = 0.068) and change in TQOL (2.0 vs 7.2; p = 0.116) in the ITT population. In the EE population, significantly more tafamidis patients than placebo patients were NIS-LL responders (60.0% vs 38.1%; p = 0.041), and tafamidis patients had better-preserved TQOL (0.1 vs 8.9; p = 0.045). Significant differences in most secondary endpoints favored tafamidis. TTR was stabilized in 98% of tafamidis and 0% of placebo patients (p < 0.0001). Adverse events were similar between groups.Although the coprimary endpoints were not met in the ITT population, tafamidis was associated with no trend toward more NIS-LL responders and a significant reduction in worsening of most neurologic variables, supporting the hypothesis that preventing TTR dissociation can delay peripheral neurologic impairment.This study provides Class II evidence that 20 mg tafamidis QD was associated with no difference in clinical progression in patients with TTR-FAP, as measured by the NIS-LL and the Norfolk QOL-DN score. Secondary outcomes demonstrated a significant delay in peripheral neurologic impairment with tafamidis, which was well tolerated over 18 months.

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Relative apical sparing of longitudinal strain using two-dimensional speckle-tracking echocardiography is both sensitive and specific for the diagnosis of cardiac amyloidosis

2012-08-03

Dermot Phelan , Patrick Collier , Paaladinesh Thavendiranathan +5 more

The diagnosis of cardiac amyloidosis (CA) is challenging owing to vague symptomatology and non-specific echocardiographic findings.To describe regional patterns in longitudinal strain (LS) using two-dimensional speckle-tracking echocardiography in CA and … The diagnosis of cardiac amyloidosis (CA) is challenging owing to vague symptomatology and non-specific echocardiographic findings.To describe regional patterns in longitudinal strain (LS) using two-dimensional speckle-tracking echocardiography in CA and to test the hypothesis that regional differences would help differentiate CA from other causes of increased left ventricular (LV) wall thickness.55 consecutive patients with CA were compared with 30 control patients with LV hypertrophy (n=15 with hypertrophic cardiomyopathy, n=15 with aortic stenosis). A relative apical LS of 1.0, defined using the equation (average apical LS/(average basal LS + mid-LS)), was sensitive (93%) and specific (82%) in differentiating CA from controls (area under the curve 0.94). In a logistic regression multivariate analysis, relative apical LS was the only parameter predictive of CA (p=0.004).CA is characterised by regional variations in LS from base to apex. A relative 'apical sparing' pattern of LS is an easily recognisable, accurate and reproducible method of differentiating CA from other causes of LV hypertrophy.

Transthyretin (TTR) Cardiac Amyloidosis

2012-09-04

Frederick L. Ruberg , John L. Berk

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Repurposing Diflunisal for Familial Amyloid Polyneuropathy

2013-12-25

John L. Berk , Ole B. Suhr , Laura Obici +7 more

<h3>Importance</h3> Familial amyloid polyneuropathy, a lethal genetic disease caused by aggregation of variant transthyretin, induces progressive peripheral nerve deficits and disability. Diflunisal, a nonsteroidal anti-inflammatory agent, stabilizes transthyretin tetramers and … <h3>Importance</h3> Familial amyloid polyneuropathy, a lethal genetic disease caused by aggregation of variant transthyretin, induces progressive peripheral nerve deficits and disability. Diflunisal, a nonsteroidal anti-inflammatory agent, stabilizes transthyretin tetramers and prevents amyloid fibril formation in vitro. <h3>Objective</h3> To determine the effect of diflunisal on polyneuropathy progression in patients with familial amyloid polyneuropathy. <h3>Design, Setting, and Participants</h3> International randomized, double-blind, placebo-controlled study conducted among 130 patients with familial amyloid polyneuropathy exhibiting clinically detectable peripheral or autonomic neuropathy at amyloid centers in Sweden (Umeå), Italy (Pavia), Japan (Matsumoto and Kumamoto), England (London), and the United States (Boston, Massachusetts; New York, New York; and Rochester, Minnesota) from 2006 through 2012. <h3>Intervention</h3> Participants were randomly assigned to receive diflunisal, 250 mg (n=64), or placebo (n=66) twice daily for 2 years. <h3>Main Outcomes and Measures</h3> The primary end point, the difference in polyneuropathy progression between treatments, was measured by the Neuropathy Impairment Score plus 7 nerve tests (NIS+7) which ranges from 0 (no neurological deficits) to 270 points (no detectable peripheral nerve function). Secondary outcomes included a quality-of-life questionnaire (36-Item Short-Form Health Survey [SF-36]) and modified body mass index. Because of attrition, we used likelihood-based modeling and multiple imputation analysis of baseline to 2-year data. <h3>Results</h3> By multiple imputation, the NIS+7 score increased by 25.0 (95% CI, 18.4-31.6) points in the placebo group and by 8.7 (95% CI, 3.3-14.1) points in the diflunisal group, a difference of 16.3 points (95% CI, 8.1-24.5 points;<i>P</i> < .001). Mean SF-36 physical scores decreased by 4.9 (95% CI, −7.6 to −2.2) points in the placebo group and increased by 1.5 (95% CI, −0.8 to 3.7) points in the diflunisal group (<i>P</i> < .001). Mean SF-36 mental scores declined by 1.1 (95% CI, −4.3 to 2.0) points in the placebo group while increasing by 3.7 (95% CI, 1.0-6.4) points in the diflunisal group (<i>P</i> = .02). By responder analysis, 29.7% of the diflunisal group and 9.4% of the placebo group exhibited neurological stability at 2 years (<2-point increase in NIS+7 score;<i>P</i> = .007). <h3>Conclusions and Relevance</h3> Among patients with familial amyloid polyneuropathy, the use of diflunisal compared with placebo for 2 years reduced the rate of progression of neurological impairment and preserved quality of life. Although longer-term follow-up studies are needed, these findings suggest benefit of this treatment for familial amyloid polyneuropathy. <h3>Trial Registration</h3> clinicaltrials.gov Identifier:NCT00294671

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The characterization of soluble amyloid prepared in water

1968-04-01

Mordechai Pras , Dorothea Zucker‐Franklin , A. Rimon +1 more

Amyloid was extracted from the spleen of a patient with primary amyloidosis by homogenizing it at high speed with water after preliminary treatments, first to remove proteins soluble in saline, … Amyloid was extracted from the spleen of a patient with primary amyloidosis by homogenizing it at high speed with water after preliminary treatments, first to remove proteins soluble in saline, and then to remove salts. The extracts containing amyloid appeared to be clear at concentrations up to 6 mg/ml of protein. The material gave little sediment on being centrifuged up to 20,000 g for 1 hr, but the protein was sedimented at 100,000 g in 1 hr. The amyloid could be precipitated from the extracts by addition of NaCl to 0.0075 mole/liter or of CaCl(2) to 0.0025 mole/liter. The protein-bound Congo red formed a red precipitate and this property was used to estimate recovery and purity of amyloid during extraction. On electronmicroscopy the isolated amyloid proved to be morphologically pure. It existed either as single filaments measuring 60-80 A in diameter or as large aggregates of these filaments.Freshly isolated amyloid in water sedimented as a single homogeneous peak with an s degrees (20,[unk]) of about 45-50S. On standing, the solution became cloudy and more rapidly sedimenting components appeared. On electrophoresis the material migrated as a homogeneous peak towards the anode. The protein had an amino acid composition different from that of all known serum proteins. It was rich in acidic amino acids and had little cysteine and methionine and no hydroxyproline. The total content of carbohydrate was less than 2%.

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Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade

2012-05-29

Christine E. Bulawa , Stephen Connelly , Michael J. DeVit +7 more

The transthyretin amyloidoses (ATTR) are invariably fatal diseases characterized by progressive neuropathy and/or cardiomyopathy. ATTR are caused by aggregation of transthyretin (TTR), a natively tetrameric protein involved in the transport … The transthyretin amyloidoses (ATTR) are invariably fatal diseases characterized by progressive neuropathy and/or cardiomyopathy. ATTR are caused by aggregation of transthyretin (TTR), a natively tetrameric protein involved in the transport of thyroxine and the vitamin A–retinol-binding protein complex. Mutations within TTR that cause autosomal dominant forms of disease facilitate tetramer dissociation, monomer misfolding, and aggregation, although wild-type TTR can also form amyloid fibrils in elderly patients. Because tetramer dissociation is the rate-limiting step in TTR amyloidogenesis, targeted therapies have focused on small molecules that kinetically stabilize the tetramer, inhibiting TTR amyloid fibril formation. One such compound, tafamidis meglumine (Fx-1006A), has recently completed Phase II/III trials for the treatment of Transthyretin Type Familial Amyloid Polyneuropathy (TTR-FAP) and demonstrated a slowing of disease progression in patients heterozygous for the V30M TTR mutation. Herein we describe the molecular and structural basis of TTR tetramer stabilization by tafamidis. Tafamidis binds selectively and with negative cooperativity (K d s ∼2 nM and ∼200 nM) to the two normally unoccupied thyroxine-binding sites of the tetramer, and kinetically stabilizes TTR. Patient-derived amyloidogenic variants of TTR, including kinetically and thermodynamically less stable mutants, are also stabilized by tafamidis binding. The crystal structure of tafamidis-bound TTR suggests that binding stabilizes the weaker dimer-dimer interface against dissociation, the rate-limiting step of amyloidogenesis.

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Molecular Mechanisms of Amyloidosis

2003-08-07

Giampaolo Merlini , Vittorio Bellotti

Amyloidosis affects millions of people, as a cause of Alzheimer's disease or a complication of dialysis, and also causes rare conditions. The many forms of the disorder have one underlying … Amyloidosis affects millions of people, as a cause of Alzheimer's disease or a complication of dialysis, and also causes rare conditions. The many forms of the disorder have one underlying principle: misfolded proteins. Prompt, correct diagnosis is essential, especially in the inherited forms of amyloidosis. This article reviews the molecular basis of various types of amyloidosis and proposes new ways of treating these disorders.

Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction

2015-07-28

Esther González-López , María Gallego‐Delgado , Gonzalo Guzzo-Merello +7 more

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous clinical syndrome with multiple underlying causes. Wild-type transthyretin (TTR) amyloidosis (ATTRwt) is an underdiagnosed cause of HFpEF that might benefit … Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous clinical syndrome with multiple underlying causes. Wild-type transthyretin (TTR) amyloidosis (ATTRwt) is an underdiagnosed cause of HFpEF that might benefit from new specific treatments. ATTRwt can be diagnosed non-invasively by 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) scintigraphy. We sought to determine the prevalence of ATTRwt among elderly patients admitted due to HFpEF. We prospectively screened all consecutive patients ≥60 years old admitted due to HFpEF [left ventricular (LV) ejection fraction ≥50%] with LV hypertrophy (≥12 mm). All eligible patients were offered a 99mTc-DPD scintigraphy. The study included 120 HFpEF patients (59% women, 82 ± 8 years). A total of 16 patients (13.3%; 95% confidence interval: 7.2–19.5) showed a moderate-to-severe uptake on the 99mTc-DPD scintigraphy. All patients with a positive scan underwent genetic testing of the TTR gene, and no mutations were found. An endomyocardial biopsy was performed in four patients, confirming ATTRwt in all cases. There were no differences in age, gender, hypertension, diabetes, coronary artery disease, or atrial fibrillation between ATTRwt patients and patients with other HFpEF forms. Although patients with ATTRwt exhibited higher median N-terminal pro-brain natriuretic peptide (6467 vs. 3173 pg/L; P = 0.019), median troponin I (0.135 vs. 0.025 µg/L; P < 0.001), mean LV maximal wall thickness (17 ± 3.4 vs. 14 ± 2.5 mm; P = 0.001), rate of pericardial effusion (44 vs. 19%; P = 0.047), and rate of pacemakers (44 vs. 12%; P = 0.004), clinical overlap between ATTRwt and other HFpEF forms was high. ATTRwt is an underdiagnosed disease that accounts for a significant number (13%) of HFpEF cases. The effect of emerging TTR-modifying drugs should be evaluated in these patients.

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Revised Prognostic Staging System for Light Chain Amyloidosis Incorporating Cardiac Biomarkers and Serum Free Light Chain Measurements

2012-02-14

Shaji Kumar , Angela Dispenzieri , Martha Q. Lacy +7 more

Purpose Cardiac involvement predicts poor prognosis in light chain (AL) amyloidosis, and the current prognostic classification is based on cardiac biomarkers troponin-T (cTnT) and N-terminal pro–B-type natriuretic peptide (NT-ProBNP). However, … Purpose Cardiac involvement predicts poor prognosis in light chain (AL) amyloidosis, and the current prognostic classification is based on cardiac biomarkers troponin-T (cTnT) and N-terminal pro–B-type natriuretic peptide (NT-ProBNP). However, long-term outcome is dependent on the underlying plasma cell clone, and incorporation of clonal characteristics may allow for better risk stratification. Patients and Methods We developed a prognostic model based on 810 patients with newly diagnosed AL amyloidosis, which was further examined in two other datasets: 303 patients undergoing stem-cell transplantation, and 103 patients enrolled onto different clinical trials. Results We examined the prognostic value of plasma cell–related characteristics (ie, difference between involved and uninvolved light chain [FLC-diff], marrow plasma cell percentage, circulating plasma cells, plasma cell labeling index, and β 2 microglobulin). In a multivariate model that included these characteristics as well as cTnT and NT-ProBNP, only FLC-diff, cTnT, and NT-ProBNP were independently prognostic for overall survival (OS). Patients were assigned a score of 1 for each of FLC-diff ≥ 18 mg/dL, cTnT ≥ 0.025 ng/mL, and NT-ProBNP ≥ 1,800 pg/mL, creating stages I to IV with scores of 0 to 3 points, respectively. The proportions of patients with stages I, II, III and IV disease were 189 (25%), 206 (27%), 186 (25%) and 177 (23%), and their median OS from diagnosis was 94.1, 40.3, 14, and 5.8 months, respectively (P < .001). This classification system was validated in the other datasets. Conclusion Incorporation of serum FLC-diff into the current staging system improves risk stratification for patients with AL amyloidosis and will help develop risk-adapted therapies for AL amyloidosis.

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The Systemic Amyloidoses

1997-09-25

Rodney H. Falk , Raymond L. Comenzo , Martha Skinner

Amyloidosis is not a single disease but a term for diseases that share a common feature: the extracellular deposition of pathologic insoluble fibrillar proteins in organs and tissues. In the … Amyloidosis is not a single disease but a term for diseases that share a common feature: the extracellular deposition of pathologic insoluble fibrillar proteins in organs and tissues. In the mid-19th century, Virchow adopted the botanical term "amyloid," meaning starch or cellulose, to describe abnormal extracellular material seen in the liver at autopsy.1 Subsequently, amyloid was found to stain with Congo red, appearing red microscopically in normal light but apple green when viewed in polarized light.2,3 Almost a century after Virchow's observations, the fibrillar nature of amyloid was described with the use of electron microscopy and the characteristic beta-pleated–sheet . . .

A Trial of Three Regimens for Primary Amyloidosis: Colchicine Alone, Melphalan and Prednisone, and Melphalan, Prednisone, and Colchicine

1997-04-24

Robert A. Kyle , Morie A. Gertz , Philip R. Greipp +4 more

Primary systemic amyloidosis is an uncommon disease characterized by the accumulation in vital organs of a fibrillar protein consisting of monoclonal light chains.We treated 220 patients with biopsy-proved amyloidosis. The … Primary systemic amyloidosis is an uncommon disease characterized by the accumulation in vital organs of a fibrillar protein consisting of monoclonal light chains.We treated 220 patients with biopsy-proved amyloidosis. The patients were randomly assigned to receive colchicine (72 patients), melphalan and prednisone (77), or melphalan, prednisone, and colchicine (71). They were stratified according to their chief clinical manifestations: renal disease (105 patients), cardiac involvement (46), peripheral neuropathy (19), or other (50).The median duration of survival after randomization was 8.5 months in the colchicine group, 18 months in the group assigned to melphalan and prednisone, and 17 months in the group assigned to melphalan, prednisone, and colchicine (P<0.001). Among patients who had a reduction in serum or urine monoclonal protein at 12 months, the overall length of survival was 50 months, whereas among those without a reduction at 12 months, the overall length of survival was 36 months (P=0.03). Thirty-four patients (15 percent) survived for five years or longer.Therapy with melphalan and prednisone results in objective responses and prolonged survival as compared with colchicine in patients with primary amyloidosis.

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Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis

2016-04-23

Julian D. Gillmore , Matthew J. Maurer , Rodney H. Falk +7 more

Background— Cardiac transthyretin (ATTR) amyloidosis is a progressive and fatal cardiomyopathy for which several promising therapies are in development. The diagnosis is frequently delayed or missed because of the limited … Background— Cardiac transthyretin (ATTR) amyloidosis is a progressive and fatal cardiomyopathy for which several promising therapies are in development. The diagnosis is frequently delayed or missed because of the limited specificity of echocardiography and the traditional requirement for histological confirmation. It has long been recognized that technetium-labeled bone scintigraphy tracers can localize to myocardial amyloid deposits, and use of this imaging modality for the diagnosis of cardiac ATTR amyloidosis has lately been revisited. We conducted a multicenter study to ascertain the diagnostic value of bone scintigraphy in this disease. Methods and Results— Results of bone scintigraphy and biochemical investigations were analyzed from 1217 patients with suspected cardiac amyloidosis referred for evaluation in specialist centers. Of 857 patients with histologically proven amyloid (374 with endomyocardial biopsies) and 360 patients subsequently confirmed to have nonamyloid cardiomyopathies, myocardial radiotracer uptake on bone scintigraphy was >99% sensitive and 86% specific for cardiac ATTR amyloid, with false positives almost exclusively from uptake in patients with cardiac AL amyloidosis. Importantly, the combined findings of grade 2 or 3 myocardial radiotracer uptake on bone scintigraphy and the absence of a monoclonal protein in serum or urine had a specificity and positive predictive value for cardiac ATTR amyloidosis of 100% (positive predictive value confidence interval, 98.0–100). Conclusions— Bone scintigraphy enables the diagnosis of cardiac ATTR amyloidosis to be made reliably without the need for histology in patients who do not have a monoclonal gammopathy. We propose noninvasive diagnostic criteria for cardiac ATTR amyloidosis that are applicable to the majority of patients with this disease.

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A Report of Three Cases

1986-04-01

William D. Travis , Robert G. Castile , Gordon F. Vawter +4 more

The authors report the pathologic features of three cases of amyloidosis associated with cystic fibrosis. Renal biopsy led to the diagnosis (case 1) or suspicion (case 2) of amyloidosis in … The authors report the pathologic features of three cases of amyloidosis associated with cystic fibrosis. Renal biopsy led to the diagnosis (case 1) or suspicion (case 2) of amyloidosis in patients who were 23 and 21 years old, respectively. The third patient died at age 22 years, and amyloidosis was not discovered until autopsy. Immunohistochemical staining and potassium-permanganate pretreatment of histologic sections in all three cases provided evidence that the amyloid seen in these patients is of the secondary (AA) type. Congo red staining in each case and electron microscopy in case 1 confirmed the initial diagnosis of amyloidosis. A markedly elevated serum amyloid A protein (160 μg/mL; normal less than 1 μg/mL) in case 1 indicated the presence of large quantities of the precursor protein from which the AA fibrils of secondary amyloid are derived. The kidneys, spleen, and liver contained amyloid deposits in autopsy material from all three cases. Involvement of other organs by amyloid was variable. Review of autopsy material in Boston from 23 additional cystic fibrosis patients with long-term survival did not reveal any evidence of amyloidosis. It appears that secondary amyloidosis is emerging as a significant, although rare, complication of cystic fibrosis as greater numbers of these patients survive into adult-hood.

The serum proteins in multiple myelomatosis

1940-09-01

R. A. Kekwick

Research Article| September 01 1940 The serum proteins in multiple myelomatosis Ralph Ambrose Kekwick Ralph Ambrose Kekwick 1The Lister Institute, London Search for other works by this author on: This … Research Article| September 01 1940 The serum proteins in multiple myelomatosis Ralph Ambrose Kekwick Ralph Ambrose Kekwick 1The Lister Institute, London Search for other works by this author on: This Site PubMed Google Scholar Biochem J (1940) 34 (8-9): 1248–1257. https://doi.org/10.1042/bj0341248 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Cite Icon Cite Get Permissions Citation Ralph Ambrose Kekwick; The serum proteins in multiple myelomatosis. Biochem J 1 September 1940; 34 (8-9): 1248–1257. doi: https://doi.org/10.1042/bj0341248 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Journal Search Advanced Search © 1940 CAMBRIDGE UNIVERSITY PRESS1940 Article PDF first page preview Close Modal You do not currently have access to this content.

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Natural History of Wild-Type Transthyretin Cardiac Amyloidosis and Risk Stratification Using a Novel Staging System

2016-08-30

Martha Grogan , Christopher G. Scott , Robert A. Kyle +7 more

P1‐146: <i>Chlamydia Pneumoniae‐</i>Infected Astrocytes Alter Their Expression of Adam10, Bace1, and Presenilin‐1 Proteases

2016-07-01

Zein Al-Atrache , Ahmad Cader , Denah M. Appelt

Utilizing β-amyloid precursor protein (βAPP) as a substrate, α-, β-, and γ-secretases are responsible for sequential cleavage events leading to the formation of β-amyloid, the classic pathologic hallmark of Alzheimer’s … Utilizing β-amyloid precursor protein (βAPP) as a substrate, α-, β-, and γ-secretases are responsible for sequential cleavage events leading to the formation of β-amyloid, the classic pathologic hallmark of Alzheimer’s Disease. Members of this class of proteases also catalyze the activation of numerous other membrane-localized proteins implicated in cell growth and neuroinflammation such as NOTCH and the Interleukin/TNF-receptor family, respectively. This investigation addresses if an in vitro Chlamydia pneumoniae infection of human astrocytes affects the processing of βAPP through modifying the protein expression of the following βAPP processing proteases: A Disintegrin and Metalloproteinase-10 (ADAM10), βAPP cleaving enzyme-1 (BACE1), and presenilin-1 (PSEN1). Human astrocytoma cells (CCF-STTG1) were infected in vitro with Chlamydia pneumoniae strain AR39 (MOI=1). At 6-72 hours post infection, protein level of β-amyloid, ADAM10, BACE1, and presenilin-1 N-terminal fragment (NTF) relative to uninfected controls were detected by immunofluorescence and quantified by western blot analysis. Cytoplasmic labeling of Aβ1-42 was increased in infected cells relative to that of uninfected cells. Membrane-localized labeling of BACE1 and cytoplasmic labeling of PSEN1 NTF was also enhanced at earlier (6 hrs.) and later (48/72 hrs.) time points post infection relative to that of uninfected astrocytes. Increases in quantified BACE1 and PSEN1, but not ADAM10, followed a similar temporal increase most notable at 48 hrs. post infection. These data indicate that infection of human astrocytes with Chlamydia pneumoniae strain AR39 promotes the processing of βAPP characteristic of Alzheimer’s Disease through enhancing BACE1 and PSEN1, but not ADAM10, protein levels. Increases in active secretase protein may coincide with the 24-48 hr. lifecycle of Chlamydial intracellular growth and replication and the consequent astrocytic inflammatory response.

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Incidence and natural history of primary systemic amyloidosis in Olmsted County, Minnesota, 1950 through 1989 [see comments]

1992-04-01

RA Kyle , Athena Linos , C. Mary Beard +4 more

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Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis

2018-07-04

Merrill D. Benson , Márcia Waddington‐Cruz , John L. Berk +7 more

Hereditary transthyretin amyloidosis is caused by pathogenic single-nucleotide variants in the gene encoding transthyretin (TTR) that induce transthyretin misfolding and systemic deposition of amyloid. Progressive amyloid accumulation leads to multiorgan … Hereditary transthyretin amyloidosis is caused by pathogenic single-nucleotide variants in the gene encoding transthyretin (TTR) that induce transthyretin misfolding and systemic deposition of amyloid. Progressive amyloid accumulation leads to multiorgan dysfunction and death. Inotersen, a 2′-O-methoxyethyl–modified antisense oligonucleotide, inhibits hepatic production of transthyretin.

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Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis

2018-07-04

David Adams , Alejandra González‐Duarte , William O’Riordan +7 more

Patisiran, an investigational RNA interference therapeutic agent, specifically inhibits hepatic synthesis of transthyretin. Patisiran, an investigational RNA interference therapeutic agent, specifically inhibits hepatic synthesis of transthyretin.

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Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy

2018-08-27

Matthew J. Maurer , Jeffrey H. Schwartz , Balarama Gundapaneni +7 more

Transthyretin amyloid cardiomyopathy is caused by the deposition of transthyretin amyloid fibrils in the myocardium. The deposition occurs when wild-type or variant transthyretin becomes unstable and misfolds. Tafamidis binds to … Transthyretin amyloid cardiomyopathy is caused by the deposition of transthyretin amyloid fibrils in the myocardium. The deposition occurs when wild-type or variant transthyretin becomes unstable and misfolds. Tafamidis binds to transthyretin, preventing tetramer dissociation and amyloidogenesis.In a multicenter, international, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 441 patients with transthyretin amyloid cardiomyopathy in a 2:1:2 ratio to receive 80 mg of tafamidis, 20 mg of tafamidis, or placebo for 30 months. In the primary analysis, we hierarchically assessed all-cause mortality, followed by frequency of cardiovascular-related hospitalizations according to the Finkelstein-Schoenfeld method. Key secondary end points were the change from baseline to month 30 for the 6-minute walk test and the score on the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS), in which higher scores indicate better health status.In the primary analysis, all-cause mortality and rates of cardiovascular-related hospitalizations were lower among the 264 patients who received tafamidis than among the 177 patients who received placebo (P<0.001). Tafamidis was associated with lower all-cause mortality than placebo (78 of 264 [29.5%] vs. 76 of 177 [42.9%]; hazard ratio, 0.70; 95% confidence interval [CI], 0.51 to 0.96) and a lower rate of cardiovascular-related hospitalizations, with a relative risk ratio of 0.68 (0.48 per year vs. 0.70 per year; 95% CI, 0.56 to 0.81). At month 30, tafamidis was also associated with a lower rate of decline in distance for the 6-minute walk test (P<0.001) and a lower rate of decline in KCCQ-OS score (P<0.001). The incidence and types of adverse events were similar in the two groups.In patients with transthyretin amyloid cardiomyopathy, tafamidis was associated with reductions in all-cause mortality and cardiovascular-related hospitalizations and reduced the decline in functional capacity and quality of life as compared with placebo. (Funded by Pfizer; ATTR-ACT ClinicalTrials.gov number, NCT01994889 .).

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Transthyretin Amyloid Cardiomyopathy

2019-06-01

Frederick L. Ruberg , Martha Grogan , Mazen Hanna +2 more

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Diagnosis and treatment of cardiac amyloidosis: a position statement of the ESC Working Group on Myocardial and Pericardial Diseases

2021-02-03

Pablo García‐Pavía , Claudio Rapezzi , Yehuda Adler +7 more

Abstract Cardiac amyloidosis is a serious and progressive infiltrative disease that is caused by the deposition of amyloid fibrils at the cardiac level. It can be due to rare genetic … Abstract Cardiac amyloidosis is a serious and progressive infiltrative disease that is caused by the deposition of amyloid fibrils at the cardiac level. It can be due to rare genetic variants in the hereditary forms or as a consequence of acquired conditions. Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that cardiac amyloidosis is a more frequent disease than traditionally considered. In this position paper the Working Group on Myocardial and Pericardial Disease proposes an invasive and non-invasive definition of cardiac amyloidosis, addresses clinical scenarios and situations to suspect the condition and proposes a diagnostic algorithm to aid diagnosis. Furthermore, we also review how to monitor and treat cardiac amyloidosis, in an attempt to bridge the gap between the latest advances in the field and clinical practice.

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CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis

2021-06-26

Julian D. Gillmore , Ed Gane , Jörg Täubel +7 more

Transthyretin amyloidosis, also called ATTR amyloidosis, is a life-threatening disease characterized by progressive accumulation of misfolded transthyretin (TTR) protein in tissues, predominantly the nerves and heart. NTLA-2001 is an in … Transthyretin amyloidosis, also called ATTR amyloidosis, is a life-threatening disease characterized by progressive accumulation of misfolded transthyretin (TTR) protein in tissues, predominantly the nerves and heart. NTLA-2001 is an in vivo gene-editing therapeutic agent that is designed to treat ATTR amyloidosis by reducing the concentration of TTR in serum. It is based on the clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease (CRISPR-Cas9) system and comprises a lipid nanoparticle encapsulating messenger RNA for Cas9 protein and a single guide RNA targeting TTR.

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Amyloidosis (AL). Clinical and laboratory features in 229 cases.

1983-10-01

Robert A. Kyle , Philip R. Greipp

Natural History and Outcome in Systemic AA Amyloidosis

2007-06-06

Helen J. Lachmann , Hugh J. B. Goodman , Janet A. Gilbertson +4 more

Deposition of amyloid fibrils derived from circulating acute-phase reactant serum amyloid A protein (SAA) causes systemic AA amyloidosis, a serious complication of many chronic inflammatory disorders. Little is known about … Deposition of amyloid fibrils derived from circulating acute-phase reactant serum amyloid A protein (SAA) causes systemic AA amyloidosis, a serious complication of many chronic inflammatory disorders. Little is known about the natural history of AA amyloidosis or its response to treatment.We evaluated clinical features, organ function, and survival among 374 patients with AA amyloidosis who were followed for a median of 86 months. The SAA concentration was measured serially, and the amyloid burden was estimated with the use of whole-body serum amyloid P component scintigraphy. Therapy for inflammatory diseases was administered to suppress the production of SAA.Median survival after diagnosis was 133 months; renal dysfunction was the predominant disease manifestation. Mortality, amyloid burden, and renal prognosis all significantly correlated with the SAA concentration during follow-up. The risk of death was 17.7 times as high among patients with SAA concentrations in the highest eighth, or octile, (>or=155 mg per liter) as among those with concentrations in the lowest octile (<4 mg per liter); and the risk of death was four times as high in the next-to-lowest octile (4 to 9 mg per liter). The median SAA concentration during follow-up was 6 mg per liter in patients in whom renal function improved and 28 mg per liter in those in whom it deteriorated (P<0.001). Amyloid deposits regressed in 60% of patients who had a median SAA concentration of less than 10 mg per liter, and survival among these patients was superior to survival among those in whom amyloid deposits did not regress (P=0.04).The effects of renal dysfunction dominate the course of AA amyloidosis, which is associated with a relatively favorable outcome in patients with SAA concentrations that remain in the low-normal range (<4 mg per liter).

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Systemic amyloidosis

2015-12-22

Ashutosh D. Wechalekar , Julian D. Gillmore , Philip N. Hawkins

Beyond the Heart: Exploring Extracardiac Manifestations in Cardiac Amyloidosis for Early Diagnosis

2025-06-25

Marcus Saldanha , Lijun Chen , Joshua J. Solomon +4 more | Current Cardiology Reports

Vutrisiran bei Transthyretin-Amyloidose effektiv

2025-06-25

| DMW - Deutsche Medizinische Wochenschrift

Tongue Involvement in Light Chain Amyloidosis

2025-06-25

Paula Matias , Jorge Almeida , Pedro Vieira‐Marques | QJM

Bei HFpEF an Amyloidose denken

2025-06-24

Peter Stiefelhagen | CardioVasc

Visual grading for noninvasive assessment of transthyretin-related cardiomyopathy with bone scintigraphy: time for moving forward?

2025-06-24

Federico Caobelli , Sharmila Dorbala | European Journal of Nuclear Medicine and Molecular Imaging

DIFFICULTIES IN DIAGNOSIS OF TRANSHYRETIN AMYLOIDOSIS WITH POLYNEUROPATHY. CLINICAL CASE

2025-06-24

E S Ostapchuk , Oleg Pavlovich Glinin , Yulia Valerievna Alekseeva | Journal of clinical practice

Background: Thanks to advances and accessibility in the field of genetic research, practitioners have the opportunity to diagnose systemic transthyretin amyloidosis affecting the nervous and cardiovascular systems. Clinical case description: … Background: Thanks to advances and accessibility in the field of genetic research, practitioners have the opportunity to diagnose systemic transthyretin amyloidosis affecting the nervous and cardiovascular systems. Clinical case description: We describe a clinical case of transthyretin amyloidosis, manifested by polyneuropathy with severe neuropathic pain syndrome, the development of severe autonomic failure and damage to the cardiovascular system in a 63-year-old man. This clinical picture developed over 3 years with numerous calls to various specialists: rheumatologists, neurosurgeons, endocrinologists, neurologists, therapists; the patient underwent surgical interventions on the spinal cord, carotid artery and heart vessels. The disease led to severe cachexia and disability of the patient. Conclusion: This observation reflects the classic form of transthyretin amyloidosis involving the nervous and cardiovascular systems, which, with timely diagnosis, has pathogenetic treatment and slows down the manifestations of the disease.

NOVAS TERAPIAS NO TRATAMENTO DE AMILOIDOSE CARDÍACA

2025-06-23

GEOVANA CERESÉR DOS SANTOS , Maria Laura Zschornack Strelow , GABRIELA CARMINATI LINO +4 more | Editora Pasteur eBooks

Benefits of Patisiran on Functional Capacity in ATTR Cardiac Amyloidosis

2025-06-23

John L. Berk , Olivier Lairez , Pedro Vellosa Schwartzmann +5 more | JACC Advances

Bullous Amyloidosis with Lesional Nikolsky’s Sign Positivity

2025-06-23

Ayşe Öktem , Ozge Yali , Devrim Deniz Kuscu +4 more | Indian Journal of Dermatology

Vutrisiran (Amvuttra) for transthyretin amyloid cardiomyopathy.

2025-06-23

| PubMed

Stacking Ensemble Learning-based Models Enabling Accurate Diagnosis of Cardiac Amyloidosis using SPECT/CT:an International and Multicentre Study

2025-06-23

Qu Mo , Jing Cui , Suotang Jia +7 more

ABSTRACT PURPOSE Cardiac amyloidosis (CA), a life-threatening infiltrative cardiomyopathy, can be non-invasively diagnosed using [ 99m Tc]Tc-bisphosphonate SPECT/CT. However, subjective visual interpretation risks diagnostic inaccuracies. We developed and validated a … ABSTRACT PURPOSE Cardiac amyloidosis (CA), a life-threatening infiltrative cardiomyopathy, can be non-invasively diagnosed using [ 99m Tc]Tc-bisphosphonate SPECT/CT. However, subjective visual interpretation risks diagnostic inaccuracies. We developed and validated a machine learning (ML) framework leveraging SPECT/CT radiomics to automate CA detection. METHODS This retrospective multicenter study analyzed 290 patients of suspected CA who underwent [ 99m Tc]Tc-PYP or [ 99m Tc]Tc-DPD SPECT/CT. Radiomic features were extracted from co-registered SPECT and CT images, harmonized via intra-class correlation and Pearson correlation filtering, and optimized through LASSO regression. A stacking ensemble model incorporating support vector machine (SVM), random forest (RF), gradient boosting decision tree (GBDT), and adaptive boosting (AdaBoost) classifiers was constructed. The model was validated using an internal validation set (n = 54) and two external test set (n = 54 and n = 58).Model performance was evaluated using the area under the receiver operating characteristic curve (AUC), calibration, and decision curve analysis (DCA). Feature importance was interpreted using SHapley Additive exPlanations (SHAP) values. RESULTS Of 290 patients, 117 (40.3%) had CA. The stacking radiomics model attained AUCs of 0.871, 0.824, and 0.839 in the validation, test 1, and test 2 cohorts, respectively, significantly outperforming the clinical model (AUC 0.546 in validation set, P <0.05). DCA demonstrated superior net benefit over the clinical model across relevant thresholds, and SHAP analysis highlighted wavelet-transformed first-order and texture features as key predictors. CONCLUSION A stacking ML model with SPECT/CT radiomics improves CA diagnosis, showing strong generalizability across varied imaging protocols and populations and highlighting its potential as a decision-support tool.

Novel Pathogenic Variant c.258A>C, p.(Glu86Asp) in the TTR Gene in a Bulgarian Patient with Hereditary Transthyretin Amyloidosis

2025-06-22

Zornitsa Pavlova , Sashka Zhelyazkova , Мариана Господинова +7 more | Genes

Hereditary transthyretin amyloidosis (ATTRv) is an autosomal dominant disorder caused by pathogenic variants in the TTR gene. The destabilized mutant form of the transport protein transthyretin (TTR) leads to the … Hereditary transthyretin amyloidosis (ATTRv) is an autosomal dominant disorder caused by pathogenic variants in the TTR gene. The destabilized mutant form of the transport protein transthyretin (TTR) leads to the extracellular deposition of amyloid fibrils. Materials and Methods: A 65-year-old female patient with suspected clinical diagnosis of ATTR was referred for genetic testing for pathogenic variants in the TTR gene after physical, neurological and cardiac testing. Results: The patient had had cardiac dysfunction, atrial fibrillation and supraventricular tachycardia for around 10 years before the suspected and confirmed cardiac amyloidosis. The molecular genetic testing showed a heterozygous pathogenic variant in exon 3 of the TTR gene NM_000371.4(TTR): c.258A>C, p.(Glu86Asp). This variant in the TTR gene is classified as pathogenic in accordance with ACMG/AMP for the interpretation of variants. Conclusions: The presented case of a very rare pathogenic variant in the TTR gene displays the valuable role of genetic testing on the way to clarifying a diagnosis.

Irbesartan/Nifedipine/Spironolactone

2025-06-21

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Losartan/prednisone/tacrolimus

2025-06-21

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Cyclophosphamide/lenalidomide

2025-06-21

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Amivantamab

2025-06-21

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Nifedipine

2025-06-21

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Carbimazole

2025-06-21

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Harvesting the Richness of CMR With Multimodal AI: A New Dawn to Differentiate HCM and Subtype Cardiac Amyloidosis?

2025-06-20

Parker Martin , Yuchi Han | Circulation Cardiovascular Imaging

40 years of CEPARM: transforming amyloidosis related to transthyretin from neglect to recognition

2025-06-20

Márcia Waddington‐Cruz , Marleide da Mota Gomes | Arquivos de Neuro-Psiquiatria

Abstract Variant transthyretin amyloidosis with polyneuropathy (ATTRv-PN) and cardiomyopathy (ATTRv-CM), formerly known as familial amyloidotic polyneuropathy (FAP), is a severe, progressive disorder caused by mutations in the transthyretin (TTR) gene. … Abstract Variant transthyretin amyloidosis with polyneuropathy (ATTRv-PN) and cardiomyopathy (ATTRv-CM), formerly known as familial amyloidotic polyneuropathy (FAP), is a severe, progressive disorder caused by mutations in the transthyretin (TTR) gene. Historically, FAP was considered a neglected disease due to its rarity and the limited understanding of its pathophysiology, which led to minimal research funding and few therapeutic options. The present article explores the transformative role of Centro de Paramiloidose Antônio Rodrigues de Mello (CEPARM), established in 1984, in elevating the status of FAP through significant advancements in research and treatment. Although CEPARM was not the sole catalyst for this shift, its contributions in liver transplantation, the development of pharmacological therapies, and holistic patient care have substantially improved the recognition and management of FAP. The article also examines CEPARM's impact on patient care, the ongoing challenges, and ethical considerations within the field.

ALECT2 amyloidosis in a patient with myeloma cast nephropathy

2025-06-19

Lihong Bu , Samar M. Said , Matthew T. Howard +1 more | Kidney International

Characterization, outcome and identification of prognostic factors for patients with systemic immunoglobulin light-chain amyloidosis requiring dialysis prior to initial anti-clonal therapy

2025-06-19

Lilli Sophie Sester , Paolo Milani , Fenia Theodorakakou +7 more | Haematologica

AL amyloidosis is a serious disease characterized by the deposition of immunoglobulin light chains in multiple organs. Renal involvement occurs in up to 70% of patients, but only a minority … AL amyloidosis is a serious disease characterized by the deposition of immunoglobulin light chains in multiple organs. Renal involvement occurs in up to 70% of patients, but only a minority require dialysis before initiating anti-clonal treatment. Understanding the occurrence of end-stage organ damage is crucial to pave the way for reversing deposition. Currently, there is no detailed analysis available for this rare patient subgroup. We conducted a systematic search across three amyloidosis centers and characterized 68 biopsy-proven AL amyloidosis patients who required dialysis prior to initial anti-clonal therapy. In our cohort the second most affected organ was the heart. Renal parameters exhibited variability. Residual urine output and proteinuria ranged widely, while anuria had developed in only a few patients. Among the treated patients, 84% received Bortezomib as first-line therapy. The median overall survival (OS) was 44.8 months, with a median event-free survival (EFS) of 16.8 months. Our univariate statistical analysis revealed that underlying clonal disease, indicated by plasma cell infiltration, but not dFLC, impacted OS. Importantly, higher levels of troponins were associated with worse OS, confirmed by multivariate analysis, whereas NTproBNP levels and classical echocardiographic parameters such as septal thickness and longitudinal strain did not demonstrate significant prognostic value. This study provides crucial insights into this unique cohort of dialysis-dependent AL amyloidosis patients. The underlying clonal disease and markers of cardiac damage are important prognostic criteria. These findings emphasize the need to refine prognostic scoring systems for dialysis-dependent AL amyloidosis patients to better stratify risk and optimize treatment approaches.

Associations of serum total light chain kappa and lambda levels with all-cause mortality in Chinese centenarians

2025-06-19

Yuting Duan , Zhe Li , Weiguang Zhang +7 more | Immunity & Ageing

Crescentic glomerulonephritis associated with myelodysplatic syndrome and visceral leishmaniasis

2025-06-19

Antoine Decaestecker , Adrien Daniel , Zoé Malbranque +2 more | Journal of Nephrology

A comprehensive evaluation of cardiac amyloidosis epidemiology and diagnostics in French Guiana

2025-06-17

Benoit Desjardins , Karen Franck , Nathalie Deschamps +7 more | PLoS ONE

Background Cardiac amyloidosis (CA) is a potentially fatal systemic disease that has received increasing attention in recent years. However, there is no data on its epidemiology in French Guiana. This … Background Cardiac amyloidosis (CA) is a potentially fatal systemic disease that has received increasing attention in recent years. However, there is no data on its epidemiology in French Guiana. This study aimed to evaluate the epidemiological characteristics of cardiac amyloidosis and describe the regional diagnostic pathways in French Guiana. Methods We performed a multicenter retrospective study of Guianese patients with confirmed or suspected cardiac amyloidosis who were followed up in hospitals in French Guiana by private cardiologists. Results A total of 47 patients were included. The study population was predominantly male (n = 29, 61.7%). The mean age of the population was 72.8 years (SD = 12.2). Most patients were from the island of Cayenne (n = 34, 72.3%), had at least one cardiovascular risk factor (n = 32, 68.1%), and more than half had extracardiac amyloid involvement (n = 25, 53.2%). More than half of the patients were hospitalized at a reference center outside French Guiana (29, 61.7%), mainly at Henri Mondor Hospital (n = 20, 69%) and Martinique (n = 6, 20.7%). Bone scintigraphy was performed in 27 patients (57.5%) and hyperfixation was observed in 25 patients (93%). Anatomopathological examinations were performed in 33 patients (70.2%). Amyloid typing of the biopsied tissue revealed predominantly ATTR (n = 14, 62.6%), AL amyloidosis (n = 1, 4.5%), and AA amyloidosis (4.5%). Among the ATTR amyloidoses, we found mainly ATTRm (n = 22, 75.8%). Genetic mutation testing was performed in approximately half of the patients (n = 25, 51.1%), mostly for the VAL122ILE mutation (n = 21, 84%), and in one case for the IL107VAL mutation (4%). Of the patients with ATTR amyloidosis, 22 (75.9%) were treated with tafamidis. Of the included patients, 18 (38.3%) died. The median overall survival (OS) was 38 months. Survival analysis from the date of diagnosis showed a probability of survival at 30 days, one year, 1.5 years and 4 years of 97% (95% confidence interval [CI]: 90–100), 68% (95%CI 55–84)), 64% (95%CI 51–79)), 32% (95%CI 29–41)), respectively. Conclusion This study provides the first information on the diagnostic pathway for cardiac amyloidosis in French Guiana. The increasing proportion of undiagnosed patients has led us to create a French Guianese Amyloidosis Team to simplify the diagnostic pathway by focusing on cardiac MRI and biopsy, which can be performed locally. This is particularly important, as current and future therapeutic advances mean that more effective treatments are on the horizon.

Relative Survival Modeling for Appraising the Cost-Effectiveness of Life-Extending Treatments: An Application to Tafamidis for the Treatment of Transthyretin Amyloidosis with Cardiomyopathy

2025-06-17

Robert D. Young , Jack Said , Samuel Large | Medical Decision Making

Background Economic evaluations for life-extending treatments frequently require clinical trial data to be extrapolated beyond the trial duration to estimate changes in life expectancy. Conventional survival models often display hazard … Background Economic evaluations for life-extending treatments frequently require clinical trial data to be extrapolated beyond the trial duration to estimate changes in life expectancy. Conventional survival models often display hazard profiles that do not rise as expected in an aging population and require the incorporation of external data to ensure plausibility. Relative survival (RS) models can enable the incorporation of external data at model fitting. A comparison was performed between RS and “standard” all-cause survival (ACS) in modeling outcomes from the tafamidis for the treatment of transthyretin amyloid cardiomyopathy (ATTR-ACT) trial. Methods Patient-level data from the 30-mo ATTR-ACT trial were used to develop survival models based on parametric ACS and RS models. The latter was composed of an expected hazard and an independent excess hazard. Models were selected according to statistical goodness of fit and clinical plausibility, with extrapolation up to 72 mo validated against ATTR-ACT long-term extension (LTE) data. Results Information criteria were too similar to discriminate between RS or ACS models. Several ACS models were affected by capping with general population mortality rates and considered implausible. Selected RS models matched the empirical hazard function, could not fall below general population hazards, and predicted well compared with the LTE data. The preferred RS model predicted the restricted mean survival (RMST) to 72 mo of 51.0 mo (95% confidence interval [CI]: 46.1, 55.3); this compared favorably to the LTE RMST of 50.9 mo (95% CI: 47.7, 53.9). Discussion RS models can improve the accuracy for modeling populations with high background mortality rates (e.g., the ATTR-CM trial). RS modeling enforces a plausible long-term hazard profile, enables flexibility in medium-term hazard profiles, and increases the robustness of medical decision making. Highlights To inform survival extrapolations for health technology assessment, a relative survival model incorporating external data per the recommendations of the National Institute for Health and Care Excellence (NICE) Decision Support Unit was used in support of the NICE evaluation of tafamidis for treatment of transthyretin amyloid cardiomyopathy (ATTR-CM). Relative survival modeling allowed selection of a broader range of hazard profiles compared with all-cause survival modeling by ensuring plausible long-term predictions. Predictions from plausible relative survival models of overall survival in patients with ATTR-CM, extrapolated from the ATTR-ACT trial, validated very well to outcomes after a doubling of follow-up and demonstrated improved precision and accuracy versus parametric all-cause survival models.

The Amyloidosis Intersection: Dual Amyloid Types in a Single Host

2025-06-17

Soumya Ramireddy , Tatiana Prokaeva , Hui Chen +7 more | European Journal Of Haematology

ABSTRACT Background Advances in fibril typing by mass spectrometry have improved the accuracy of amyloidosis diagnosis. Dual amyloidogenic proteins have been reported in deposits in sole and multiple different organs. … ABSTRACT Background Advances in fibril typing by mass spectrometry have improved the accuracy of amyloidosis diagnosis. Dual amyloidogenic proteins have been reported in deposits in sole and multiple different organs. Methods Five patients with dual amyloidoses were diagnosed between 1995 and 2022 by Congo red staining and fibril typing using the best available methods at the time of evaluation. Sequencing of TTR and GSN genes was performed. Literature search identified 46 additional cases. Results Three patients exhibited Waldenström macroglobulinemia‐associated AL ( n = 3) amyloidoses in conjunction with ATTRwt or AGel amyloidosis; two patients featured AL/ATTRwt and AA/ATTRwt amyloidoses. One patient demonstrated dual amyloidoses within one anatomical site; three patients featured two amyloidosis types at different anatomical sites; and one patient had dual amyloid deposits in a single anatomical site along with different sites. The time interval between diagnoses was 0–288 months, with the heart and kidneys being the most affected organs. Conclusions Our findings underscore the complexity of clinical presentation in amyloidosis, as multiple amyloid types can co‐exist in a single individual and affect various anatomical sites. Accurate assessment of the clinical phenotype and thorough amyloid fibril typing from the target organs are essential for precise diagnosis and tailored treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT00898235

Rare Diagnosis of Localized Breast Amyloidosis in the Setting of Lymphoplasmacytic Lymphoma

2025-06-16

Mark J. Koury , Karthik Shankar , Walter M. Klein +1 more | Ochsner Journal

Impact of Tafamidis on survival in elderly patients: Insights from the Healthcare European Amyloidosis Registry

2025-06-16

Antoine Jobbe Duval , Mounira Kharoubi , Erwan Donal +7 more | International Journal of Cardiology

Impact of mechanical stress on human transthyretin protein amyloid formation

2025-06-15

You Meng , Xinxin Zhang , Yanli Zhang +7 more | International Journal of Biological Macromolecules

A successful control of cardiac amyloidosis by idecabtagene vicleucel in a patient with relapsed and refractory multiple myeloma: a case report and literature review

2025-06-14

Yayoi Ueda , Toshiki Terao , Nobuharu Fujii +7 more | International Journal of Hematology

A Rare Case of Tracheal Amyloidosis in a Middle-Aged Person

2025-06-14

Muhammad Waqas Iqbal , Danial Kaleem , Hira Gul +2 more | Cureus

A case of gastrointestinal amyloidosis diagnosed by characteristic endoscopic findings and computed tomography

2025-06-13

Yukimura Fukaya , Satoshi Sato , Kazuhito Misawa +1 more | Progress of Digestive Endoscopy

Comparing Effects of Tafamidis in Controlling Left Ventricular and Left Atrial Strains in Patients With Wild-Type Transthyretin Amyloid Cardiomyopathy

2025-06-13

Chisa Eguchi , Hiroaki Kawano , Rosy Haruna Nishizawa +7 more | Circulation Reports

Management der isolierten Amyloidose der Harnblase

2025-06-12

Agneta Seebold , Thomas Büttner , G. Fechner +2 more | Deleted Journal

Zusammenfassung Die isolierte Amyloidose der Harnblase ist eine durch Amyloidablagerungen charakterisierte seltene Erkrankung. Wir berichten über einen Patienten mit rezidivierender schmerzloser Makrohämaturie sowie irritativen und dysurischen Miktionsbeschwerden – charakteristischen Symptomen … Zusammenfassung Die isolierte Amyloidose der Harnblase ist eine durch Amyloidablagerungen charakterisierte seltene Erkrankung. Wir berichten über einen Patienten mit rezidivierender schmerzloser Makrohämaturie sowie irritativen und dysurischen Miktionsbeschwerden – charakteristischen Symptomen der Harnblasenamyloidose. Der Fallbericht diskutiert die Bedeutung verschiedener Diagnose- und Therapiemethoden, Intervallen und Techniken der Verlaufskontrolle sowie Maßnahmen der langfristigen Symptomkontrolle.

Hepatic involvement in light chain amyloidosis: analysis of 130 patients and predictors of hepatic response and survival

2025-06-12

Matthew J. Rees , Nadia Toumeh , Angela Dispenzieri +7 more | Amyloid

Organ response is key to improving outcomes in light chain (AL) amyloidosis. We investigated factors associated hepatic response (HepR) in a large cohort of patients with hepatic AL amyloidosis. Retrospective … Organ response is key to improving outcomes in light chain (AL) amyloidosis. We investigated factors associated hepatic response (HepR) in a large cohort of patients with hepatic AL amyloidosis. Retrospective study of newly-diagnosed AL amyloidosis patients (n = 130) with liver involvement evaluated at the Mayo Clinic between 2000-2021. Patients were eligible if they had documented liver involvement and baseline alkaline phosphatase (ALP)≥1.5x upper limit of normal (ULN). HepR was defined as >50% reduction in ALP from baseline or ALP normalization. HepRs were assessed at 6, 12, 24 month after treatment initiation and the best HepR at any time point. The median baseline ALP was 2.88-fold the ULN (ALP:ULN, IQR: 2.15-4.41), and the median bilirubin was 0.7 mg/dL. HepR rates increased with time from 28% at 6 months, 36% at 12 months and 48% at 24 months. The median time to HepR was 21.5 months (95%CI = 15.4-29.5). Baseline ALP ≥ 4xULN consistently predicted HepR across all time points. Hematological response (HemR) also independently predicted HepR at 12, 24 months and best response. At best hepatic response, kappa isotype, and front-line ASCT were further independent predictors of HepR. The degree of baseline ALP elevation and HemR are reliable predictors of HepR.

Enhanced analytic methodology enables postmortem diagnosis of hereditary AApoAI amyloidosis

2025-06-12

Jeanne L. Theis , Linda Hasadsri , Surendra Dasari +6 more | Amyloid

The Role of Artificial Intelligence in Cardiac Amyloidosis: A Focus on Diagnosis and Clinical Application

2025-06-11

Roshan Wardak , David Snipelisky | Journal of Cardiovascular Development and Disease

The aim of this review is to provide an update on contemporary and evolving artificial intelligence (AI) methods and their role in diagnosing and managing cardiac amyloidosis (CA). AI is … The aim of this review is to provide an update on contemporary and evolving artificial intelligence (AI) methods and their role in diagnosing and managing cardiac amyloidosis (CA). AI is the broadest term which describes a variety of different techniques that enable computers to mimic human intelligence. It is widely used across different diagnostic tests including electrocardiograms, echocardiography, scintigraphy and cardiac magnetic resonance (CMR). Through a comprehensive search among four databases, we identified several insights into clinical applications, diagnostic modalities and different utilization of AI in CA. The elusive nature of CA, which often makes early diagnosis challenging, can greatly benefit from the integration of AI into the diagnostic process. The variability in diagnostic strategies of CA underscores the need for more AI-focused prospective clinical trials to establish evidence-based guidelines for AI-driven diagnostic pathways. Our review highlights the capabilities of AI, particularly in the diagnosis of cardiac amyloidosis.