scholarly journals Overview of systemic and localized amyloidosis

2013 ◽  
Vol 4 (4) ◽  
pp. 231-247 ◽  
Author(s):  
Saulius Girnius
Keyword(s):  
Protein Misfolding ◽  
Clinical Manifestations ◽  
Organ Damage ◽  
Precursor Protein ◽  
Al Amyloidosis ◽  
Folding Intermediates ◽  
Amyloid A ◽  
Localized Amyloidosis ◽  
Amyloid Deposits ◽  
Cell Transplants

Amyloidosis is a family of protein misfolding disorders, in which insoluble fibrillar proteins deposit extracellularly and cause end organ damage. Depending on the precursor protein, clinical manifestations in amyloidosis vary significantly. In systemic amyloidosis, the heart, kidneys, and nerves are most commonly affected, resulting in congestive heart failure, arrhythmia, nephrotic syndrome, renal failure, and peripheral and autonomic neuropathies. In localized amyloidosis, amyloid deposits at the site of production, so only one organ is disrupted. Once amyloidosis is confirmed histologically, the precursor subtype must be identified using immunohistochemistry, immunofixation, electron microscopy, or laser microdissection and mass spectrometry. Treatment should not be initiated prior to the identification of the type of amyloidosis. Currently, treatment focuses on the suppression of the precursor protein: in AL amyloidosis, chemotherapy or autologous stem cell transplants suppress production of immunoglobulin light chains; in AA amyloidosis, anti-microbial and anti-inflammatory agents suppress amyloid A production; and in AF amyloidosis, a liver transplantation removes the source of mutant transthyretin protein production. Newer drugs are being developed to target amyloidosis at an epigenetic level or stabilize folding intermediates, but there are currently in development.

The patient with amyloidosis

2015 ◽  
Author(s):  
Helen J. Lachmann ◽  
Giampaolo Merlini
Keyword(s):  
Incidental Finding ◽  
Systemic Disease ◽  
Acute Phase Reactant ◽  
Organ Damage ◽  
Al Amyloidosis ◽  
Amyloid Formation ◽  
Heavy Proteinuria ◽  
Amyloid A ◽  
Amyloid Deposits

Amyloidosis is a disorder of protein folding in which normally soluble plasma proteins are deposited in the extracellular space in an abnormal insoluble fibrillar form. The process of amyloid formation and deposition causes cytotoxicity and progressive organ dysfunction. Amyloid is remarkably diverse and can be hereditary or acquired, localized or systemic, and lethal or merely an incidental finding. The most important numerically are AL amyloidosis, in which the fibrils are composed of monoclonal immunoglobulin light chains, and AA amyloidosis, in which the acute phase reactant Serum Amyloid A component forms the fibrils.The kidney is involved in 75% of patients with systemic amyloidosis. Heavy proteinuria or nephrotic syndrome is characteristic of most amyloid variants.Without treatment, systemic disease is usually fatal but measures that reduce the supply of amyloid fibril precursor proteins can result in regression of amyloid deposits, prevention of organ failure, and improved quality of life and survival. Early diagnosis, before irreversible organ damage has occurred, is the key to effective treatment. Recent advances in diagnosis and therapy have much improved the outlook of patients with AL amyloidosis, but agents with broader promise are under investigation.

How I Treat AL Amyloidosis

Blood ◽  
2021 ◽  
Author(s):  
Giovanni Palladini ◽  
Giampaolo Merlini
Keyword(s):  
Clinical Trials ◽  
Randomized Clinical Trials ◽  
Correct Diagnosis ◽  
Clinical Manifestations ◽  
Standard Of Care ◽  
Organ Involvement ◽  
Al Amyloidosis ◽  
Amyloid Deposits ◽  
Organ Response ◽  
Effective Drugs

The treatment of patients with systemic light chain (AL) amyloidosis is a challenge to hematologists. Despite its generally small size, the underlying clone causes a rapidly progressing, often devastating multiorgan dysfunction through the toxic light chains that form amyloid deposits. Clinical manifestations are deceitful and too often recognized at an irreversible stage. However, hematologists are in the unique position to diagnose AL amyloidosis at a pre-symptomatic stage checking biomarkers of amyloid organ involvement in patients with monoclonal gammopathies at higher risk to develop the disease. Adequate technology and expertise are needed for a prompt and correct diagnosis, particularly for ruling out non-AL amyloidoses that are now also treatable. Therapy should be carefully tailored based on severity of organ involvement and clonal characteristics, and early and continual monitoring of response is critical. Three recent randomized clinical trials moved AL amyloidosis to evidence-based era. Above all, the daratumumab-bortezomib combination is a new standard-of-care for newly diagnosed patients inducing rapid and deep responses that translate into high rates of organ response. The availability of new effective drugs allows to better personalize the therapy, reduce toxicity, and improve outcomes. Patients should be treated within clinical trials whenever possible.

scholarly journals Solid Organ Transplantation in Amyloidosis

2020 ◽  
Vol 143 (4) ◽  
pp. 352-364 ◽  
Author(s):  
Foteini Theodorakakou ◽  
Despina Fotiou ◽  
Meletios A. Dimopoulos ◽  
Efstathios Kastritis
Keyword(s):  
Organ Transplantation ◽  
Solid Organ Transplantation ◽  
Organ Damage ◽  
Precursor Protein ◽  
Multidisciplinary Teams ◽  
Al Amyloidosis ◽  
Solid Organ ◽  
Transthyretin Amyloidosis ◽  
Improved Outcomes ◽  
Life Saving

Amyloidosis comprises a diverse group of diseases characterized by misfolding of precursor proteins which eventually form amyloid aggregates and preceding intermediaries, which are deposited in target tissues causing progressive organ damage. In all forms of amyloidosis, vital organs may fail; depending on the specific amyloidosis type, this may occur rapidly or progress slowly. Beyond therapies to reduce the precursor protein (chemotherapy for light chain [AL] amyloidosis, anti-inflammatory therapy in serum A amyloid­osis [AA], and antisense RNA therapy in transthyretin amyloidosis [ATTR]), organ transplantation may also be a means to reduce amyloidogenic protein, e.g., in types of amyloid­osis in which the variant precursor is produced by the liver. Heart transplantation is a life-saving approach to the treatment of patients with advanced cardiac amyloidosis; however, amyloidosis may still be considered a contraindication to the procedure despite data supporting improved outcomes, similar to patients with other indications. Kidney transplantation is associated with particularly favorable outcomes in patients with amyloidosis, especially if the precursor protein has been eliminated. Overall, outcomes of solid organ transplantation are improving, but more data are needed to refine the selection criteria and the timing for organ transplantation, which should be performed in highly experienced centers involving multidisciplinary teams with close patient follow-up to detect amyloid recurrence.

scholarly journals Recent Advances in the Diagnosis, Risk Stratification, and Management of Systemic Light-Chain Amyloidosis

2019 ◽  
Vol 141 (2) ◽  
pp. 93-106 ◽  
Author(s):  
Iuliana Vaxman ◽  
Morie Gertz
Keyword(s):  
Plasma Cell ◽  
Light Chain ◽  
Cell Clone ◽  
Proteasome Inhibitors ◽  
Clinical Manifestations ◽  
Al Amyloidosis ◽  
Amyloid Deposits ◽  
Protein Fibrils ◽  
Risk Patients ◽  
Intensive Search

The term amyloidosis refers to a group of disorders in which protein fibrils accumulate in certain organs, disrupt their tissue architecture, and impair the function of the effected organ. The clinical manifestations and prognosis vary widely depending on the specific type of the affected protein. Immunoglobulin light-chain (AL) amyloidosis is the most common form of systemic amyloidosis, characterized by deposition of a misfolded monoclonal light-chain that is secreted from a plasma cell clone. Demonstrating amyloid deposits in a tissue biopsy stained with Congo red is mandatory for the diagnosis. Novel agents (proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, venetoclax) and autologous stem cell transplantation, used for eliminating the underlying plasma cell clone, have improved the outcome for low- and intermediate-risk patients, but the prognosis for high-risk patients is still grave. Randomized studies evaluating antibodies that target the amyloid deposits (PRONTO, VITAL) were recently stopped due to futility and currently there is an intensive search for novel treatment approaches to AL amyloidosis. Early diagnosis is of paramount importance for effective treatment and prognosis, due to the progressive nature of this disease.

Recurrent diffuse gastric bleeding as a leading symptom of gastrointestinal AL amyloidosis

2017 ◽  
Vol 55 (12) ◽  
pp. 1318-1322 ◽  
Author(s):  
Caspar Franck ◽  
Marino Venerito ◽  
Jochen Weigt ◽  
Albert Roessner ◽  
Peter Malfertheiner
Keyword(s):  
Plasma Cells ◽  
Serum Proteins ◽  
Histopathological Examination ◽  
Disease Incidence ◽  
Clinical Manifestations ◽  
Current Treatment ◽  
Al Amyloidosis ◽  
Gastric Bleeding ◽  
Amyloid Deposits ◽  
Leading Symptom

AbstractAmyloidosis is a rare disease (incidence about 0.8/100 000) characterized by extracellular tissue deposition of fibrils composed of low molecular weight subunits of a variety of serum proteins. Clinical manifestations are largely determined by the type of precursor protein, the tissue distribution and the amount of amyloid deposition. Gastrointestinal (GI) manifestations of amyloidosis are even more uncommon (3 % of all amyloidosis patients). Symptoms of GI amyloidosis are nonspecific, heterogeneous, and include weight loss, GI bleeding, heartburn, early satiety, diarrhea and abdominal pain. The histopathological examination of biopsy specimens from the GI tract leads to the diagnosis.Herein we report the case of a 63-year-old woman with recurrent diffuse gastric bleeding. Endoscopic biopsies revealed distinct amyloid deposits in the mucosa of the stomach. Further histochemical assessment confirmed systemic light chain (AL) amyloidosis with clinically predominant gastrointestinal manifestation. An induction therapy with bortezomib and dexamethasone was initiated.Our report illustrates the importance of the multidisciplinary approach for diagnosis and management of AL amyloidosis. Current treatment of systemic AL amyloidosis is based on cytostatic targeting of immunoglobulin producing plasma cells. Therapeutic options are limited and highly toxic, making the development of novel treatment approaches an urgent need.

scholarly journals Should the Reporting of Bone Marrow Positivity for Amyloid Be Revised?: A Critical Assessment Based on 66 Biopsies From a Single Institution

2020 ◽  
Vol 144 (8) ◽  
pp. 967-973 ◽  
Author(s):  
Sara Javidiparsijani ◽  
Maria M. Picken
Keyword(s):  
Bone Marrow ◽  
Spatial Distribution ◽  
Plasma Cells ◽  
Treatment Options ◽  
Clinical Information ◽  
Al Amyloidosis ◽  
Significant Heterogeneity ◽  
Amyloid A ◽  
Amyloid Deposits ◽  
Amyloid Light Chain

Context.— Amyloidoses are rare but heterogeneous disorders for which diagnosis is contingent upon the detection of deposits by Congo red stain and amyloid protein typing determines the treatment options. Objective.— To address the reporting of bone marrow (BM) involvement by amyloid in relation to the spatial distribution of deposits and to explore whether the location of deposits may have clinical relevance. Design.— We examined 66 BM biopsies positive for amyloid with regard to the location and type of amyloid, the percentage and clonality of plasma cells, other organ involvement, and relevant clinical information. Results.— In 21 cases, amyloid deposits involved BM stroma, whereas 45 cases were nonstromal. All cases of stromal involvement were typed as amyloid light chain (AL) amyloidosis (or presumed AL), whereas nonstromal involvement was associated with at least 3 types of amyloidosis: AL, amyloid transthyretin (ATTR), and amyloid A (AA). The initial diagnosis of amyloidosis was made in a BM specimen in 21 of 66 cases (31.8%). Plasma cells ranged from 1% to 80% (mean, 13.4%; median, 8%; <10% in 44 of 66 specimens [66.6%]) and were monoclonal in 58 of 66 cases (87.8%), and in 54 of 66 cases (81.8%) amyloid deposits were documented in at least one other organ. Conclusions.— This study demonstrates that there is significant heterogeneity in the spatial distribution of amyloid in BM biopsy specimens with medullary, extramedullary, purely vascular, or combined involvement. Whereas stromal deposits were associated exclusively with AL, nonstromal and purely vascular deposits were seen in at least 3 types of systemic amyloidosis (AL, AA, and ATTR). We discuss the reporting of BM biopsy tissue positivity for amyloid deposits.

scholarly journals High-sensitivity diagnosis of AA amyloidosis using Congo red and immunohistochemistry detects missed amyloid deposits.

1995 ◽  
Vol 43 (9) ◽  
pp. 863-869 ◽  
Author(s):  
R P Linke ◽  
H V Gärtner ◽  
H Michels
Keyword(s):  
Congo Red ◽  
High Sensitivity ◽  
Organ Damage ◽  
Aa Amyloidosis ◽  
Amyloid A ◽  
Biopsy Specimens ◽  
Pediatric Diseases ◽  
Amyloid Deposits ◽  
Renal Biopsies ◽  
Rectal Biopsies

Biopsy diagnosis of early amyloid-A (AA) amyloidosis has often been difficult. Examination of 57 consecutive biopsy specimens from 42 patients with inflammatory pediatric diseases permitted comparison of the precision of biopsy amyloid diagnosis in six different laboratories (labs), which applied the following methods: Congo red alone (four unspecialized labs combined as Lab 1), Congo red and electron microscopy (Lab 2), or Congo red and immunohistochemistry using monoclonal antibodies (Lab 3). Lab 3 reexamined the diagnoses made by Lab 1 and Lab 2. Of the 42 patients, 17 patients with 32 biopsies were selected for this study based on the presence of amyloid in at least one biopsy. Whereas massive or no amyloid was concordantly recognized by all labs in 18 biopsies from nine patients, discordance was demonstrated in 14 biopsies from eight patients. Comparison of Labs 1-3 revealed amyloid in 12 rectal and 18 renal biopsies evaluated by Lab 3, whereas Lab 2 missed amyloid in two of 18 renal biopsies and Lab 1 missed amyloid in 11 of 12 rectal biopsies. Most amyloid was missed when only minute amounts of amyloid were present. Had our technique (Lab 3) been available at the time of biopsy, amyloid could have been diagnosed years earlier, thereby sparing the patient further biopsies and allowing initiation of earlier treatment before organ damage could occur.

scholarly journals Systemic ATTR-amyloidosis, a Rare Form of Internal Organ Damage

2019 ◽  
Vol 15 (3) ◽  
pp. 349-358 ◽  
Author(s):  
V. V. Rameev ◽  
R. P. Myasnikov ◽  
P. P. Vinogradov ◽  
L. V. Kozlovskaya ◽  
S. V. Moiseev ◽  
...  
Keyword(s):  
Clinical Manifestations ◽  
Organ Damage ◽  
Al Amyloidosis ◽  
Hemodynamic Changes ◽  
Attr Amyloidosis ◽  
Different Types ◽  
Diagnostic Difficulties ◽  
Methods Of Treatment ◽  
Russian Patient ◽  
Inflammatory Component

The article presents the case report of a rare hereditary form of systemic ATTR-amyloidosis in Russian patient with a discussion of approaches to the diagnosis and treatment of this form, also based on the own experience in the management of such patients. Modern ideas about the pathogenesis of the disease as well as detailed information about the clinical manifestations of amyloid cardiopathy and of other organs are presented. The nature of structural and hemodynamic changes in the heart is discussed on the basis of experience, including own, ultrasound examination of the heart in patients with amyloidosis, especially the article focuses the reader's attention on the true infiltrative nature of transtiretin amyloid cardiopathy in contrast to AL-amyloidosis, in which there is a significant inflammatory component that determines a more unfavorable natural course of AL-amyloidosis of the heart. The article discusses the differential diagnosis of different types of amyloidosis, the diagnostic difficulties associated with weak congophilia of transtiretin amyloidosis and at the same time substantiates the need for morphological verification of the diagnosis. Modern methods of treatment of ATTR-amyloidosis are discussed.

scholarly journals AL amyloidosis: untangling new therapies

Hematology ◽  
2021 ◽  
Vol 2021 (1) ◽  
pp. 682-688
Author(s):  
Susan Bal ◽  
Heather Landau
Keyword(s):  
Protein Misfolding ◽  
Plasma Cells ◽  
Delayed Diagnosis ◽  
Organ Damage ◽  
Al Amyloidosis ◽  
Immunoglobulin Light Chains ◽  
Organ Function ◽  
New Therapies ◽  
Protein Misfolding Disorder ◽  
Careful Investigation

Abstract Systemic light chain (AL) amyloidosis is a protein misfolding disorder characterized by the deposition of abnormal immunoglobulin light chains in fibrillary aggregates, resulting in end-organ damage. Several unique challenges face treating physicians, including delayed diagnosis, advanced vital organ involvement, and morbidity with treatment. Aggressive supportive care and risk-adapted application of plasma cell–directed therapies are the cornerstones of management. The therapeutic revolution in multiple myeloma will likely further expand the arsenal against plasma cells. Careful investigation of these agents will be critical to establish their role in this fragile population. The promise of fibril-directed therapies to restore organ function remains despite early disappointments. In this review, we discuss new therapies to tackle AL amyloidosis using a case-based approach.

Testicular Involvement is a Hallmark of Apo A-I Leu75Pro Mutation Amyloidosis

2020 ◽  
Vol 105 (12) ◽  
pp. e4758-e4766
Author(s):  
Andrea Delbarba ◽  
Paolo Facondo ◽  
Simona Fisogni ◽  
Claudia Izzi ◽  
Filippo Maffezzoni ◽  
...  
Keyword(s):  
Follicle Stimulating Hormone ◽  
Organ Damage ◽  
University Hospital ◽  
Reproductive Hormone ◽  
Testicular Dysfunction ◽  
Amyloid Deposits ◽  
Scrotal Ultrasound ◽  
Almost All ◽  
The University ◽  
Male Subjects

Abstract Context Apo A-I Leu75Pro is a rare hereditary form of amyloidosis that mainly involves the kidney, the liver, and the testis. Objective To define the characteristics of organ damage and testis impairment in the largest cohort collected to date of men with Apo A-I Leu75Pro amyloidosis. Design, Setting, and Patients Retrospective study from a prospectively collected database of 129 male subjects >18 years with Apo A-I Leu75Pro amyloidosis from a reference center at the University Hospital of Brescia, Italy. Main outcome measures We evaluated liver and renal function, scrotal ultrasound, reproductive hormone levels, testis biopsy, hypogonadal symptoms, and fertility. Results Progressive involvement of testis, kidney, and liver was observed in 96/129 (74.4%) cases. Testis impairment was found in 88/129 patients (68.2%), liver in 59 (45.7%) and renal in 50 (38.8%). Testis damage was often the first manifestation of the disease and the only dysfunction in 30% of younger patients (<38 years). Testicular involvement was characterized mainly by primary (73/88 patients, 83.0%) and subclinical (8/88, 9.1%) hypogonadism. Almost all (85/88, 96.6%) also had high follicle-stimulating hormone, suggesting a primary global damage of endocrine and spermatogenic functions, and 30% of them did not conceive. Macroorchidism was found in 53/88 (60.2%) patients, especially in men <54 years (30/33, 90.9%). Apo A-I amyloid deposits were found in Sertoli cells, germinal epithelium, and vessel walls. Conclusion In men with Apo A-I Leu75Pro amyloidosis, testicular involvement is the hallmark of the disease, characterized by global primary testicular dysfunction and macroorchidism due to amyloid deposits.

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