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Zhang X, Tang F, Gao YY, Song DZ, Liang J. Hepatomegaly and jaundice as the presenting symptoms of systemic light-chain amyloidosis: A case report. World J Gastrointest Oncol 2024; 16:550-556. [PMID: 38425387 PMCID: PMC10900159 DOI: 10.4251/wjgo.v16.i2.550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Revised: 12/11/2023] [Accepted: 12/26/2023] [Indexed: 02/02/2024] Open
Abstract
BACKGROUND Light chain (AL) amyloidosis is a plasma cell dyscrasia characterized by the pathologic production and extracellular tissue deposition of fibrillar proteins derived from immunoglobulin AL fragments secreted by a clone of plasma cells, which leads to progressive dysfunction of the affected organs. The two most commonly affected organs are the heart and kidneys, and liver is rarely the dominant affected organ with only 3.9% of cases, making them prone to misdiagnosis and missed diagnosis. CASE SUMMARY A 65-year-old woman was admitted with a 3-mo history of progressive jaundice and marked hepatomegaly. Initially, based on enhanced computed tomography scan and angiography, Budd-Chiari syndrome was considered and balloon dilatation of significant hepatic vein stenoses was performed. However, additional diagnostic procedures, including liver biopsy and bone marrow-examination, revealed immunoglobulin kapa AL amyloidosis with extensive liver involvement and hepatic vascular compression. The disease course was progressive and fatal, and the patient eventually died 5 mo after initial presentation of symptoms. CONCLUSION AL amyloidosis with isolated liver involvement is very rare, and can be easily misdiagnosed as a vascular disease.
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Affiliation(s)
- Xu Zhang
- Department of Gastroenterology and Hepatology, The Third Central Hospital of Tianjin, Tianjin 300170, China
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Artificial Cell Engineering Technology Research Center, Tianjin Institute of Hepatobiliary Disease, Tianjin 300170, China
| | - Fei Tang
- Department of Gastroenterology and Hepatology, The Third Central Hospital of Tianjin, Tianjin 300170, China
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Artificial Cell Engineering Technology Research Center, Tianjin Institute of Hepatobiliary Disease, Tianjin 300170, China
| | - Yan-Ying Gao
- Department of Gastroenterology and Hepatology, The Third Central Hospital of Tianjin, Tianjin 300170, China
| | - De-Zhao Song
- Department of Interventional Radiology, The Third Central Hospital of Tianjin, Tianjin 300170, China
| | - Jing Liang
- Department of Gastroenterology and Hepatology, The Third Central Hospital of Tianjin, Tianjin 300170, China
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Das S, Ailawadhi S, Sher T, Roy V, Fernandez A, Parrondo RD. Anti-B Cell Maturation Antigen Chimeric Antigen Receptor T Cell Therapy for the Treatment of AL Amyloidosis and Concurrent Relapsed/Refractory Multiple Myeloma: Preliminary Efficacy and Safety. Curr Oncol 2023; 30:9627-9633. [PMID: 37999117 PMCID: PMC10670199 DOI: 10.3390/curroncol30110697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 10/10/2023] [Accepted: 10/25/2023] [Indexed: 11/25/2023] Open
Abstract
While immunotherapies, such as CAR T therapy and bi-specific antibodies, have revolutionized the treatment of multiple myeloma (MM), patients with AL amyloidosis have been excluded from trials with these agents due to concerns of underlying autonomic, cardiac, and renal dysfunction, leading to potentially fatal toxicities from these therapies. In this communication, we described the outcomes of two patients with AL amyloidosis and concurrent MM with underlying cardiac and/or renal dysfunction who underwent anti-BCMA CAR T cell therapy with ide-cel or cilta-cel, received cytokine release syndrome prophylaxis, and tolerated therapy well with manageable toxicities and achieved a MRD-negative state. We described the preliminary efficacy and safety of CAR T in patients with AL amyloidosis and highlighted the importance of patient selection and medical optimization of cardiac and renal function prior to CAR T.
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Affiliation(s)
- Saurav Das
- Division of Hematology-Oncology and Blood and Marrow Transplantation Program, Mayo Clinic, Jacksonville, FL 32224, USA; (S.D.); (S.A.); (T.S.); (V.R.); (A.F.)
| | - Sikander Ailawadhi
- Division of Hematology-Oncology and Blood and Marrow Transplantation Program, Mayo Clinic, Jacksonville, FL 32224, USA; (S.D.); (S.A.); (T.S.); (V.R.); (A.F.)
| | - Taimur Sher
- Division of Hematology-Oncology and Blood and Marrow Transplantation Program, Mayo Clinic, Jacksonville, FL 32224, USA; (S.D.); (S.A.); (T.S.); (V.R.); (A.F.)
| | - Vivek Roy
- Division of Hematology-Oncology and Blood and Marrow Transplantation Program, Mayo Clinic, Jacksonville, FL 32224, USA; (S.D.); (S.A.); (T.S.); (V.R.); (A.F.)
| | - Andre Fernandez
- Division of Hematology-Oncology and Blood and Marrow Transplantation Program, Mayo Clinic, Jacksonville, FL 32224, USA; (S.D.); (S.A.); (T.S.); (V.R.); (A.F.)
| | - Ricardo D. Parrondo
- Division of Hematology-Oncology and Blood and Marrow Transplantation Program, Mayo Clinic, Jacksonville, FL 32224, USA; (S.D.); (S.A.); (T.S.); (V.R.); (A.F.)
- Mangurian Building, 3rd Floor, 4500 San Pablo Road S, Jacksonville, FL 32224, USA
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Palmer C, Truong VT, Slivnick JA, Wolking S, Coleman P, Mazur W, Zareba KM. Atrial function and geometry differences in transthyretin versus immunoglobulin light chain amyloidosis: a cardiac magnetic resonance study. Sci Rep 2022; 12:140. [PMID: 34996915 PMCID: PMC8742089 DOI: 10.1038/s41598-021-03359-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 11/24/2021] [Indexed: 11/24/2022] Open
Abstract
To determine the differences in left atrial (LA) function and geometry assessed by cardiac magnetic resonance (CMR) between transthyretin (ATTR) and immunoglobulin light chain (AL) cardiac amyloidosis (CA). We performed a retrospective analysis of 54 consecutive patients (68.5% male, mean age 67 ± 11 years) with confirmed CA (24 ATTR, 30 AL) who underwent comprehensive CMR examinations. LA structural and functional assessment including LA volume, LA sphericity index, and LA strain parameters were compared between both subtypes. In addition, 15 age-matched controls were compared to all groups. Patients with ATTR-CA were older (73 ± 9 vs. 62 ± 10 years, p < 0.001) and more likely to be male (83.3% vs. 56.7%, p = 0.036) when compared to AL-CA. No significant difference existed in LA maximum volume and LA sphericity index between ATTR-CA and AL-CA. LA minimum volumes were larger in ATTR-CA when compared with AL-CA. There was a significant difference in LA function with worse strain values in ATTR vs AL: left atrial reservoir [7.4 (6.3–12.8) in ATTR vs. 13.8 (6.90–24.8) in AL, p = 0.017] and booster strains [3.6 (2.6–5.5) in ATTR vs. 5.2 (3.6–12.1) in AL, p = 0.039]. After adjusting for age, LA reservoir remained significantly lower in ATTR-CA compared to AL-CA (p = 0.03), but not LA booster (p = 0.16). We demonstrate novel differences in LA function between ATTR-CA and AL-CA despite similar LA geometry. Our findings of more impaired LA function in ATTR may offer insight into higher AF burden in these patients.
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Affiliation(s)
- Cassady Palmer
- The Christ Hospital Health Network, 2123 Auburn Ave, Ste 138, Cincinnati, OH, 45219, USA.
| | - Vien T Truong
- The Christ Hospital Health Network, 2123 Auburn Ave, Ste 138, Cincinnati, OH, 45219, USA.,The Lindner Research Center, Cincinnati, OH, USA
| | | | - Sarah Wolking
- The Christ Hospital Health Network, 2123 Auburn Ave, Ste 138, Cincinnati, OH, 45219, USA
| | - Paige Coleman
- The Christ Hospital Health Network, 2123 Auburn Ave, Ste 138, Cincinnati, OH, 45219, USA
| | - Wojciech Mazur
- The Christ Hospital Health Network, 2123 Auburn Ave, Ste 138, Cincinnati, OH, 45219, USA
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Abstract
Amyloidosis constitutes a large spectrum of diseases characterized by an extracellular deposition of a fibrillar aggregate, generating insoluble and toxic amasses that may be deposited in tissues in bundles with an abnormal cross-β-sheet conformation, known as amyloid. Amyloid may lead to a cell damage and an impairment of organ function. Several different proteins are recognized as able to produce amyloid fibrils with a different tissue tropism related to the molecular structure. The deposition of amyloid may occur as a consequence of the presence of an abnormal protein, caused by high plasma levels of a normal protein, or as a result of the aging process along with some environmental factors. Although amyloidosis is rare, amyloid deposits play a role in several conditions as degenerative diseases. Thus, the development of antiamyloid curative treatments may be a rational approach to treat neurodegenerative conditions like Alzheimer's disease in the future. Nowadays, novel treatment options are currently refined through controlled trials, as new drug targets and different therapeutic approaches have been identified and validated through modern advances in basic research. Fibril formation stabilizers, proteasome inhibitors, and immunotherapy revealed promising results in improving the outcomes of patients with systemic amyloidosis, and these novel algorithms will be effectively combined with current treatments based on chemotherapeutic regimens. The aim of this review is to provide an update on diagnosis and treatment for systemic amyloidosis.
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Pacoureau L, Labeyrie C, Catalan P, Echaniz-Laguna A, Henriquez S, Laparra A, Cauquil C, Chrétien P, Hacein-Bey-Abina S, Goujard C, Adam C, Lambotte O, Adams D, Noël N. Neuropathies périphériques associées aux syndromes lymphoprolifératifs : spectre clinique et démarche diagnostique. Rev Med Interne 2021; 42:844-854. [PMID: 34373143 DOI: 10.1016/j.revmed.2021.06.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 06/17/2021] [Accepted: 06/20/2021] [Indexed: 10/20/2022]
Abstract
Lymphoproliferative syndromes (multiple myeloma, Waldenström's disease, chronic lymphocytic leukemia, lymphomas) may be associated with peripheral neuropathies. The mechanism can be dysimmune, associated or not with monoclonal gammopathies; paraneoplastic; infiltrative; or more commonly, iatrogenic or due to vitamin deficiency. The diagnosis can be complex, especially when the neuropathy is the presenting manifestation, requiring a close cooperation between internists and neurologists. The positive diagnosis of the neuropathy is based on a systematic electro-clinical investigation, which specifies the topography and the mechanism of the nerve damage, sometimes reinforced by imaging examinations, in particular, nerve and/or plexus MRI. The imputability of the neuropathy to a lymphoproliferative syndrome is based on a set of arguments including the clinical context (B signs, tumour syndrome), first-line laboratory tests (hemogram, protein electrophoresis, viral serologies, complement), auto-antibodies discussed according to the neuropathy (anti-MAG, anti-gangliosides) and sometimes more invasive examinations (bone marrow or neuro-muscular biopsies).
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Affiliation(s)
- L Pacoureau
- Service de médecine interne et immunologie clinique, Assistance publique-Hôpitaux Paris Saclay, Hôpital Bicêtre, 94275 Le Kremlin-Bicêtre cedex, France
| | - C Labeyrie
- Service de neurologie, Assistance publique-Hôpitaux de Paris, Groupe hospitalier universitaire Paris Sud, Hôpital Bicêtre, 94275 Le Kremlin-Bicêtre cedex, France; Centre de référence neuropathies amyloïdes familiales et autres neuropathies rares (NNERF), Groupe hospitalier universitaire Paris Sud, Hôpital Bicêtre, 94275 Le Kremlin-Bicêtre cedex, France
| | - P Catalan
- Service de médecine interne et immunologie clinique, Assistance publique-Hôpitaux Paris Saclay, Hôpital Bicêtre, 94275 Le Kremlin-Bicêtre cedex, France; Université Paris Saclay, Faculté de médecine, Le Kremlin Bicêtre, France
| | - A Echaniz-Laguna
- Université Paris Saclay, Faculté de médecine, Le Kremlin Bicêtre, France; Service de neurologie, Assistance publique-Hôpitaux de Paris, Groupe hospitalier universitaire Paris Sud, Hôpital Bicêtre, 94275 Le Kremlin-Bicêtre cedex, France; Centre de référence neuropathies amyloïdes familiales et autres neuropathies rares (NNERF), Groupe hospitalier universitaire Paris Sud, Hôpital Bicêtre, 94275 Le Kremlin-Bicêtre cedex, France
| | - S Henriquez
- Service de médecine interne et immunologie clinique, Assistance publique-Hôpitaux Paris Saclay, Hôpital Bicêtre, 94275 Le Kremlin-Bicêtre cedex, France; Université Paris Saclay, Faculté de médecine, Le Kremlin Bicêtre, France
| | - A Laparra
- Service de médecine interne et immunologie clinique, Assistance publique-Hôpitaux Paris Saclay, Hôpital Bicêtre, 94275 Le Kremlin-Bicêtre cedex, France; Université Paris Saclay, Faculté de médecine, Le Kremlin Bicêtre, France
| | - C Cauquil
- Service de neurologie, Assistance publique-Hôpitaux de Paris, Groupe hospitalier universitaire Paris Sud, Hôpital Bicêtre, 94275 Le Kremlin-Bicêtre cedex, France; Centre de référence neuropathies amyloïdes familiales et autres neuropathies rares (NNERF), Groupe hospitalier universitaire Paris Sud, Hôpital Bicêtre, 94275 Le Kremlin-Bicêtre cedex, France
| | - P Chrétien
- INSERM, UTCBS, Unité des technologies chimiques et biologiques pour la Santé, Université de Paris, CNRS, 75006 Paris, France; Service d'immunologie biologique, Assistance publique-Hôpitaux de Paris, Groupe hospitalier universitaire Paris Sud, Hôpital Bicêtre, 94275 Le Kremlin-Bicêtre cedex, France
| | - S Hacein-Bey-Abina
- INSERM, UTCBS, Unité des technologies chimiques et biologiques pour la Santé, Université de Paris, CNRS, 75006 Paris, France; Service d'immunologie biologique, Assistance publique-Hôpitaux de Paris, Groupe hospitalier universitaire Paris Sud, Hôpital Bicêtre, 94275 Le Kremlin-Bicêtre cedex, France
| | - C Goujard
- Service de médecine interne et immunologie clinique, Assistance publique-Hôpitaux Paris Saclay, Hôpital Bicêtre, 94275 Le Kremlin-Bicêtre cedex, France; Université Paris Saclay, Faculté de médecine, Le Kremlin Bicêtre, France
| | - C Adam
- Service d'anatomie pathologique et neuropathologie, Assistance publique-Hôpitaux de Paris, Groupe Hospitalier Universitaire Paris Sud, Hôpital Bicêtre, 94275 Le Kremlin-Bicêtre cedex, France
| | - O Lambotte
- Service de médecine interne et immunologie clinique, Assistance publique-Hôpitaux Paris Saclay, Hôpital Bicêtre, 94275 Le Kremlin-Bicêtre cedex, France; Université Paris Saclay, Faculté de médecine, Le Kremlin Bicêtre, France; Inserm UMR 1184, Immunologie des maladies virales et auto-immunes (IMVA), Université Paris Saclay, 94275 Le Kremlin-Bicêtre cedex, France; CEA, DSV/iMETI, Division of Immuno-Virology, IDMIT, Université Paris Saclay, 94275 Le Kremlin-Bicêtre cedex, France
| | - D Adams
- Université Paris Saclay, Faculté de médecine, Le Kremlin Bicêtre, France; Service de neurologie, Assistance publique-Hôpitaux de Paris, Groupe hospitalier universitaire Paris Sud, Hôpital Bicêtre, 94275 Le Kremlin-Bicêtre cedex, France; Centre de référence neuropathies amyloïdes familiales et autres neuropathies rares (NNERF), Groupe hospitalier universitaire Paris Sud, Hôpital Bicêtre, 94275 Le Kremlin-Bicêtre cedex, France
| | - N Noël
- Service de médecine interne et immunologie clinique, Assistance publique-Hôpitaux Paris Saclay, Hôpital Bicêtre, 94275 Le Kremlin-Bicêtre cedex, France; Université Paris Saclay, Faculté de médecine, Le Kremlin Bicêtre, France; Inserm UMR 1184, Immunologie des maladies virales et auto-immunes (IMVA), Université Paris Saclay, 94275 Le Kremlin-Bicêtre cedex, France; CEA, DSV/iMETI, Division of Immuno-Virology, IDMIT, Université Paris Saclay, 94275 Le Kremlin-Bicêtre cedex, France.
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Dhingra H, Singh A, Baliyan A, Bansal V. Thymic amyloidoma mimicking sclerosing thymoma in a triple vessel disease patient: An incidental finding. INDIAN J PATHOL MICR 2021; 63:608-610. [PMID: 33154315 DOI: 10.4103/ijpm.ijpm_432_19] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
A 65 year old man who underwent coronary artery bypass graft (CABG) for triple vessel disease was found to have enlarged thymus. Biopsy of the thymic mass revealed localised amyloid deposits demonstrating strong apple green birefringence on polarised microscopy. Localized thymic amyloidosis is an extremely rare finding with present case as the seventh in the world and the first in India. Review of literature of thymic amyloidoma and its close differential sclerosing thymoma is hereby described.
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Affiliation(s)
- Harshi Dhingra
- Department of Pathology, Adesh Institute of Medical Sciences and Research, Bathinda, Punjab, India
| | - Amarjit Singh
- Department of Pathology, Adesh Institute of Medical Sciences and Research, Bathinda, Punjab, India
| | - Asif Baliyan
- Focus Imaging and Research Centre Pvt Ltd., Laboratory Medicine Division, New Delhi, India
| | - Vinisha Bansal
- Department of Pathology, Government Medical College and Hospital, Sector 32-A, Chandigarh, India
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Zampieri M, Nardi G, Del Monaco G, Allinovi M, Gabriele M, Zocchi C, Casagrande S, Fumagalli C, Di Mario C, Olivotto I, Perfetto F, Cappelli F. Changes in the perceived epidemiology of amyloidosis: 20 year-experience from a Tertiary Referral Centre in Tuscany. Int J Cardiol 2021; 335:123-127. [PMID: 33865873 DOI: 10.1016/j.ijcard.2021.04.023] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 03/22/2021] [Accepted: 04/12/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND Amyloidosis is considered a rare heterogeneous condition comprising different entities. Epidemiological data are limited and often controversial. We aimed to examine epidemiological changes in amyloidosis diagnosed over a 20-year period at a tertiary referral centre for amyloidosis. METHODS We retrospectively reviewed medical files from all patients diagnosed with amyloidosis between January 2000 and December 2019, at Careggi University Hospital, Florence, Italy. Diagnosis of amyloidosis was performed as per current clinical practice and scientific evidence at the time of patient evaluation. RESULTS We reported data on 654 consecutive patients: 274 (42%) wild type transthyretin amyloidosis (wtATTR), 68 (10%) genetic variant amyloidosis (vATTR), 281 (43%) light-chain amyloidosis (AL) and 31 (5%) serum amyloid A amyloidosis (AA). With limited fluctuations, the absolute number of new AL diagnosis increased during the 20-year period. wtATTR was unrecognized before 2009 but represented by far the most common aetiology at the end of the observation period. AA represented a residual diagnosis throughout the entire examined period. CONCLUSIONS Following a rapid and marked increase in the number of new diagnoses over the last decade, ATTR represents by far the most common type of amyloidosis in our regional centre. These data contrasts with recent reports from national referral institutions and may help shed light on the epidemiology of the disease at the community level.
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Affiliation(s)
- Mattia Zampieri
- Tuscan Regional Amyloidosis Centre, Careggi University Hospital, Florence, Italy; Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy.
| | - Giulia Nardi
- Tuscan Regional Amyloidosis Centre, Careggi University Hospital, Florence, Italy
| | - Guido Del Monaco
- Tuscan Regional Amyloidosis Centre, Careggi University Hospital, Florence, Italy
| | - Marco Allinovi
- Tuscan Regional Amyloidosis Centre, Careggi University Hospital, Florence, Italy
| | - Martina Gabriele
- Tuscan Regional Amyloidosis Centre, Careggi University Hospital, Florence, Italy
| | - Chiara Zocchi
- Tuscan Regional Amyloidosis Centre, Careggi University Hospital, Florence, Italy; Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy
| | - Silvia Casagrande
- Tuscan Regional Amyloidosis Centre, Careggi University Hospital, Florence, Italy
| | - Carlo Fumagalli
- Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy; Geriatric Cardiology - Intensive Care Unit, Azienda ospedaliera Careggi, Florence, Italy
| | - Carlo Di Mario
- Division of Interventional Structural Cardiology, Cardiothoracovascular Department, Careggi University Hospital, Florence, Italy
| | - Iacopo Olivotto
- Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy
| | - Federico Perfetto
- Tuscan Regional Amyloidosis Centre, Careggi University Hospital, Florence, Italy; IV Internal Medicine Division, Careggi University Hospital, Florence, Italy
| | - Francesco Cappelli
- Tuscan Regional Amyloidosis Centre, Careggi University Hospital, Florence, Italy; Division of Interventional Structural Cardiology, Cardiothoracovascular Department, Careggi University Hospital, Florence, Italy
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Gertz MA. Immunoglobulin light chain amyloidosis: 2020 update on diagnosis, prognosis, and treatment. Am J Hematol 2020; 95:848-860. [PMID: 32267020 DOI: 10.1002/ajh.25819] [Citation(s) in RCA: 92] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 04/02/2020] [Indexed: 01/10/2023]
Abstract
DISEASE OVERVIEW Immunoglobulin light chain amyloidosis is a clonal, nonproliferative plasma cell disorder in which fragments of immunoglobulin light or heavy chain are deposited in tissues. Clinical features depend on organs involved but can include heart failure with preserved ejection fraction, nephrotic syndrome, hepatic dysfunction, peripheral/autonomic neuropathy, and "atypical smoldering multiple myeloma or monoclonal gammopathy undetermined significance (MGUS)." DIAGNOSIS Tissue biopsy stained with Congo red demonstrating amyloid deposits with apple-green birefringence is required for diagnosis. Invasive organ biopsy is not required in 85% of patients. Verification that amyloid is composed of immunoglobulin light chains is mandatory. The gold standard is laser capture mass spectroscopy. PROGNOSIS N-terminal pro-brain natriuretic peptide (NT-proBNP), serum troponin T, and difference between involved and uninvolved immunoglobulin free light chain (FLC) values are used to classify patients into four groups of similar size; median survivals are 94.1, 40.3, 14.0, and 5.8 months. THERAPY All patients with a systemic amyloid syndrome require therapy to prevent deposition of amyloid in other organs and prevent progressive organ failure. Stem cell transplant (SCT) is preferred, but only 20% of patients are eligible. Requirements for safe SCT include systolic blood pressure >90 mmHg, troponin T < 0.06 ng/mL and serum creatinine ≤1.7 mg/dL. Nontransplant candidates can be offered cyclophosphamide-bortezomib-dexamethasone or daratumumab-containing regimens as it appears to be highly active in AL amyloidosis. FUTURE CHALLENGES Delayed diagnosis remains a major obstacle to initiating effective therapy prior to the development of end-stage organ failure.
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Affiliation(s)
- Morie A. Gertz
- Division of HematologyMayo Clinic Rochester Minnesota USA
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9
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Parrondo RD, Majeed U, Sher T. Antibody-based immunotherapy for treatment of immunoglobulin light-chain amyloidosis. Br J Haematol 2020; 191:673-681. [PMID: 32298469 DOI: 10.1111/bjh.16697] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 04/05/2020] [Accepted: 04/07/2020] [Indexed: 12/19/2022]
Abstract
Immunoglobulin light-chain (AL) amyloidosis is a clonal plasma cell disorder characterised by production and deposition of misfolded monoclonal light chains in vital organs with potential to cause irreversible organ damage. The treatment of AL amyloidosis has evolved along the lines of multiple myeloma (MM) owing to clonal plasma cells being at the root of both disease processes. Treatment with melphalan and autologous haematopoietic cell transplantation, as well as proteasome inhibitors and immunomodulatory agents, are the standard of care for AL amyloidosis. While these treatment modalities are highly effective against the neoplastic plasma cells, patients often relapse and those with advanced disease may be unable to tolerate these treatments due to side-effects. Immunotherapy with monoclonal antibodies, bispecific antibodies, antibody-drug conjugates and chimeric antigen receptor T cells have revolutionised the treatment armamentarium for MM. These novel immunotherapy agents are in the early phases of evaluation and clinical development for patients with AL amyloidosis. The present review aims to discuss the role of novel immunotherapies currently in development and their potential for use in the treatment of AL amyloidosis.
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Affiliation(s)
- Ricardo D Parrondo
- Department of Medicine, Hematology-Oncology, Mayo Clinic Florida, Jacksonville, FL, USA
| | - Umair Majeed
- Department of Medicine, Hematology-Oncology, Mayo Clinic Florida, Jacksonville, FL, USA
| | - Taimur Sher
- Department of Medicine, Hematology-Oncology, Mayo Clinic Florida, Jacksonville, FL, USA
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Lin X, Galaqin N, Tainaka R, Shimamori K, Kuragano M, Noguchi TQP, Tokuraku K. Real-Time 3D Imaging and Inhibition Analysis of Various Amyloid Aggregations Using Quantum Dots. Int J Mol Sci 2020; 21:E1978. [PMID: 32183170 PMCID: PMC7139405 DOI: 10.3390/ijms21061978] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 03/01/2020] [Accepted: 03/11/2020] [Indexed: 02/07/2023] Open
Abstract
Amyloidosis refers to aggregates of protein that accumulate and are deposited as amyloid fibrils into plaques. When these are detected in organs, they are the main hallmark of Alzheimer's disease, Parkinson's disease, and other related diseases. Recent medical advances have shown that many precursors and proteins can induce amyloidosis even though the mechanism of amyloid aggregation and the relationship of these proteins to amyloidosis remains mostly unclear. In this study, we report the real-time 3D-imaging and inhibition analysis of amyloid β (Aβ), tau, and α-synuclein aggregation utilizing the affinity between quantum dots (QD) and amyloid aggregates. We successfully visualized these amyloid aggregations in real-time using fluorescence microscopy and confocal microscopy simply by adding commercially available QD. The observation by transmission electron microscopy (TEM) showed that QD particles bound to all amyloid fibrils. The 3D-imaging with QD revealed differences between amyloid aggregates composed of different amyloid peptides that could not be detected by TEM. We were also able to quantify the inhibition activities of these proteins by rosmarinic acid, which has high activity for Aβ aggregation, from fluorescence micrographs as half-maximal effective concentrations. These imaging techniques with QD serve as quick, easy, and powerful tools to understand amyloidosis and to discover drugs for therapies.
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Affiliation(s)
- Xuguang Lin
- Department of Applied Science and Engineering, Muroran Institute of Technology, Muroran 050-8585, Japan; (X.L.); (N.G.); (R.T.); (K.S.); (M.K.)
| | - Nuomin Galaqin
- Department of Applied Science and Engineering, Muroran Institute of Technology, Muroran 050-8585, Japan; (X.L.); (N.G.); (R.T.); (K.S.); (M.K.)
| | - Reina Tainaka
- Department of Applied Science and Engineering, Muroran Institute of Technology, Muroran 050-8585, Japan; (X.L.); (N.G.); (R.T.); (K.S.); (M.K.)
| | - Keiya Shimamori
- Department of Applied Science and Engineering, Muroran Institute of Technology, Muroran 050-8585, Japan; (X.L.); (N.G.); (R.T.); (K.S.); (M.K.)
| | - Masahiro Kuragano
- Department of Applied Science and Engineering, Muroran Institute of Technology, Muroran 050-8585, Japan; (X.L.); (N.G.); (R.T.); (K.S.); (M.K.)
| | - Taro Q. P. Noguchi
- Department of Chemical Science and Engineering, National Institute of Technology, Miyakonojo College, Miyakonojo 885-8567, Japan;
| | - Kiyotaka Tokuraku
- Department of Applied Science and Engineering, Muroran Institute of Technology, Muroran 050-8585, Japan; (X.L.); (N.G.); (R.T.); (K.S.); (M.K.)
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Mair M, Straka C, Buratti T, Tauber M, Mitterer M, Fong D. Clinical outcomes and prognostic factors in patients with multiple myeloma in South Tyrol: a retrospective single-center analysis. Ann Hematol 2020; 99:1031-1040. [PMID: 32140891 DOI: 10.1007/s00277-020-03969-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Accepted: 02/18/2020] [Indexed: 12/13/2022]
Abstract
High-dose chemotherapy followed by autologous stem cell transplantation (HD-ASCT) as well as the introduction of novel agents (NA) significantly improved survival for patients with multiple myeloma (MM). A total of 150 unselected newly diagnosed MM patients treated at our institution from 1998 to 2017 were retrospectively analyzed. Median age at diagnosis was 69 years (range 33-93 years) with a median follow-up of 48.6 months. The median overall survival (OS) for the entire cohort was 60.7 months (range 0.3-280.1). Patients who received frontline HD-ASCT (p < 0.01) or NA-based first-line treatment (p = 0.043) had a significantly better OS. According to the revised Myeloma Comorbidity Index (R-MCI), patients were defined as fit (36.5%), intermediate-fit (44.5%), or frail (19%) with a significant difference in OS between these categories (p < 0.01). Multivariate analysis revealed R-MCI as an independent prognostic factor for OS (p < 0.01). Presence of subclinical amyloid deposits (A+) was detected in 18 out of 66 patients (27.3%) and significantly correlated with a serum free light chain (sFLC) ratio ≥ 100 (p = 0.01) and bone marrow plasma cell infiltration > 60% (p = 0.04). Furthermore, patients with A+ had significantly worse OS compared with their counterparts (p = 0.048). Our results corroborate the efficacy of both early HD-ASCT and the use of new agents as initial therapy of MM patients in "real-world" daily clinical practice. The R-MCI is an easily applicable tool to stratify MM patients and may support treatment decisions. The prognostic value of subclinical amyloid deposition should be validated within prospective studies.
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Affiliation(s)
- Maximilian Mair
- Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria
| | - Christian Straka
- Hematology, Oncology and Infectiology, Munich Schwabing Hospital, Munich, Germany
| | - Thomas Buratti
- Department of Oncology and Hematology, Franz Tappeiner Hospital, Merano, Italy
| | - Martina Tauber
- Department of Pathology, Bolzano Regional Hospital, Bolzano, Italy
| | - Manfred Mitterer
- Department of Oncology and Hematology, Franz Tappeiner Hospital, Merano, Italy
| | - Dominic Fong
- Department of Oncology and Hematology, Franz Tappeiner Hospital, Merano, Italy.
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12
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Singh S. Amyloidosis presenting as a solitary nasal mass. INDIAN JOURNAL OF MEDICAL SPECIALITIES 2020. [DOI: 10.4103/injms.injms_82_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
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13
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Giannini G, Nast CC. An Organ System-Based Approach to Differential Diagnosis of Amyloid Type in Surgical Pathology. Arch Pathol Lab Med 2019; 144:379-387. [PMID: 31697170 DOI: 10.5858/arpa.2018-0509-ra] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT.— Amyloidosis is an uncommon but important entity. A protein-based classification of amyloidosis defines the underlying disease process, directing clinical management and providing prognostic information. However, in routine surgical pathology there often is no attempt to classify amyloid other than staining to determine light chain-associated amyloidosis. Systemic and localized amyloidosis vary with respect to frequency of organ involvement by different amyloid types, and most amyloid proteins have commercial antibodies available for identification. OBJECTIVE.— To provide a guide for the likelihood of amyloid type by organ system. DATA SOURCES.— Literature review based on PubMed searches containing the word amyloid, specifically addressing the prevalence and significance of amyloid proteins in each organ system other than the brain, and the authors' practice experience. CONCLUSIONS.— In patients with amyloidosis, determination of the responsible protein is critical for appropriate patient care. In large subspecialty practices and reference laboratories with experience in using and analyzing relevant immunohistochemistry, most amyloid proteins can be identified with an organ-specific algorithm. Referring to an organ-based algorithm may be helpful in providing clinicians with a more specific differential diagnosis regarding amyloid type to help guide clinical evaluation and treatment. When the protein cannot be characterized, mass spectrometry can be performed to definitively classify the amyloid type.
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Affiliation(s)
- Gabriel Giannini
- From the Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California
| | - Cynthia C Nast
- From the Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California
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Ablasser K, Verheyen N, Glantschnig T, Agnetti G, Rainer PP. Unfolding Cardiac Amyloidosis –From Pathophysiology to Cure. Curr Med Chem 2019; 26:2865-2878. [DOI: 10.2174/0929867325666180104153338] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Revised: 12/04/2017] [Accepted: 12/06/2017] [Indexed: 12/13/2022]
Abstract
Deposition of amyloidogenic proteins leading to the formation of amyloid fibrils in the myocardium causes cardiac amyloidosis. Although any form of systemic amyloidosis can affect the heart, light-chain (AL) or transthyretin amyloidosis (ATTR) account for the majority of diagnosed cardiac amyloid deposition. The extent of cardiac disease independently predicts mortality. Thus, the reversal of arrest of adverse cardiac remodeling is the target of current therapies. Here, we provide a condensed overview on the pathophysiology of AL and ATTR cardiac amyloidoses and describe treatments that are currently used or investigated in clinical or preclinical trials. We also briefly discuss acquired amyloid deposition in cardiovascular disease other than AL or ATTR.
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Affiliation(s)
- Klemens Ablasser
- Division of Cardiology, Medical University of Graz, Graz, Austria
| | - Nicolas Verheyen
- Division of Cardiology, Medical University of Graz, Graz, Austria
| | | | - Giulio Agnetti
- Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD, United States
| | - Peter P. Rainer
- Division of Cardiology, Medical University of Graz, Graz, Austria
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15
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Vaxman I, Gertz M. Recent Advances in the Diagnosis, Risk Stratification, and Management of Systemic Light-Chain Amyloidosis. Acta Haematol 2019; 141:93-106. [PMID: 30650422 DOI: 10.1159/000495455] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Accepted: 11/15/2018] [Indexed: 12/19/2022]
Abstract
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.
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Affiliation(s)
- Iuliana Vaxman
- Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA
- Institute of Hematology, Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Morie Gertz
- Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA,
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Gertz MA. Immunoglobulin light chain amyloidosis: 2018 Update on diagnosis, prognosis, and treatment. Am J Hematol 2018; 93:1169-1180. [PMID: 30040145 DOI: 10.1002/ajh.25149] [Citation(s) in RCA: 87] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Revised: 05/11/2018] [Accepted: 05/11/2018] [Indexed: 11/10/2022]
Abstract
DISEASE OVERVIEW Immunoglobulin light chain amyloidosis is a clonal, nonproliferative plasma cell disorder in which fragments of immunoglobulin light or heavy chain are deposited in tissues. Clinical features depend on organs involved but can include restrictive cardiomyopathy, nephrotic syndrome, hepatic dysfunction, peripheral/autonomic neuropathy, and "atypical multiple myeloma." DIAGNOSIS Tissue biopsy stained with Congo red demonstrating amyloid deposits with apple-green birefringence is required for diagnosis. Invasive organ biopsy is not required because amyloid deposits can be found in bone marrow, salivary gland, or subcutaneous fat aspirate in 85% of patients. Verification that amyloid is composed of immunoglobulin light chains is mandatory. The gold standard is laser capture mass spectroscopy. PROGNOSIS N-terminal pro-brain natriuretic peptide (NT-proBNP), serum troponin T, and difference between involved and uninvolved immunoglobulin free light chain values are used to classify patients into four groups of similar size; median survivals are 94.1, 40.3, 14.0, and 5.8 months. THERAPY All patients with a systemic amyloid syndrome require therapy to prevent deposition of amyloid in other organs and prevent progressive organ failure. Stem cell transplant (SCT) is preferred, but only 20% of patients are eligible. Requirements for safe SCT include systolic blood pressure >90 mm Hg, troponin T < 0.06 ng/mL, age < 70 years, and serum creatinine ≤1.7 mg/dL. Nontransplant candidates can be offered melphalan-dexamethasone or cyclophosphamide-bortezomib-dexamethasone. Daratumumab appears to be highly active in AL amyloidosis. Antibodies designed to dissolve existing amyloid deposits are under study. FUTURE CHALLENGES Delayed diagnosis remains a major obstacle to initiating effective therapy. EDUCATIONAL OBJECTIVES Upon completion of this educational activity, participants will be better able to: Master recognition of clinical presentations that should raise suspicion of amyloidosis. Understand simple techniques for confirming the diagnosis and providing material to classify the protein subunit. Recognize that a tissue diagnosis of amyloidosis does not indicate whether the amyloid is systemic or of immunoglobulin light chain origin. Understand the roles of the newly introduced chemotherapeutic and investigational antibody regimens for the therapy of light chain amyloidosis.
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Affiliation(s)
- Morie A. Gertz
- Division of Hematology; Mayo Clinic; Rochester Minnesota
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Warsame R, Kumar SK, Gertz MA, Lacy MQ, Buadi FK, Hayman SR, Leung N, Dingli D, Lust JA, Lin Y, Russell S, Kapoor P, Go RS, Kourelis T, Gonsalves W, Zeldenrust SR, Kyle RA, Vincent Rajkumar S, Zemla T, Sloan J, Dispenzieri A. Hematology patient reported symptom screen to assess quality of life for AL amyloidosis. Am J Hematol 2017; 92:435-440. [PMID: 28181278 DOI: 10.1002/ajh.24676] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Revised: 01/27/2017] [Accepted: 02/03/2017] [Indexed: 11/07/2022]
Abstract
Patients with light chain amyloidosis (AL) often have delayed diagnosis and present with significant symptomatology; this may result in decreased quality of life (QOL). We prospectively employ a "Hematology Patient Reported Symptom Screen" (HPRSS), which is three questions about fatigue, pain, and QOL, scored 0-10. The aim of this study is to better understand QOL and determine if HPRSS parameters predict for clinical outcomes. From 2009 to 2014, 302 newly diagnosed AL patients were included. Baseline median scores [interquartile range] for fatigue, pain, and QOL were 6 [3,7], 2 [0,5], 5 [3,8], respectively. Median overall survival was 53 months, with 102 (34%) deaths in the first year. There were significant differences in baseline HPRSS between those that lived longer than one year and early death patients in the domains of fatigue (5 [IQR 3, 7] vs. 7 [IQR 5, 8], P < 0.0001) and QOL (6 [IQR 4, 8] vs. 5 [IQR 3, 7], P = 0.006). On univariate analysis fatigue, QOL, physician-reported performance status, autologous stem cell transplant (ASCT), and Mayo stage were prognostic for survival. On multivariate analysis Mayo stage, ASCT, and baseline fatigue remained independently prognostic. When analyses were restricted to the 125 patients with HPRSS measurements at 12 months, we found that over time QOL scores improved significantly 6 [IQR 3.5, 8] → 7 [IQR 5, 8] (P = 0.01). Asking AL patients to rate their fatigue and QOL has predictive value. Baseline patient reported fatigue is an independent prognostic factor for survival. Survival at one year was associated with significant improvement in QOL.
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Affiliation(s)
- Rahma Warsame
- Division of HematologyMayo ClinicRochester Minnesota USA
| | - Shaji K. Kumar
- Division of HematologyMayo ClinicRochester Minnesota USA
| | - Morie A. Gertz
- Division of HematologyMayo ClinicRochester Minnesota USA
| | - Martha Q. Lacy
- Division of HematologyMayo ClinicRochester Minnesota USA
| | | | | | - Nelson Leung
- Division of HematologyMayo ClinicRochester Minnesota USA
| | - David Dingli
- Division of HematologyMayo ClinicRochester Minnesota USA
| | - John A. Lust
- Division of HematologyMayo ClinicRochester Minnesota USA
| | - Yi Lin
- Division of HematologyMayo ClinicRochester Minnesota USA
| | | | | | - Ronald S. Go
- Division of HematologyMayo ClinicRochester Minnesota USA
| | | | | | | | - Robert A. Kyle
- Division of HematologyMayo ClinicRochester Minnesota USA
| | | | - Tyler Zemla
- Department of BiostatisticsMayo ClinicRochester Minnesota USA
| | - Jeffrey Sloan
- Department of BiostatisticsMayo ClinicRochester Minnesota USA
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18
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Jelinek T, Kryukova E, Kufova Z, Kryukov F, Hajek R. Proteasome inhibitors in AL amyloidosis: focus on mechanism of action and clinical activity. Hematol Oncol 2016; 35:408-419. [PMID: 27647123 DOI: 10.1002/hon.2351] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2016] [Revised: 08/08/2016] [Accepted: 08/10/2016] [Indexed: 11/11/2022]
Abstract
Proteasome inhibitors are the backbone in the treatment of multiple myeloma with 3 of its representatives (bortezomib, carfilzomib, and ixazomib) having already been approved. There is a different situation altogether in the treatment of amyloid light chain (AL) amyloidosis where owing to the rarity of this entity neither of these drugs has currently gained approval. Amyloid light chain plasma cells are possibly more vulnerable to bortezomib than myeloma plasmocytes because of a slightly distinct mechanism of action, which is described in depth in this manuscript. Bortezomib is highly active and rapidly effective as a single agent and even more potent in combination with dexamethasone and alkylators. Bortezomib-based regimens have become a standard part of the initial treatment of AL amyloidosis in the majority of centers. We have reviewed all available data on bortezomib in various combinations and settings. Carfilzomib seems to be effective but also toxic in these fragile patients with a high rate of cardiac events. Oral ixazomib has shown a surprisingly high efficacy with manageable toxicity and has received the Food and Drug Administration Breakthrough Therapy designation in 2014 for relapsed AL amyloidosis patients. In this review we have comprehensively described the current available knowledge of these 3 proteasome inhibitors and their use in AL amyloidosis.
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Affiliation(s)
- T Jelinek
- Department of Haematooncology, University Hospital Ostrava, Ostrava, Czech Republic.,Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
| | - E Kryukova
- Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
| | - Z Kufova
- Department of Haematooncology, University Hospital Ostrava, Ostrava, Czech Republic.,Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
| | - F Kryukov
- Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
| | - R Hajek
- Department of Haematooncology, University Hospital Ostrava, Ostrava, Czech Republic.,Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
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19
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Gertz MA. Immunoglobulin light chain amyloidosis: 2016 update on diagnosis, prognosis, and treatment. Am J Hematol 2016; 91:947-56. [PMID: 27527836 DOI: 10.1002/ajh.24433] [Citation(s) in RCA: 90] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2016] [Accepted: 05/22/2016] [Indexed: 02/01/2023]
Abstract
DISEASE OVERVIEW Immunoglobulin light chain amyloidosis is a clonal, nonproliferative plasma cell disorder in which fragments of immunoglobulin light chain are deposited in tissues. Clinical features depend on organs involved but can include restrictive cardiomyopathy, nephrotic syndrome, hepatic failure, peripheral/autonomic neuropathy, and atypical multiple myeloma. DIAGNOSIS Tissue biopsy stained with Congo red demonstrating amyloid deposits with applegreen birefringence is required for diagnosis. Invasive organ biopsy is not required because amyloid deposits can be found in bone marrow biopsy or subcutaneous fat aspirate in 85% of patients. Verification that amyloid is composed of immunoglobulin light chains is mandatory. PROGNOSIS N-terminal pro-brain natriuretic peptide (NTproBNP), serum troponin T, and difference between involved and uninvolved immunoglobulin free light chain values are used to classify patients into four groups of similar size; median survivals are 94.1, 40.3, 14.0, and 5.8 months. THERAPY All patients with a systemic amyloid syndrome require therapy to prevent deposition of amyloid in other organs and prevent progressive organ failure of involved sites. Stem cell transplant (SCT) is preferred, but only 20% of patients are eligible. Requirements for safe SCT include systolic blood pressure >90 mmHg, troponin T <0.06 ng mL21, age <70 years, and serum creatinine 1.7 mg dL21. Nontransplant candidates can be offered melphalan-dexamethasone or cyclophosphamide-bortezomib-dexamethasone. Other combinations of chemotherapy with agents such as cyclophosphamide-thalidomide (or lenalidomide)-dexamethasone, bortezomib-dexamethasone, and melphalan-prednisone-lenalidomide have documented activity. Antibodies designed to dissolve existing amyloid deposits are under study for previously treated and untreated patients. Late diagnosis remains a major obstacle to initiating effective therapy. Am. J. Hematol., 2016. © 2016 Wiley Periodicals, Inc. Am. J. Hematol. 91:948-956, 2016. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Morie A. Gertz
- Division of Hematology; Mayo Clinic; Rochester Minnesota
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20
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Zhang J, Shao C, Zhu J, Tu C, Lv X. Abdominal distension and diarrhea as the main symptoms of primary amyloidosis: A case report and literature review. Exp Ther Med 2016; 11:1809-1811. [PMID: 27168808 DOI: 10.3892/etm.2016.3093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Accepted: 10/29/2015] [Indexed: 11/06/2022] Open
Abstract
Amyloidosis is a systemic disease caused by the accumulation of extracellular protein into amyloid deposits. Due to the involvement of a variety of organs and tissues, the disease has no specific clinical features and a high rate of misdiagnosis. The present study describes one case of primary amyloidosis, as confirmed by biopsies of rectal and renal tissues using Congo red staining, demonstrating that abdominal distension and diarrhea were the main symptoms of disease. The current case is also discussed within the context of a review of the associated literature.
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Affiliation(s)
- Jian Zhang
- Department of Hepatopancreatobiliary Surgery, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, P.R. China
| | - Chuxiao Shao
- Department of Hepatopancreatobiliary Surgery, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, P.R. China
| | - Jinde Zhu
- Department of Hepatopancreatobiliary Surgery, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, P.R. China
| | - Chaoyong Tu
- Department of Hepatopancreatobiliary Surgery, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, P.R. China
| | - Xinliang Lv
- Department of Hepatopancreatobiliary Surgery, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, P.R. China
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21
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Muchtar E, Buadi FK, Dispenzieri A, Gertz MA. Immunoglobulin Light-Chain Amyloidosis: From Basics to New Developments in Diagnosis, Prognosis and Therapy. Acta Haematol 2016; 135:172-90. [PMID: 26771835 DOI: 10.1159/000443200] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Accepted: 12/03/2015] [Indexed: 11/19/2022]
Abstract
Immunoglobulin amyloid light-chain (AL) amyloidosis is the most common form of systemic amyloidosis, where the culprit amyloidogenic protein is immunoglobulin light chains produced by marrow clonal plasma cells. AL amyloidosis is an infrequent disease, and since presentation is variable and often nonspecific, diagnosis is often delayed. This results in cumulative organ damage and has a negative prognostic effect. AL amyloidosis can also be challenging on the diagnostic level, especially when demonstration of Congo red-positive tissue is not readily obtained. Since as many as 31 known amyloidogenic proteins have been identified to date, determination of the amyloid type is required. While several typing methods are available, mass spectrometry has become the gold standard for amyloid typing. Upon confirming the diagnosis of amyloidosis, a pursuit for organ involvement is essential, with a focus on heart involvement, even in the absence of suggestive symptoms for involvement, as this has both prognostic and treatment implications. Details regarding initial treatment options, including stem cell transplantation, are provided in this review. AL amyloidosis management requires a multidisciplinary approach with careful patient monitoring, as organ impairment has a major effect on morbidity and treatment tolerability until a response to treatment is achieved and recovery emerges.
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Affiliation(s)
- Eli Muchtar
- Division of Hematology, Mayo Clinic, Rochester, Minn., USA
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Jelinek T, Kufova Z, Hajek R. Immunomodulatory drugs in AL amyloidosis. Crit Rev Oncol Hematol 2016; 99:249-60. [PMID: 26806146 DOI: 10.1016/j.critrevonc.2016.01.004] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2014] [Revised: 11/20/2015] [Accepted: 01/12/2016] [Indexed: 01/20/2023] Open
Abstract
Immunoglobulin light chain amyloidosis (AL amyloidosis) is indeed a rare plasma cell disorder, yet the most common of the systemic amyloidoses. The choice of adequate treatment modality is complicated and depends dominantly on the risk stratification of these fragile patients. Immunomodulatory drugs (IMiDs) are currently used in newly diagnosed patients as well as in salvage therapy in relapsed/refractory patients. IMiDs have a pleiotropic effect on malignant cells and the exact mechanism of their action has been described recently. Thalidomide is the most ancient representative, effective but toxic. Lenalidomide seems to be more effective, nevertheless the toxicity remains high, especially in patients with renal insufficiency. Pomalidomide is the newest IMiD used in this indication with a good balance between efficacy and tolerable toxicity and represents the most promising compound. This review is focused on the evaluation of all three representatives of IMiDs and their roles in the treatment of this malignant disorder.
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Affiliation(s)
- T Jelinek
- Department of Haematooncology, University Hospital Ostrava, Ostrava, Czech Republic; Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic.
| | - Z Kufova
- Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
| | - R Hajek
- Department of Haematooncology, University Hospital Ostrava, Ostrava, Czech Republic; Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic.
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23
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Mikhaleva LM, Gioeva ZV, Rёken K. [Histological and immunohistochemical examinations in the diagnosis of hepatic amyloidosis]. Arkh Patol 2015; 77:11-16. [PMID: 26485775 DOI: 10.17116/patol201577411-16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
OBJECTIVE to investigate the histopathology of amyloid in liver biopsy specimens. MATERIAL AND METHODS. A total of 46 liver biopsy specimens were investigated in patients with histologically verified amyloidosis in 2006 to 2009 from the Amyloid Registry of the Charité University Hospital (Berlin). The liver biopsy specimens were fixed in formalin and embedded in paraffin. The paraffin sections were stained with hematoxylin and eosin and with Congo red. Amyloid was immunohistochemically classified using antibodies against amyloid P component, AA amyloid, apolipoprotein Al, lysozyme, fibrinogen, transthyretin, and κ and λ light chains. RESULTS Amyloid deposits were diagnosed in the 46 liver biopsy specimens from 17 women and 29 men (mean age 60 years). Immunohistochemical subtyping was successful in 91% of the cases. AL amyloidosis was diagnosed in 87% of the biopsy specimens and further classified as AL lambda-light chain amyloidosis (57%) and AL kappa-light chain amyloidosis (30%). The 46 liver biopsy specimens showed one case of AA amyloidosis (2%) and one case of transthyretin amyloidosis (2%). The type of amyloid could not be classified in 9% of the biopsy specimens. CONCLUSION The investigation revealed that the most common types of hepatic amyloidosis are AL lambda- and AL kappa-light chain amyloidosis associated with the signs of parenchymal atrophy and steatosis.
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Affiliation(s)
- L M Mikhaleva
- Research Institute of Human Morphology, Moscow, Russia
| | - Z V Gioeva
- Research Institute of Human Morphology, Moscow, Russia
| | - K Rёken
- Institute of Pathology, Christian Albrecht University, Kiel, Germany
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24
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Gertz MA. Immunoglobulin light chain amyloidosis: 2014 update on diagnosis, prognosis, and treatment. Am J Hematol 2014; 89:1132-40. [PMID: 25407896 DOI: 10.1002/ajh.23828] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2014] [Accepted: 08/08/2014] [Indexed: 11/07/2022]
Abstract
DISEASE OVERVIEW Immunoglobulin light chain amyloidosis is a clonal, nonproliferative plasma cell disorder in which fragments of immunoglobulin light chain are deposited in tissues. Clinical features depend on organs involved but can include restrictive cardiomyopathy, nephrotic syndrome, hepatic failure, peripheral/autonomic neuropathy, and atypical multiple myeloma. DIAGNOSIS Tissue biopsy stained with Congo red demonstrating amyloid deposits with apple-green birefringence is required for diagnosis. Invasive organ biopsy is not required because amyloid deposits can be found in bone marrow biopsy or subcutaneous fat aspirate in 85% of patients. Verification that amyloid is composed of immunoglobulin light chains is mandatory. PROGNOSIS N-terminal pro-brain natriuretic peptide (NT-proBNP), serum troponin T, and difference between involved and uninvolved immunoglobulin free light chain values are used to classify patients into four groups of similar size; median survivals are 94.1, 40.3, 14.0, and 5.8 months. THERAPY All patients with a systemic amyloid syndrome require therapy to prevent deposition of amyloid in other organs and prevent progressive organ failure of involved sites. Stem cell transplant (SCT) is preferred, but only 20% of patients are eligible. Requirements for safe SCT include NT-proBNP <5,000 ng/mL, troponin T <0.06 ng/mL, age <70 years, <3 organs involved, and serum creatinine ≤1.7 mg/dL. Nontransplant candidates can be offered melphalan-dexamethasone or cyclophosphamide-bortezomib-dexamethasone. Other combinations of chemotherapy with agents such as cyclophosphamide-thalidomide (or lenalidomide)-dexamethasone, bortezomib-dexamethasone, and melphalan-prednisone-lenalidomide have documented activity. Future Challenges: Late diagnosis remains a major obstacle to initiating effective therapy. Recognizing the presenting syndromes is necessary for improving survival.
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Affiliation(s)
- Morie A Gertz
- Division of Hematology, Mayo Clinic, Rochester, Minnesota
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25
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Ericson S, Shah N, Liberman J, Aboulafia DM. Fatal Bleeding Due to Acquired Factor IX and X Deficiency: A Rare Complication of Primary Amyloidosis; Case Report and Review of the Literature. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2014; 14:e81-6. [DOI: 10.1016/j.clml.2013.08.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/03/2013] [Accepted: 08/28/2013] [Indexed: 11/15/2022]
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Abstract
Amyloidosis often involves the gastrointestinal tract. The small intestine is the most commonly involved gastrointestinal site. Gastrointestinal manifestations of amyloidosis involvement of the small intestine include diarrhea, gastrointestinal bleeding, and obstruction. High index of suspicion leading to early diagnosis is important in tailoring appropriate therapeutic management of these patients.
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Abstract
Serum amyloid A (SAA) represents an evolutionarily conserved family of inflammatory acute-phase proteins. It is also a major constituent of secondary amyloidosis. To understand its function and structural transition to amyloid, we determined a structure of human SAA1.1 in two crystal forms, representing a prototypic member of the family. Native SAA1.1 exists as a hexamer, with subunits displaying a unique four-helix bundle fold stabilized by its long C-terminal tail. Structure-based mutational studies revealed two positive-charge clusters, near the center and apex of the hexamer, that are involved in SAA association with heparin. The binding of high-density lipoprotein involves only the apex region of SAA and can be inhibited by heparin. Peptide amyloid formation assays identified the N-terminal helices 1 and 3 as amyloidogenic peptides of SAA1.1. Both peptides are secluded in the hexameric structure of SAA1.1, suggesting that the native SAA is nonpathogenic. Furthermore, dissociation of the SAA hexamer appears insufficient to initiate amyloidogenic transition, and proteolytic cleavage or removal of the C-terminal tail of SAA resulted in formation of various-sized structural aggregates containing ∼5-nm regular repeating protofibril-like units. The combined structural and functional studies provide mechanistic insights into the pathogenic contribution of glycosaminoglycan in SAA1.1-mediated AA amyloid formation.
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28
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Warsame R, Bang SM, Kumar SK, Gertz MA, Lacy MQ, Buadi F, Dingli D, Hayman SR, Kapoor P, Kyle RA, Leung N, Lust JA, Russell SJ, Witzig TE, Zeldenrust SR, Rajkumar SV, Dispenzieri A. Outcomes and treatments of patients with immunoglobulin light chain amyloidosis who progress or relapse postautologous stem cell transplant. Eur J Haematol 2014; 92:485-90. [DOI: 10.1111/ejh.12282] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/28/2014] [Indexed: 11/28/2022]
Affiliation(s)
- Rahma Warsame
- Division of Hematology and Internal Medicine; Mayo Clinic; Rochester MN USA
| | - Soo Mee Bang
- Division of Hematology; Seoul National Hospital; Seoul Korea
| | - Shaji K. Kumar
- Division of Hematology and Internal Medicine; Mayo Clinic; Rochester MN USA
| | - Morie A. Gertz
- Division of Hematology and Internal Medicine; Mayo Clinic; Rochester MN USA
| | - Martha Q. Lacy
- Division of Hematology and Internal Medicine; Mayo Clinic; Rochester MN USA
| | - Francis Buadi
- Division of Hematology and Internal Medicine; Mayo Clinic; Rochester MN USA
| | - David Dingli
- Division of Hematology and Internal Medicine; Mayo Clinic; Rochester MN USA
| | - Suzanne R. Hayman
- Division of Hematology and Internal Medicine; Mayo Clinic; Rochester MN USA
| | - Prashant Kapoor
- Division of Hematology and Internal Medicine; Mayo Clinic; Rochester MN USA
| | - Robert A. Kyle
- Division of Hematology and Internal Medicine; Mayo Clinic; Rochester MN USA
| | - Nelson Leung
- Division of Hematology and Internal Medicine; Mayo Clinic; Rochester MN USA
| | - John A. Lust
- Division of Hematology and Internal Medicine; Mayo Clinic; Rochester MN USA
| | - Stephen J. Russell
- Division of Hematology and Internal Medicine; Mayo Clinic; Rochester MN USA
| | - Thomas E. Witzig
- Division of Hematology and Internal Medicine; Mayo Clinic; Rochester MN USA
| | | | | | - Angela Dispenzieri
- Division of Hematology and Internal Medicine; Mayo Clinic; Rochester MN USA
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29
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Sachchithanantham S, Wechalekar AD, Hawkins PN. An evaluation of current treatment options for immunoglobulin light-chain amyloidosis. Expert Opin Orphan Drugs 2014. [DOI: 10.1517/21678707.2014.881285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Primary systemic Al amyloidosis presenting as temporal arteritis. Case Rep Rheumatol 2014; 2014:549641. [PMID: 24551471 PMCID: PMC3914325 DOI: 10.1155/2014/549641] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2013] [Accepted: 09/15/2013] [Indexed: 11/17/2022] Open
Abstract
Temporal arteritis is most common vasculitis in elderly and imitated by miscellaneous disorders. Temporal artery biopsy is the gold standard test in the diagnosis of giant cell arteritis (GCA). Hereby, we describe a case of a 67-year-old man who presented initially with temporal arteritis; however, a lip biopsy then revealed AL amyloidosis. In this respect, temporal artery biopsy should be performed for definitive diagnosis of GCA particularly patients with systemic symptoms and treatment resistant.
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31
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Son SM, Lee YM, Kim SW, Lee OJ. Localized thymic amyloidosis presenting with myasthenia gravis: case report. J Korean Med Sci 2014; 29:145-8. [PMID: 24431920 PMCID: PMC3890467 DOI: 10.3346/jkms.2014.29.1.145] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2013] [Accepted: 07/08/2013] [Indexed: 01/08/2023] Open
Abstract
A mediastinal mass was incidentally found on chest radiography in a 46-yr-old woman who had had myasthenia gravis (MG) for 2 months. Computed tomography revealed a 4-cm in size, well-defined, and lobulating mass with nodular calcification that was located in the thymus. Microscopically, the mass consisted of diffuse amorphous eosinophilic materials. These deposits exhibited apple-green birefringence under polarized light microscopy after Congo red staining. Immunohistochemical analysis revealed that they were positive for both kappa and lambda light chains and negative for amyloid A. A diagnosis of localized primary thymic amyloidosis was finally made. After thymectomy, the symptoms of MG were controlled with reduced corticosteroid requirements. Localized thymic amyloidosis associated with MG has not been reported to date.
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Affiliation(s)
- Seung-Myoung Son
- Department of Pathology, Chungbuk National University College of Medicine, Cheongju, Korea
| | - Yong-Moon Lee
- Department of Pathology, Chungbuk National University College of Medicine, Cheongju, Korea
| | - Si Wook Kim
- Department of Thoracic and Cardiovascular Surgery, Chungbuk National University College of Medicine, Cheongju, Korea
| | - Ok-Jun Lee
- Department of Pathology, Chungbuk National University College of Medicine, Cheongju, Korea
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32
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Kim GH, Lee WK, Na SH, Lee JS. Undiagnosed light chain systemic amyloidosis: does it matter to anesthesiologists? -a case report-. Korean J Anesthesiol 2013; 65:453-5. [PMID: 24363850 PMCID: PMC3866343 DOI: 10.4097/kjae.2013.65.5.453] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2012] [Revised: 09/17/2012] [Accepted: 10/10/2012] [Indexed: 11/10/2022] Open
Abstract
Light chain systemic amyloidosis is rare but may accompany laryngeal or pulmonary involvement, which may increase the risk in airway management. We present a case of a patient planned for resection of cervical epidural mass. The patient had face and neck ecchymoses and purpuras with an unknown cause. Mask ventilation and intubation were successful, but the operation was cancelled to evaluate bleeding from facial skin lesions. A diagnosis of light chain systemic amyloidosis prompted evaluation of involvement of other organs and treatment. This case shows the importance of preoperative evaluation and careful airway management in patients with systemic amyloidosis.
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Affiliation(s)
- Gwan Ho Kim
- Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Woo Kyung Lee
- Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Se Hee Na
- Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Jong Seok Lee
- Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, Seoul, Korea. ; Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Korea
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33
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Gaduputi V, Badipatla K, Patel H, Tariq H, Ihimoyan A. Primary systemic amyloidosis with extensive gastrointestinal involvement. Case Rep Gastroenterol 2013; 7:511-5. [PMID: 24474901 PMCID: PMC3901606 DOI: 10.1159/000357589] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
We report this case of a 42-year-old woman who presented with a debilitating illness manifested by intractable nausea, vomiting, diarrhea and unchecked weight loss. The patient had multisystem involvement that presented as anemia, abnormal liver function tests and progressively deteriorating renal function necessitating dialysis. She was found to be profoundly hypoalbuminemic secondary to malabsorptive and protein-losing enteropathy in tandem with nephrotic range proteinuria. Intolerance to enteral feeding led the patient to be dependent on parenteral nutrition. Serum immunofixation revealed IgG lambda monoclonal protein. The patient underwent endoscopic evaluation with biopsies taken from the gastrointestinal tract that confirmed the diagnosis of primary systemic light-chain amyloidosis. A subsequent bone marrow biopsy revealed normocellular bone marrow with deposition of amyloid. The patient was not considered for autologous stem cell transplantation as the outcomes in patients with multisystem involvement are often poor, with a high mortality risk. Diffuse primary systemic light-chain amyloidosis involving the gastrointestinal tract is a rare entity and is to be considered among differentials in patients presenting with unexplained malabsorptive symptoms.
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Affiliation(s)
- V Gaduputi
- Bronx-Lebanon Hospital Center, New York, N.Y., USA
| | - K Badipatla
- Bronx-Lebanon Hospital Center, New York, N.Y., USA
| | - H Patel
- Bronx-Lebanon Hospital Center, New York, N.Y., USA
| | - H Tariq
- Bronx-Lebanon Hospital Center, New York, N.Y., USA
| | - A Ihimoyan
- Bronx-Lebanon Hospital Center, New York, N.Y., USA
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34
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Left ventricular device implantation for advanced cardiac amyloidosis. J Heart Lung Transplant 2013; 32:563-8. [DOI: 10.1016/j.healun.2013.01.987] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2012] [Revised: 01/10/2013] [Accepted: 01/14/2013] [Indexed: 11/19/2022] Open
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35
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Gertz MA. Immunoglobulin light chain amyloidosis: 2013 update on diagnosis, prognosis, and treatment. Am J Hematol 2013; 88:416-25. [PMID: 23605846 DOI: 10.1002/ajh.23400] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2013] [Accepted: 01/16/2013] [Indexed: 12/30/2022]
Abstract
DISEASE OVERVIEW Immunoglobulin (Ig) light chain amyloidosis is a clonal, nonproliferative plasma cell disorder in which fragments of Ig light chain are deposited in tissues. Clinical features depend on organs involved but can include restrictive cardiomyopathy, nephrotic syndrome, hepatic failure, peripheral/autonomic neuropathy, and atypical multiple myeloma. DIAGNOSIS Tissue biopsy stained with Congo red demonstrating amyloid deposits with apple-green birefringence is required for diagnosis. Invasive organ biopsy is not required because amyloid deposits can be found in bone marrow biopsy or subcutaneous fat aspirate in 85% of patients. Verification that amyloid is of immunoglobulin origin is mandatory. PROGNOSIS N-terminal pro-brain natriuretic peptide (NT-proBNP), serum troponin T, and immunoglobulin free light chain values are used to classify patients into four groups of similar size; median survivals are 94.1, 40.3, 14.0, and 5.8 months. THERAPY All patients with a visceral amyloid syndrome require therapy to prevent deposition of amyloid in other viscera and prevent progressive organ failure of involved sites. Stem cell transplant (SCT) is preferred, but only 20% of patients are eligible. Requirements for safe SCT include NT-proBNP <5,000 ng/mL, troponin T < 0.06 ng/mL, age <70 years, <3 organs involved, and serum creatinine ≤1.7 mg/dL. Nontransplant candidates can be offered melphalan-dexamethasone. Pomalidomide appears to have activity, as do other combinations of chemotherapy with agents such as cyclophosphamide-thalidomide (or lenalidomide or bortezomib)-dexamethasone, bortezomib-dexamethasone, and melphalan-prednisone-lenalidomide. FUTURE CHALLENGES Late diagnosis remains a major obstacle to initiating effective therapy when organ dysfunction is still recoverable. Recognizing the presenting syndromes is necessary for improving survival.
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Affiliation(s)
- Morie A. Gertz
- Division of Hematology; Mayo Clinic; Rochester; Minnesota
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36
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Light-chain amyloidosis: SCT, novel agents and beyond. Bone Marrow Transplant 2012; 48:1022-7. [DOI: 10.1038/bmt.2012.199] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2011] [Revised: 07/17/2012] [Accepted: 09/13/2012] [Indexed: 02/07/2023]
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Abstract
There have been enormous strides in our understanding of autoimmunity. These strides have come under the umbrellas of epidemiology, immunological phenotype and function, disease definitions and classification and especially new therapeutic reagents. However, while these advances have been herculean, there remains enormous voids. Some of these voids include genetic susceptibility and the interaction of genes and environment. The voids include induction of tolerance in preclinical disease and definitions of host susceptibility and responses to the expensive biologic agents. The voids include the so-called clustering of human autoimmune diseases and the issues of whether the incidence is rising in our western society. Other voids include the relationships between microbiology, vaccination, gut flora, overzealous use of antibiotics, and the role of nanoparticles and environmental pollution in either the induction or the natural history of disease. One cannot even begin to address even a fraction of these issues. However, in this special issue, we are attempting to discuss clinical issues in autoimmunity that are not usually found in generic reviews. The goal is to bring to the readership provocative articles that ultimately will lead to improvement in patient care.
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38
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Abstract
The first textbook on autoimmunity was published by Ian Mackay and McFarland Burnett in 1963. It was the first attempt to summarize existing knowledge on human autoimmunity. Since that time, there have been tens of thousands of experimental papers and numerous textbooks that focus on the diagnosis and treatment of human autoimmunity. There have been at least as many, if not more, directed at similar issues in animal models. Enormous strides have been made not only in diagnosis, but also in the pathophysiology and especially in treatment. We have gone from the era of simple HLA typing to deep sequencing and, more recently, epigenetic analysis. We have gone from the era of white blood cell differentials to detailed lymphoid phenotyping. We have gone from the era of simple antinuclear antibodies to detailed and sophisticated immunodiagnosis with recombinant autoantigens and disease-specific epitopes. We have gone from the era of using only corticosteroids to selective biologic agents. Diseases that were previously considered idiopathic are now very much understood as autoimmune. We are in the era of autoinflammatory reactions and the concept of both innate versus adaptive immunity in mediating immunopathology. In this edition of Clinical Reviews in Allergy and Immunology, we focus on key and cutting-edge issues in the pathophysiology of autoimmunity. The issues are very much oriented and driven by hypothesis, i.e., a prediction of events expected to occur based on observations. It is not meant to be a complete summary of potential mechanisms of autoimmunity, but rather an attempt to accelerate discussion and better understanding. The primary goal is obviously to help our patients with autoimmune disease.
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Affiliation(s)
- Wesley H Brooks
- Experimental HTS Core, SRB-3, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612-9416, USA.
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39
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Clos AL, Kayed R, Lasagna-Reeves CA. Association of skin with the pathogenesis and treatment of neurodegenerative amyloidosis. Front Neurol 2012; 3:5. [PMID: 22319507 PMCID: PMC3262151 DOI: 10.3389/fneur.2012.00005] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2011] [Accepted: 01/04/2012] [Indexed: 12/12/2022] Open
Abstract
Amyloidosis are a large group of conformational diseases characterized by abnormal protein folding and assembly which results in the accumulation of insoluble protein aggregates that may accumulate systemically or locally in certain organs or tissue. In local amyloidosis, amyloid deposits are restricted to a particular organ or tissue. Alzheimer’s, Parkinson’s disease, and amyotrophic lateral sclerosis are some examples of neurodegenerative amyloidosis. Local manifestation of protein aggregation in the skin has also been reported. Brain and skin are highly connected at a physiological and pathological level. Recently several studies demonstrated a strong connection between brain and skin in different amyloid diseases. In the present review, we discuss the relevance of the “brain–skin connection” in different neurodegenerative amyloidosis, not only at the pathological level, but also as a strategy for the treatment of these diseases.
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Affiliation(s)
- Audra L Clos
- Department of Dermatology, MD Anderson Cancer Center, University of Texas Houston, TX, USA
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40
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Gertz MA. Immunoglobulin light chain amyloidosis: 2012 update on diagnosis, prognosis, and treatment. Am J Hematol 2012. [DOI: 10.1002/ajh.22248] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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41
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Rosenzweig M, Landau H. Light chain (AL) amyloidosis: update on diagnosis and management. J Hematol Oncol 2011; 4:47. [PMID: 22100031 PMCID: PMC3228694 DOI: 10.1186/1756-8722-4-47] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2011] [Accepted: 11/18/2011] [Indexed: 03/19/2023] Open
Abstract
Light chain (AL) amyloidosis is a plasma cell dyscrasia characterized by the pathologic production of fibrillar proteins comprised of monoclonal light chains which deposit in tissues and cause organ dysfunction. The diagnosis can be challenging, requiring a biopsy and often specialized testing to confirm the subtype of systemic disease. The goal of treatment is eradication of the monoclonal plasma cell population and suppression of the pathologic light chains which can result in organ improvement and extend patient survival. Standard treatment approaches include high dose melphalan (HDM) followed by autologous hematopoietic stem cell transplantation (SCT) or oral melphalan with dexamethasone (MDex). The use of novel agents (thalidomide, lenalidomide and bortezomib) alone and in combination with steroids and alkylating agents has shown efficacy and continues to be explored. A risk adapted approach to SCT followed by novel agents as consolidation reduces treatment related mortality with promising outcomes. Immunotherapeutic approaches targeting pathologic plasma cells and amyloid precursor proteins or fibrils are being developed. Referral of patients to specialized centers focusing on AL amyloidosis and conducting clinical trials is essential to improving patient outcomes.
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Affiliation(s)
| | - Heather Landau
- Memorial Sloan- Kettering Cancer Center Department, New York, New York, USA
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42
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Gertz MA. Immunoglobulin light chain amyloidosis: 2011 update on diagnosis, risk-stratification, and management. Am J Hematol 2011; 86:180-6. [PMID: 21264900 DOI: 10.1002/ajh.21934] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Immunoglobulin (Ig) light chain amyloidosis is a clonal but nonproliferative plasma cell disorder in which fragments of an Ig light chain are deposited in tissues. The clinical features depend on the organs involved but can include restrictive cardiomyopathy, nephrotic syndrome, hepatic failure, and peripheral/autonomic neuropathy. Tissue biopsy stained with Congo red demonstrating amyloid deposits with apple-green birefringence is required for diagnosis. Invasive organ biopsy is not required because amyloid deposits can be found in bone marrow biopsy or subcutaneous fat aspirate in 85% of patients. N-terminal pro-brain natriuretic peptide and serum troponin T values are used to classify patients into three groups of approximately equal size; median survivals are 26.4, 10.5, and 3.5 months, respectively. All patients with a visceral amyloid syndrome require therapy to prevent deposition of amyloid in other viscera and to prevent progressive organ failure of involved sites. Stem cell transplant (SCT) is a preferred technique, but only 20% of patients are eligible. Requirements for safe SCT include mild or no cardiac involvement, troponin T value <0.06 ng/mL, age younger than 70 years, <3 organs involved, and serum creatinine value ≤1.7 mg/dL. Nontransplant candidates can be offered melphalan-dexamethasone. Pomalidomide appears to have activity, as do other combinations of chemotherapy with agents such as cyclophosphamide-thalidomide-dexamethasone, bortezomib-dexamethasone, and melphalan-prednisone-lenalidomide. Late diagnosis remains a major obstacle to initiating effective therapy when organ dysfunction is still recoverable. Recognizing the presenting syndromes is necessary for improvement in survival.
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Affiliation(s)
- Morie A. Gertz
- Division of Hematology, Mayo Clinic, Rochester, Minnesota
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43
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Ha SY, Lee JJ, Park H, Han J, Kim HK, Lee KS. Localized Primary Thymic Amyloidosis Presenting as a Mediastinal Mass - A Case Report -. KOREAN JOURNAL OF PATHOLOGY 2011. [DOI: 10.4132/koreanjpathol.2011.45.s1.s41] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Affiliation(s)
- Sang Yun Ha
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jae Jun Lee
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Heejung Park
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Joungho Han
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hong Kwan Kim
- Department of Thoracic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kyung Soo Lee
- Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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44
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Clos AL, Lasagna-Reeves CA, Wagner R, Kelly B, Jackson GR, Kayed R. Therapeutic removal of amyloid deposits in cutaneous amyloidosis by localised intra-lesional injections of anti-amyloid antibodies. Exp Dermatol 2010; 19:904-11. [DOI: 10.1111/j.1600-0625.2010.01121.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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