The nonspecific and often vague nature of symptoms that are associated with AL amyloidosis frequently leads to delays in diagnosis such that organ dysfunction is advanced by the time treatment is initiated. In multiple myeloma, VAD may induce a quick clonal response. CPHPC administration depleted SAP from the circulation and from amyloid deposits in murine models, and studies in humans demonstrated rapid SAP clearance from the circulation (79). The median progression-free survival was 27 mo, and overall survival was 31 mo (61). Supportive treatment for amyloid-associated kidney disease, as for other causes of nephrotic syndrome, includes salt restriction, diuretics, and treatment of hyperlipidemia. Although the long-term survival is statistically inferior to that of patients with nonamyloid heart disease, the actuarial 5-yr survival seems to be 50% with treatment for the underlying plasma cell dyscrasia. Explore the symptoms and treatments of this rare but serious disease. Treatment strategies that have evolved during the past decade are prolonging survival and preserving organ function in patients with this disease. Amyloid deposition in the gastrointestinal tract predisposes to gastrointestinal bleeding during periods of cytopenia; this can be exacerbated by amyloid-associated coagulopathies such as factor X deficiency. Immunoglobulin light chain amyloidosis (primary amyloidosis). 1. Mayo Clinic; 2018. Cardiac amyloidosis is caused mainly by misfolded monoclonal immunoglobulin light chains (ALs) from an abnormal clonal proliferation of plasma cells or transthyretin (TTR) amyloidosis … Immunofixation electrophoresis should be performed on the serum and urine because, in contrast to multiple myeloma, the concentration of the monoclonal light chain often is too low to be detected by simple protein electrophoresis. Published online ahead of print. Amyloidosis is often overlooked because the signs and symptoms can mimic those of more-common diseases. The thalidomide analog lenalidomide and the proteasome inhibitor bortezomib both are active in multiple myeloma (67–70). In the systemic amyloidoses, the amyloidogenic protein is produced at a site that is distant from the site of amyloid deposition. • The majority of individuals with cardiac amyloidosis have myocardial amyloid deposits formed from misfolded light chain (AL) or transthyretin (TTR) proteins. Elsevier; 2018. https://www.clinicalkey.com. 50 Clinicians should note that up to … Amyloidosis is a generic term that refers to the extracellular tissue deposition of fibrils composed of low molecular weight subunits of a variety of normal serum proteins. The presence of clinically apparent cardiac involvement is an important determinant of outcome. The Boston University Amyloid Program eligibility criteria include a confirmed tissue diagnosis of amyloidosis, clear evidence of a clonal plasma cell dyscrasia, age >18 yr, performance … Recent diagnostic and prognostic advances include the serum free light-chain assay, cardiac magnetic resonance imaging, and serologic cardiac biomarkers. 1 Introduction of the imaging-based Boston criteria for diagnosis … What's the most likely cause of my symptoms? Contrary to the typical experience in multiple myeloma, deaths have been reported during mobilization and leukapheresis in AL amyloidosis patients with cardiac or multiorgan involvement (3). Accessed Oct. 1, 2019. The combination of an abnormal κ:λ ratio and a positive serum immunofixation identified 99% of patients with AL amyloidosis (19). Reduction in proteinuria is gradual with continued improvement over 2 or more years. However, this approach does not have any impact on the underlying plasma cell dyscrasia and therefore is of limited benefit. Diagnostic testing for AL amyloidosis involves blood tests, urine tests and biopsies. The diagnostic utility of the FLC is not firmly established but is under evaluation. Accessed Oct. 1, 2019. Adverse events of thromboembolic complications, myelosuppression, and immunosuppression are noted with lenalidomide, and neurotoxicity generally is not associated with lenalidomide. The conventional treatment approach for AL amyloidosis, adopted from experience with multiple myeloma, is to administer low-dose oral melphalan in association with prednisone in a cyclical manner. The group is heterogeneous because it included four syngeneic, eight reduced-intensity conditioning, and seven full-dose allogeneic transplants, and 10 were T cell–depleted grafts. Achieving a balance between heart failure and intravascular volume depletion is particularly important, especially in patients with autonomic nervous system involvement or nephrotic syndrome. Diagnosis of amyloidosis and differentiation … A recently completed Southwest Oncology Group trial with 87 eligible and analyzable patients found that 53% of patients had a hematologic response, and the hematologic response was complete in 24%. The organs that most frequently are affected in AL amyloidosis are the kidneys and the heart (5,12); however, virtually any tissue other than the brain can be involved. Treatments that aim to induce hematologic remissions to improve patient survival and the function of affected organs, as well as aspects of symptomatic treatment that are relatively unique to this disease are presented. Precise diagnosis is important because treatment varies greatly, depending on your specific condition. All of these parameters must be present to classify the response as a CR. Because the FLC assay is quantitative, it has utility not only in diagnosis but also in following disease progression or response to treatment, as is discussed later. The eligibility criteria for HDM/SCT in AL amyloidosis vary among institutions and have evolved as experience has accrued, but all aim to make the treatment available to as many patients as possible while excluding those who are at greatest risk for severe morbidity and mortality. Amyloidosis. Your doctor is likely to ask you a number of questions. The plasma cell burden in this disorder is low, typically 5 to 10% (4), although in approximately 10 to 15% of patients, AL amyloidosis occurs in association with multiple myeloma (5). You may be asked: Mayo Clinic does not endorse companies or products. The rate of disease progression is variable in AL amyloidosis and depends on the extent of organ involvement. Bleeding in AL amyloidosis is frequent and multifactorial. The ventricular walls are concentrically thickened with normal or reduced cavity size. Low voltage on the electrocardiogram is found in a high proportion of patients and often is associated with a pseudoinfarct pattern (12). Goldman L, et al., eds. There are several types with varying symptoms; signs and symptoms may include diarrhea, weight loss, feeling tired, enlargement of the tongue, bleeding, numbness, feeling faint with standing, swelling of the legs, or enlargement of the spleen. This means that it is the best available test, against which all other tests are measured. This regimen seemed to be effective in inducing hematologic responses in patients who received total dosages of melphalan of >300 mg (60). For decades the diagnosis of multiple myeloma required the presence of end-organ damage known as the CRAB criteria, including increased calcium level, renal dysfunction, anemia, and destructive bone … When did you first begin experiencing symptoms? Tests may include: Our caring team of Mayo Clinic experts can help you with your amyloidosis-related health concerns This site complies with the HONcode standard for trustworthy health information: verify here. There are 2 levels of response assessments using validated criteria… Adequate oral or intravenous feeding is mandatory in patients who are undernourished. Overall, it seems that the combination of thalidomide and dexamethasone may be a valid option for refractory or relapsed patients. Total body irradiation (550 cGy) before SCT was investigated in a small feasibility study but is not used in current regimens because of cardiac toxicity and what seems to be greater overall morbidity and mortality. Digoxin generally is not helpful, with the possible exception in patients with atrial fibrillation and rapid ventricular response. Fitted waist-high elastic stockings and midodrine are helpful. Despite these improvements in the treatment and diagnosis of AL amyloidosis, continued basic and clinical research effort in this field is needed to help improve the outcome for these patients. Light-Chain (AL) Amyloidosis: Diagnosis and Treatment, Epidemiology of AL amyloidosis: a real-world study using US claims data, First-in-Human Phase I/II Study of NEOD001 in Patients With Light Chain Amyloidosis and Persistent Organ Dysfunction, Long-term follow-up from a phase 1/2 study of single-agent bortezomib in relapsed systemic AL amyloidosis, Formation of assemblies on cell membranes by secreted proteins: molecular studies of free {lambda} light chain aggregates found on the surface of myeloma cells, Abnormalities of serum-free light chain in patients with primary antibody deficiency in the absence of B lymphocyte clonality, Expression of D-type cyclins in AL amyloidosis plasma cells, Onco-Nephrology: Glomerular Diseases with Cancer, An unusual cause of carpal tunnel syndrome, Primary systemic amyloidosis presenting as idiopathic inflammatory colitis, Modern Treatment of Amyloidosis: Unresolved Questions, DOI: https://doi.org/10.2215/CJN.02740806, Clinical Journal of the American Society of Nephrology, FDA Regulatory Perspectives for Studies on Hemodialysis Vascular Access, Recommended Clinical Trial End Points for Dialysis Catheters, Clinical Trial End Points for Hemodialysis Vascular Access, Imaging Techniques for Assessment of Organ Involvement, Biomarkers of Prognosis and Treatment Response, Copyright © 2006 by the American Society of Nephrology. Many people die from complications of amyloidosis without ever receiving a diagnosis. There's no cure for amyloidosis. "Mayo," "Mayo Clinic," "MayoClinic.org," "Mayo Clinic Healthy Living," and the triple-shield Mayo Clinic logo are trademarks of Mayo Foundation for Medical Education and Research. Hepatomegaly is common and can occur as a result of either congestion from right heart failure or amyloid infiltration of the liver. Thank you for your help in sharing the high-quality science in CJASN. Nov. 1, 2019. An iodinated derivative of doxorubicin, 4-iodo-4-deoxydoxorubicin (IDOX), binds with high affinity to amyloid fibrils and promotes their disaggregation in vitro and in vivo in experimentally induced murine AA amyloidosis (72–74). Advanced cardiac disease, reduced renal function, involvement of more than two organs, severe hypotension, and poor performance status are predictors of high treatment-associated morbidity and mortality. Because of the fragility of these patients, reduced dosages of thalidomide should be used, and careful monitoring for toxicity is necessary. This guideline highlights the clinical features that should raise suspicion of the diagnosis and the diagnostic investigations for amyloid … Median duration of response was 24 mo (range 12 to 48) (63). However, quantitative assessment is not possible with this agent, and strongly positive scintigraphic images usually occur only in patients with severe disease, in whom echocardiography generally is diagnostic. Evaluation of the extent of amyloid deposition is desirable because it can help to prognosticate, formulate therapeutic options, and determine the response to treatment. The ability of these drugs, in combination with dexamethasone, to reduce rapidly the concentration of the circulating monoclonal protein in multiple myeloma makes them attractive options also for AL amyloidosis, although more data on response duration and toxicity are needed. Many patients with advanced disease, particularly those with cardiac involvement, are unable to tolerate the fluid retention and worsening congestive heart failure that are associated with steroid treatment. Administration of IDOX to patients with AL amyloidosis showed promising results in a small, uncontrolled series, but its efficacy was unable to be demonstrated in a larger, multicenter trial, possibly because the effect size was less than anticipated (75,76). A diagnostic approach for patients with suspected cardiac amyloidosis should include testing for monoclonal protein followed by scintigraphy or biopsy (Figure 6). Given these promising findings, cardiac MRI soon may play an important role in both the identification of amyloid cardiomyopathy and the assessment of patients after therapy. How can I best manage them together? Patients with AL amyloidosis have more difficulty tolerating the stem cell mobilization and collection processes than do patients with other underlying diseases. The data are of insufficient power to justify the use of this technique in clinical practice, and it should remain the subject of clinical trials. Publication date available at www.cjasn.org. 6th ed. The diagnosis of AL amyloidosis requires (1) demonstration of amyloid in tissue and (2) demonstration of a plasma cell dyscrasia. In AL amyloidosis, the abnormal folding is the result of either a proteolytic event or an amino acid sequence that renders a light chain thermodynamically unstable and prone to self-aggregation. This form of treatment only rarely results in CR or reversal of amyloid-related organ dysfunction (58,59). The kidney is the most common organ affected in AA amyloidosis. The biopsy may be taken from the fat under the skin on your abdomen (fat aspirate), bone marrow, or an affected organ — such as your liver or kidney. Pulsed high-dosage dexamethasone, as used in the VAD regimen, has been reported to benefit AL patients with varying response rates. The recently introduced serum free-light-chain (FLC) assay, a nephelometric immunoassay, has a sensitivity for circulating free light chains that is reportedly >10-fold that of immunofixation electrophoresis (17,18). However, increasing evidence indicating that amyloidogenic precursor proteins or precursor aggregates have direct cytotoxic effects that also contribute to disease manifestations is emerging (9). Cerebral amyloid angiopathy is a frequent incidental finding, found on screening gradient-recalled echo imaging in up to 16% of asymptomatic elderly patients 4. Depending on your signs and symptoms, you may also have thyroid and liver function tests. How severe are they, and are they continuous or occasional? Dendritic cell–based idiotype vaccination has been shown to be well tolerated but to have limited clinical impact. There was a striking difference in renal response rate among those with a CR (71%) and those with persistence of the plasma cell dyscrasia (11%) (55). Maintaining AL amyloidosis in the differential diagnosis of patients who are being evaluated for a variety of syndromes, particularly with nephrotic-range proteinuria, unexplained nonischemic cardiomyopathy, peripheral neuropathy, unexplained hepatomegaly, or atypical multiple myeloma should improve diagnostic efficiency. Have you experienced shortness of breath? In AL amyloidosis, the clonal plasma cells express light chains of the λ isotype more frequently than the κ, with a ratio of approximately 3:1, despite the greater proportion of κ than λ expressing plasma cells in a normal bone marrow. Because SAP is present in all types of amyloid deposits, targeting the SAP–amyloid interaction could have broad application (77). CR were seen in 10 of the 19 patients. Accessed Oct. 1, 2019. … Exclusion criteria included case reports, … Myocardial amyloidosis: The exemplar interstitial disease. Are you often tired? Light-chain (AL) amyloidosis is the most common form of systemic amyloidosis and is associated with an underlying plasma cell dyscrasia. Contamination of the apheresis product with clonotypic Ig-positive plasma cells has been demonstrated, but CD34 selection presently is not recommended (52). Dr Yuranga Weerakkody ◉ et al. The mainstay of the treatment of amyloid cardiomyopathy is sodium restriction and the careful administration of diuretics. This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Treatment-related toxicity was frequent (65%), and symptomatic bradycardia was a common (26%) adverse reaction (66). The utility of MRI in evaluating amyloid in other organs is not known. Improved organ function may be evident 3 to 6 mo after treatment, although more delayed responses also occur. Evidence of antigen-selective pressure on amyloidogenic VL genes as well as homogeneity of somatic mutations support the concept that the monoclonal transformation of most amyloidogenic plasma cells occurs after B cell maturation and clonal selection in the lymphoid follicle (10). The patient selection and the total number of patients who were evaluated at these centers as potential allogeneic transplant recipients are not known. Gabapentin, although well tolerated, often fails to relieve pain. In: Comprehensive Clinical Nephrology. A rapid response to therapy is essential in AL amyloidosis. AskMayoExpert. Associations between Ig VL germline gene use and amyloid-related organ involvement have been described by several groups. Jan. 13, 2020. Feehally J, et al. Severe amy… A … Coexistent AL amyloid deposits are identified either at presentation or at some time during the course of the disease in … Even if a monoclonal Ig light chain is identified in the serum or the urine, a bone marrow biopsy is mandatory to assess the plasma cell burden (21) and exclude multiple myeloma and other, less common disorders that can be associated with AL amyloidosis, such as Waldenström’s macroglobulinemia (22). The amyloidogenic protein in AL amyloidosis is an Ig light chain or a fragment of a light chain that is produced by a clonal population of plasma cells in the bone marrow. The serum FLC assay often is normal in such cases (24). amyloidosis when the diagnostic criteria for these conditions are fulfilled. Profound elevation of alkaline phosphatase with only mild elevation of transaminases is characteristic of hepatic amyloidosis because infiltration occurs in the sinusoids (14). Once a tissue diagnosis of amyloidosis has been established, confirmation of AL disease requires demonstration of a plasma cell dyscrasia by a bone marrow biopsy showing predominance of λ- or κ-producing plasma cells or by the presence of a monoclonal light chain in the serum or urine. A humanized antibody is being produced for a phase I/II clinical trial in patients with AL disease. There's no cure for amyloidosis. Gorevic PD. Several advances during the past decade have had a substantial impact on the approach to treatment and the prognosis of AL amyloidosis. Treatment algorithm for light-chain (AL) amyloidosis. At Stanford, your physician begins by conducting a complete medical history and physical exam. Regardless of the specific treatment directed against the plasma cell dyscrasia, supportive care to decrease symptoms and support organ function plays an important role in the management of this disease and requires the coordinated care by specialists in multiple disciplines. In this report, 36% of patients had a renal response at 12 months defined as a 50% reduction in 24-h urinary protein excretion in the absence of a 25% or greater reduction in creatinine clearance. Overall, the major complication rate during mobilization or collection is approximately 15% in this disease (3). The major limitation of HDM/SCT is its toxicity. Several aspects of stem cell mobilization and collection pose particular challenges in patients with AL amyloidosis. Heart muscle biopsy is considered the “gold standard” for diagnosing amyloid deposits in the heart. Renal amyloidosis and glomerular diseases with monoclonal immunoglobulin deposition. Accessed Oct. 1, 2019. Severe adverse effects impeded dosage escalation above 200 to 300 mg/d and necessitated thalidomide withdrawal in 25 to 50% of the patients (64,65). The clinical syndromes at presentation include nephrotic-range proteinuria with or without renal dysfunction, hepatomegaly, congestive heart failure, and autonomic or sensory neuropathy. However, this site suffers from relatively poor sensitivity; even in positive cases, there are frequently inadequate amyloid deposits to definitively subtype the disease (ATTR, AL, etc.). But treatment can help manage signs and symptoms and limit further production of amyloid protein. Hypotension from cardiac disease or autonomic nervous system involvement, atrial and ventricular arrhythmias in patients with amyloid cardiomyopathy, difficulties with emergent endotracheal intubation as a result of macroglossia, and spontaneous splenic and esophageal rupture also are problems that can arise during treatment in these patients. The use of sole therapy with oral melphalan administered continuously rather than cyclically has been studied in patients with cardiac amyloidosis. Mayo Clinic; 2019. Autopsy studies have found a prevalence of approximately 5-9% in patients between 60 and 69 years, and 43-58% in patients over the age of 90 4. In a small proportion of patients (approximately 10%), amyloid deposition occurs in the renal vasculature or tubulointerstitium, causing renal dysfunction without significant proteinuria (13). Prompt diagnosis of amyloidosis and appropriate referral have the potential to improve outcome for these patients. Disruption of the interaction between SAP (7) and amyloid is another approach being investigated as a degradation-promoting treatment. Strategies that combine IDOX with chemotherapy to suppress precursor production and promote amyloid resorption is a rational approach that warrants investigation. Hematologic response is associated with a substantial survival advantage, improved quality of life, and improved organ function (3,37). The current therapeutic approach to systemic amyloidosis is based on the observations that organ dysfunction improves and survival increases if the synthesis of the amyloidogenic protein precursor is halted. 2019. doi:10.1016/j.jcmg.2019.06.023. Any use of this site constitutes your agreement to the Terms and Conditions and Privacy Policy linked below. A κ:λ ratio of <0.26 strongly suggests the presence of a population of plasma cells that are producing clonal λ free light chains, whereas a ratio >1.65 suggests production of clonal κ free light chains. https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/amyloidosis/amyloidosis?query=amyloidosis. AskMayoExpert. However, these agents should be used cautiously, starting with a low dosage and withdrawing if postural hypotension develops. Diuretic resistance is common in patients with severe nephrotic syndrome, and metolazone or spironolactone may be required in conjunction with loop diuretics. Cardiac Amyloidosis Diagnosis To confirm a diagnosis of cardiac amyloidosis, you will need either a cardiac biopsy or technetium pyrophosphate scan. The initial report of renal response after HDM/SCT was published in 2001 (55). CAA is defined by histopathology—deposition of β-amyloid in the cerebrovasculature—and through the 1980s the disorder was only diagnosed in patients with available brain tissue from hematoma evacuation, biopsy, or most commonly postmortem examination. Elsevier; 2020. https://www.clinicalkey.com. © 1998-2021 Mayo Foundation for Medical Education and Research (MFMER). Importantly, a complete clonal hematologic response (CR) is not a prerequisite for clinical response, and clinical improvement still may occur in patients with a partial clonal response (3). Merck Manual Professional Version. However, the follow-up period was short, the treatment-related mortality was 40%, and only four patients were alive at 36 mo. Laboratory Approach to the Diagnosis of Amyloidosis Note: In cases of suspected familial amyloidosis, see Amyloidosis (Familial) Test Algorithm Possible Patient Presentations Nephrotic … In one report, a reduction in FLC of >90% was associated with a similar high likelihood of clinical improvement and prolonged survival, regardless of whether patients achieved a CR after treatment (38). A tissue sample may be taken and checked for signs of amyloidosis. In: Ferri's Clinical Advisor 2020. Journal of the American College of Cardiology: Cardiovascular Imaging. CHF, congestive heart failure; COM, continuous low-dosage oral melphalan; CR, complete hematologic response; Cr, creatinine; Dex, dexamethasone; HDM/SCT, high-dosage melphalan and stem cell transplantation; IV, intravenous; LVEF, left ventricular ejection fraction; Mel, melphalan; VTE, venous thromboembolic disease.
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