Bone marrow plasma cell infiltration in light chain amyloidosis: impact on organ involvement and outcome

Abstract

Objectives: Prognosis of immunoglobulin light-chain (AL) amyloidosis depends mainly on the presence of cardiac involvement and the disease burden. A higher bone marrow plasma cell (BMPC) burden has been recognized as an adverse prognostic factor. The aim of our study was to analyze the correlation between the BMPC infiltration, clinical features and outcomes in patients with AL amyloidosis.

Methods: The clinical records of 79 patients with AL amyloidosis treated at a single institution.

Results: Median BMPC infiltration at diagnosis was 11% and significantly correlated with the serum free light-chain difference (p?<?.001). Patients with more than 10% BMPCs had more frequent cardiac involvement (86 vs. 63%; p?=?.015), a trend towards a higher early mortality (27 vs. 11%; p?=?.08) and a significantly shorter progression-free survival (PFS) (median of 18 vs. 48?months, p?=?.02) and overall survival (median of 33?months vs. not reached; p?=?.046). In the multivariate analysis, a BMPC infiltration over 10% retained its adverse prognostic value for PFS (HR?=?2.26; 95% CI, 1.048–4.866; p?=?.038). The use of new drugs seemed to overcome the negative prognostic impact of a higher BMPC infiltration.

Conclusion: Higher BMPC infiltration in AL amyloidosis might be associated with increased systemic organ damage, particularly cardiac involvement and is rarely related to the development of myeloma features.     

以黄疸为特征的原发性肝淀粉样变性1例报告

淀粉样变性是由不溶性淀粉样蛋白沉积在组织器官中引起的一类进行性、预后不良的疾病,主要可分为原发性（淀粉样物质为免疫球蛋白的轻链,AL型） 和继发性（淀粉样物质为淀粉A 蛋白,AA 型）.AL 型常累及肝、肾、脾、心脏、胃肠及皮肤等多个组织器官,以往的尸解发现95%的原发性淀粉样变性患者都有肝脏淀粉样物质沉积.     

Prognosis Assessment of Cardiac Involvement in Systemic AL Amyloidosis by Magnetic Resonance Imaging

Background

Cardiac involvement is one of the most important prognostic factors in systemic AL amyloidosis. The aim of our study was to assess the role of cardiovascular magnetic resonance (CMR) imaging in prognosis evaluation in AL amyloidosis.

Methods

We retrospectively analyzed 29 consecutive patients with AL amyloidosis who had undergone CMR. Clinical, laboratory, echocardiographic, and CMR characteristics were compared between CMR-positive (ie, with CMR signs of cardiac localization of AL amyloidosis) and CMR-negative patients. Univariate and multivariate analyses were performed to assess the prognostic value of positive CMR in comparison with other prognostic factors.

Results

CMR was positive in 11 patients (38%). The overall survival rates for CMR-positive patients were 28%, 14%, and 14% versus 84%, 77%, and 45% at 1, 2, and 5 years, respectively, for CMR-negative patients (P = .002). Late gadolinium enhancement patterns, biventricular hypertrophy, and pericardial effusion on CMR were more frequent in nonsurvivors. Congestive heart failure, abnormal echocardiography, Eastern Cooperative Oncology Group grade >1, brain natriuretic peptide, and left ventricular ejection fraction <55% also were associated with a decreased survival. The presence of congestive heart failure was the only significant variable associated with survival on multivariate analysis.

Conclusion

We found that the presence of a positive CMR in AL amyloidosis was associated with a significantly increased risk of death, in particular of cardiac origin, but was not independent of clinical congestive heart failure.     

Cardiac Amyloidosis Shows Decreased Diastolic Function as Assessed by Echocardiographic Parameterized Diastolic Filling

Cardiac amyloidosis is a rare but serious condition with poor survival. One of the early findings by echocardiography is impaired diastolic function, even before the development of cardiac symptoms. Early diagnosis is important, permitting initiation of treatment aimed at improving survival. The parameterized diastolic filling (PDF) formalism entails describing the left ventricular filling pattern during early diastole using the mathematical equation for the motion of a damped harmonic oscillator. We hypothesized that echocardiographic PDF analysis could detect differences in diastolic function between patients with amyloidosis and controls. Pulsed-wave Doppler echocardiography of transmitral flow was measured in 13 patients with amyloid heart disease and 13 age- and gender matched controls. E- waves (2 to 3 per subject) were analyzed using in-house developed software. Nine PDF-derived parameters were obtained in addition to conventional echocardiographic parameters of diastolic function. Compared to controls, cardiac amyloidosis patients had a larger left atrial area (23.7 ± 7.5 cm² vs. 18.5 ± 4.8 cm², p = 0.04), greater interventricular septum wall thickness (14.4 ± 2.6 mm vs. 9.3 ± 1.3 mm, p < 0.001), lower e′ (0.06 ± 0.02 m/s vs. 0.09 ± 0.02 m/s, p < 0.001) and higher E/e′ (18.0 ± 12.9 vs. 7.7 ± 1.3, p = 0.001). The PDF parameter peak resistive force was greater in cardiac amyloidosis patients compared to controls (17.9 ± 5.7 mN vs. 13.1 ± 3.1 mN, p = 0.03), and other PDF parameters did not differ. PDF analysis revealed that patients with cardiac amyloidosis had a greater peak resistive force compared to controls, consistent with a greater degree of diastolic dysfunction. PDF analysis may be useful in characterizing diastolic function in amyloid heart disease.     

Free light chains in plasma of patients with light chain amyloidosis and non-amyloid light chain deposition disease. High proportion and heterogeneity of disulfide-linked monoclonal free light chains as pathogenic features of amyloid disease

Immunoglobulin light chain amyloidosis (AL) and non-amyloid light chain deposition disease (NALCDD) are different forms of protein aggregation disorders accompanied by a monoclonal gammopathy. Monoclonal free light chains (FLCs) are precursors of the pathological light chain tissue deposits that are fibrillar in AL and granular in NALCDD. However, direct biochemical examination of plasma FLC precursors, which would allow comparison and better understanding of these two diseases, is still lacking. In this study, we examined FLCs in plasma of patients with AL and NALCDD by employing separation on Sep-PaK C18 cartridges, micro-preparative electrophoresis, Western blotting and mass spectrometry. Comparative analysis of AL versus NALCDD and control plasma samples showed new evidence of increased level and heterogeneity of circulating disulfide-bound FLC species in AL. In addition to full length monomers comprising the disulfide-linked FLCs, the monoclonal disulfide-bound FLC fragments were typically revealed in AL plasma. We hypothesized that enhanced disulfide binding of FLCs in AL interferes with their normal clearance and metabolism, which in turn might play a role in amyloid formation. The applied methods might be useful to diagnose or predict the pathological form of the disease and shed light on the mechanisms involved in light chain aggregation in tissues.     

Classical and alternative pathway complement activation are not required for reactive systemic AA amyloid deposition in mice

During induction of reactive systemic amyloid A protein (AA) amyloidosis in mice, either by chronic inflammation or by severe acute inflammation following injection of amyloid enhancing factor, the earliest deposits form in a perifollicular distribution in the spleen. Because the splenic follicular localization of immune complexes and of the scrapie agent are both complement dependent in mice, we investigated the possible complement dependence of AA amyloid deposition. In preliminary experiments, substantial depletion of circulating C3 by cobra venom factor had little effect on experimental amyloid deposition. More importantly, mice with targeted deletion of the genes for C1q or for both factor B and C2, and therefore unable to sustain activation, respectively, of either the classical complement pathway or both the classical and alternative pathways, showed amyloid deposition similar to wild type controls. Complement activation by either the classical or alternative pathways is thus not apparently necessary for the experimental induction of systemic AA amyloid in mice.     

Amyloid and the GI tract

Amyloidosis is characterized by the extracellular deposition of an abnormal fibrillar protein, which disrupts tissue structure and function. Amyloid may be localized to a single organ, such as the GI tract, or be systemic where the amyloid type is defined by the respective fibril precursor protein. Among patients with systemic amyloidosis, histological involvement of the gastrointestinal (GI) tract is very common but often subclinical. The presence and pattern of GI symptoms varies substantially, not only between the different amyloid types but also within them. GI presentations are frequently nonspecific and include macroglossia, dyspepsia, hemorrhage, a change in bowel habit and malabsorption. Endoscopic and radiological features of amyloidosis are also nonspecific, with the small intestine most commonly affected. In the absence of specific treatments for GI amyloidosis, therapy is aimed at reducing or eliminating the supply of the respective fibril precursor protein. Supportive measures such as nutritional support and antidiarrheal agents should be instigated while awaiting the clinical improvement associated with a successful reduction in the abundance of the fibril precursor protein. GI tract surgery should be performed only if the benefits clearly outweigh the risks, as there is a risk of decompensation of organs affected by amyloid.     

Localized AL amyloidosis of the colon: an unrecognized entity

Virtually all patients who present with rectal bleeding and amyloid of the colon have evidence of systemic amyloidosis and require therapy. The small subset of patients with amyloidosis localized to the colon must be recognized and treatment avoided. We queried our file for patients who had amyloidosis of the colon but no evidence of systemic amyloidosis during long-term follow-up. We identified 3 patients who presented with rectal bleeding and who, on investigation, had primary amyloidosis of the colon but no evidence of systemic amyloidosis during a follow-up of 4.5 to 20 years. These patients had no evidence of a plasma cell dyscrasia and received no chemotherapy to prevent deposition of amyloid. It is important to recognize this rare subset and avoid treatment with alkylating agents or high-dose therapy followed by autologous stem cell transplantation. Alkylating agent therapy may be associated with myelodysplasia or acute leukemia. In addition, the cost, inconvenience, and morbidity of therapy are avoided by observation. Patients who present with rectal bleeding and a subsequent diagnosis of amyloidosis of the colon likely will be subjected to chemotherapy or transplantation. Such patients must be recognized and treatment avoided if there is no evidence of systemic amyloidosis because they remain stable for many years.