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KOS 2007: AL Amyloidosis: Diagnosis and Prognosis
By Giampaolo Merlini, MD
Giampaolo Merlini, MD
Amyloidosis Center
Fondazione IRCCS Policlinico San Matteo
University of Pavia
Pavia, Italy
06.28.07

NOTE: THE AUDIO FOR THIS PRESENTATION IS NOT AVAILABLE DUE TO TECHNICAL PROBLEMS WITH THE RECORDING.

Amyloidosis Center
Fondazione IRCCS Policlinico San Matteo
University of Pavia
Pavia, Italy

Systemic AL amyloidosis is a plasma cell disorder characterized by the overproduction and tissue deposition of a monoclonal immunoglobulin light chain (LC), or fragments containing the LC variable region and a portion of the constant region. The deposits are composed of amyloid fibrils, presenting a cross beta supersecondary structure. The process of amyloid deposition produces tissue damage and eventually organ failure, leading to death in untreated patients (1).

The optimal management of patients with AL amyloidosis requires early diagnosis, correct amyloid typing, effective treatment, tight follow-up and careful supportive therapy. One of the most important determinants of outcome is early diagnosis, as severe amyloid organ disease may preclude the use of potentially effective treatment regimens. The systemic involvement affecting vital organs such as heart, kidney and liver renders these patients particularly fragile and sensitive to the toxicity of chemotherapy.

Early diagnosis depends on the level of alertness of the physician: any patient with nephrotic-range proteinuria, unexplained right-sided heart failure, progressive peripheral neuropathy, unexplained hepatomegaly or functional hyposplenism, orthostatic hypotension and other manifestations of autonomic neuropathy with weight loss should be screened for amyloidosis. The diagnosis of AL is biopsy based and requires the presence of deposits with apple green birefringence after Congo red staining, or the prototypic, nonbranching, 10-nm diameter fibrillar structures by electron microscopy. Fine-needle aspiration of abdominal fat is innocuous, fast, inexpensive, and sensitive (87%) (2). The method is based on the almost constant involvement of subcutaneous adipose tissue in AA, AL and ATTR forms of systemic amyloidosis, and probably in other systemic amyloidoses as well. Amyloid is found both in the walls of small vessels and around the individual fat cells. False-positive Congo red-stained biopsies occur because of overstaining and inexperienced review. If the abdominal fat is negative, the second choice biopsy site at the Pavia Amyloid Center is the minor labial salivary glands. Renal and hepatic biopsies carry a small risk of bleeding and often require overnight hospitalization. Once the diagnosis of amyloidosis has been established histologically, the type must be determined because the prognosis and treatment depend on the biochemical amyloid forms. There are specific treatments available for some systemic amyloidoses, this means that exact and safe determination of the type of amyloid deposit in the individual patient is critical. This can be accomplished using immunohistochemistry, immunoelectron microscopy (3) or by biochemical methods which are applicable also to formalin-fixed tissue samples (4). Immunohistochemistry is usually reliable for identifying or ruling out AA amyloidosis, but is frequently not diagnostic with respect to AL amyloidosis. Immunoelectron microscopy and biochemical methods provide definitive results; however, they are labor-intensive and require expertise. If these techniques are not available, the DNA analysis should be performed upfront in order to exclude the hereditary amyloidoses whose clinical presentation is consistent with the patient’s manifestations. In order to characterize the amyloidosis of AL type, a plasma cell clone should be documented. The demonstration of the clone requires sensitive techniques. The bone marrow should always be examined, bearing in mind that, typically, the amyloid plasma cell clone infiltrates the bone marrow to a modest extent (median bone marrow plasma cell percentage 7%), often requiring anti-light chain immunohistochemistry/immunofluorescence for  and  light chains to be identified. Accordingly, also the circulating monoclonal protein is usually present at low concentration, being missed by screening serum electrophoresis in approximately 50% of patients. Therefore, all patients with a clinical suspicion of AL amyloidosis should undergo sensitive immunofixation electrophoresis of serum and urine that is able to detect a monoclonal protein in up to 97% of patients (2). The quantification of serum-free light chains (FLC) may complement immunofixation and represents now an irreplaceable tool for monitoringresponse to therapy. Evidence of progression or regression of amyloid deposits can be obtained from serum amyloid P (SAP) component scintigraphy.

Due to the relatively high prevalence of a monoclonal protein in the adult population the possibility of a chance coexistence of a monoclonal protein in a patient with hereditary amyloidosis should always be considered (5). Clinically, it is difficult to distinguish AL from reactive, familial, and senile systemic forms of amyloidosis, because of their overlapping clinical presentations and the lack of an informative family history in half of the patients with hereditary amyloidosis. Since mistyping of amyloidosis may have catastrophic therapeutic consequences, such as transplanting hematopoietic stem cells instead of liver, great care should be devoted to the diagnostic process. When two possible sources of amyloid have been identified, patients should be referred to centers specializing in amyloidosis for further evaluation.The prognosis of AL amyloidosis has significantly improved in the last decade due to earlier diagnosis and more effective specific and supportive treatments. The median survival of patients with AL ranges from approximately 2 years to 3.9 years, depending in part on the treatment center and the nature of referral pattern. The median survival of 822 patients with AL amyloidosis followed in Pavia is 47 months. Recently we have investigated the factors affecting renal survival in patients with amyloid renal involvement: serum creatinine, proteinuria and young age at diagnosis predicted the progression to dialysis. Response to chemotherapy prolongs both renal and overall survival. The most frequent cause of death in these patients is progression of amyloid cardiomyopathy. Actually, most patients with AL amyloidosis die of cardiac complications (~ 75% in our 822 patient population), either congestive heart failure or sudden death. Cox multivariate analysis showed that the only 2 significant independent prognostic factors were response to therapy (protective), and cardiac involvement. Median survival of patients with heart involvement was significantly shorter than that of patients without cardiac amyloidosis (24 vs 81 months, p<0.001), and patients who obtained a hematologic response to chemotherapy survived longer than other patients (median 96 vs 20 months, p<0.001). Our recent data indicate that patients with cardiac AL amyloidosis who achieve hematologic response to chemotherapy have a better outcome than non-responsive patients (median survival 68 months vs 11 months, p<0.001) irrespective of the severity of heart involvement at diagnosis. Elevated serum cardiac troponins are related to poor prognosis in AL patients (6) and our group reported that the serum N-terminal portion of natriuretic peptide type B (NT-proBNP) is a sensitive marker of myocardial dysfunction in AL and a powerful prognostic determinant (7). These two cardiac biomarkers were used to develop a reliable staging system for AL patients that can be used to stratify patients in randomized clinical trials and to compare outcomes between therapeutic interventions when randomized clinical trials are not available (8). NT-proBNP clearance relies almost exclusively on glomerular filtration while natriuretic peptide type B (BNP) is eliminated from plasma through both glomerular filtration and clearance receptors that promote its degradation. Therefore, it is likely that BNP will prove to be a more reliable marker of cardiac dysfunction than NT-proBNP in AL patients with advanced renal disease. In most of the patients, the reduction of the circulating FLC concentration induced by chemotherapy translates into a reduction of serum NT-proBNP level and improving of heart failure, often before any reduction in amyloid load can be demonstrated at echocardiography (9). This observation indicates that serum NT-proBNP can be used as a marker of cardiac response to therapy. It has been reported that normalization of FLC levels after peripheral blood stem cell transplantation predicted both complete hematologic response and organ response (10). The concurrent quantification of the FLC and of NT-proBNP in patients with cardiac amyloidosis allows titration of the anticlone treatment improving the toxicity-benefit ratio and allowing a prompt change of therapy in the case of an inadequate response.

References
1. Merlini G, Stone MJ. Dangerous small B-cell clones. Blood. 2006;108:2520-30.
2. Obici L, Perfetti V, Palladini G, Moratti R, Merlini G. Clinical aspects of systemic amyloid diseases. Biochim Biophys Acta. 2005;1753:11-22.
3. Arbustini E, Morbini P, Verga L, Concardi M, Porcu E, Pilotto A, et al. Light and electron microscopy immunohistochemical characterization of amyloid deposits. Amyloid. 1997;4:157-70.
4. Murphy CL, Eulitz M, Hrncic R, Sletten K, Westermark P, Williams T, et al. Chemical typing of amyloid protein contained in formalin-fixed paraffin-embedded biopsy specimens. Am J Clin Pathol. 2001;116:135-42.
5. Comenzo RL, Zhou P, Fleisher M, Clark B, Teruya-Feldstein J. Seeking confidence in the diagnosis of systemic AL (Ig light-chain) amyloidosis: patients can have both monoclonal gammopathies and hereditary amyloid proteins. Blood. 2006;107:3489-91.
6. Dispenzieri A, Kyle RA, Gertz MA, Therneau TM, Miller WL, Chandrasekaran K, et al. Survival in patients with primary systemic amyloidosis and raised serum cardiac troponins. Lancet. 2003;361:1787-9.
7. Palladini G, Campana C, Klersy C, Balduini A, Vadacca G, Perfetti V, et al. Serum N-terminal pro-brain natriuretic peptide is a sensitive marker of myocardial dysfunction in AL amyloidosis. Circulation. 2003;107:2440-5.
8. Dispenzieri A, Gertz MA, Kyle RA, Lacy MQ, Burritt MF, Therneau TM, et al. Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a staging system for primary systemic amyloidosis. J Clin Oncol. 2004;22:3751-7.
9. Palladini G, Lavatelli F, Russo P, Perlini S, Perfetti V, Bosoni T, et al. Circulating amyloidogenic free light chains and serum N-terminal natriuretic peptide type B decrease simultaneously in association with improvement of survival in AL. Blood. 2006;107:3854-8.
10. Dispenzieri A, Lacy MQ, Katzmann JA, Rajkumar SV, Abraham RS, Hayman SR, et al. Absolute values of immunoglobulin free light chains are prognostic in patients with primary systemic amyloidosis undergoing peripheral blood stem cell transplantation. Blood. 2006;107:3378-83.


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