Correspondence
The Systemic Amyloidoses
N Engl J Med 1998; 338:264-265January 22, 1998
- Article
To the Editor:
In the review of the systemic amyloidoses by Falk et al. (Sept. 25 issue),1 the comments about the treatment of immunoglobulin-light-chain–related (AL) amyloidosis with high-dose chemotherapy and stem-cell infusion may be premature. We and others have investigated the use of high-dose chemotherapy for a related disorder, multiple myeloma.2 Although the reported experience with high-dose chemotherapy for myeloma involves more than 1000 patients, reports on this treatment for AL amyloidosis (in full manuscript form, including all the papers cited in the review) involve fewer than 10 patients.
We are aware that the authors have accumulated further, unpublished experience with this approach; however, it is quite difficult to evaluate their results without knowledge of the details of patient selection, organ-function response, and treatment-related mortality (particularly in patients with congestive heart failure). The therapeutic response in patients with AL amyloidosis has traditionally been evaluated with the use of improvement in organ function as an end point.3 It is also quite important to use stringent criteria for objective improvement in organ involvement (e.g., >50 percent reduction in hepatomegaly). The importance of patient selection is exemplified by the experience with colchicine, which could not be confirmed.4
4 ReferencesMadhav Dhodapkar, M.D.
Bart Barlogie, M.D., Ph.D.
University of Arkansas for Medical Sciences, Little Rock, AR 72205Morie Gertz, M.D.
Mayo Clinic, Rochester, MN 559051
Falk RH ,Comenzo RL ,Skinner M . The systemic amyloidoses. N Engl J Med 1997;337:898-909
Full Text | Web of Science | Medline2
Jagannath S ,Tricot G ,Barlogie B . Autotransplants in multiple myeloma: pushing the envelope. Hematol Oncol Clin North Am 1997;11:363-381
CrossRef | Web of Science | Medline3
Gertz MA ,Kyle RA ,Greipp PR . Response rates and survival in primary systemic amyloidosis. Blood 1991;77:257-262
Web of Science | Medline4
Cohen AS ,Rubinow A ,Anderson JJ , et al. Survival of patients with primary (AL) amyloidosis: colchicine-treated cases from 1976 to 1983 compared with cases seen in previous years (1961 to 1973). Am J Med 1987;82:1182-1190
CrossRef | Web of Science | Medline
To the Editor:
We commend Falk et al. for their timely review of systemic amyloidosis. We suggest, however, that after amyloid has been detected, a simpler, more direct algorithm for evaluating the type of amyloid present should be used. The gold standard for the diagnosis of amyloidosis is immunohistochemical analysis, which can be performed on fresh or paraffinized tissue with the use of commercially available antibodies against all the common amyloid-fibril proteins (e.g., immunoglobulin κ and λ light chains, transthyretin, AA protein, and beta2-microglobulin).1,2 The most common clinical question is whether a patient has AL or transthyretin amyloidosis. For example, a patient with cardiac amyloidosis and a monoclonal serum immunoglobulin may have AL amyloidosis or may have transthyretin amyloidosis and an incidental monoclonal gammopathy of undetermined importance; both disorders are common in some elderly populations.3,4 Similarly, AL amyloidosis may develop in a patient known to be heterozygous for an amyloidogenic transthyretin variant. As Falk et al. note, the clinical findings associated with transthyretin and AL amyloidosis may be indistinguishable, so an accurate diagnosis of the type of amyloid is critical.
Falk et al. have evidently presented their multistep algorithm on the assumption that most clinical-pathology laboratories do not currently perform immunohistochemical studies on sections containing amyloid. We believe, however, that a final pathological diagnosis of amyloidosis, without further information, is inadequate and that a clinician who receives such a report should ask the pathologist, “What kind of amyloid is it?” Serum protein electrophoresis, immunofixation, and genetic studies to identify transthyretin variants can be used after the type of amyloid is known, only in the patients in whom such studies are relevant.
4 ReferencesDaniel R. Jacobson, M.D.
Gloria Gallo, M.D.
New York University Medical Center, New York, NY 10016Joel N. Buxbaum, M.D.
New York Department of Veterans Affairs Medical Center, New York, NY 100101
Hoshii Y ,Takahashi M ,Ishihara T ,Uchino F . Immunohistochemical classification of 140 autopsy cases with systemic amyloidosis. Pathol Int 1994;44:352-358
CrossRef | Web of Science | Medline2
Kaplan B ,Yakar S ,Kumar A ,Pras M ,Gallo G . Immunochemical characterization of amyloid in diagnostic biopsy tissues. Amyloid Int J Exp Clin Invest 1997;4:80-86
Web of Science3
Jacobson DR ,Pastore RD ,Yaghoubian R , et al. Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans. N Engl J Med 1997;336:466-473
Full Text | Web of Science | Medline4
Kyle RA, Lust JA. Monoclonal gammopathies of undetermined significance. In: Wiernik PH, Canellos GP, Kyle RA, Schiffer CA, eds. Neoplastic diseases of the blood. 2nd ed. New York: Churchill Livingstone, 1991:571-94.
To the Editor:
Falk et al. did not mention the use of potassium permanganate staining to differentiate between amyloid protein A (AA) and AL amyloidosis. Such staining allows an accurate differentiation between the two types.1 In the AA type, permanganate staining followed by standard Congo-red staining abolishes the green birefringence. AL and hereditary types are resistant to permanganate staining.
1 ReferencesSalah Mahmoud, M.R.C.P.
Royal Oldham Hospital, Oldham OL1 2JH, United KingdomAuthor/Editor Response
The authors reply:
To the Editor: The authors of the three letters raise questions about the diagnosis and treatment of the amyloidoses. Dr. Mahmoud comments about our omission of the use of potassium permanganate staining to differentiate between AA and AL amyloidosis.1 Unfortunately, cases of potassium permanganate–sensitive AL amyloidosis have been reported, and since there are more sensitive immunologic tests for AL amyloidosis, we believe that this test is currently of little value. This is particularly so in countries such as the United States, where AA (secondary) amyloidosis is far less common than AL amyloidosis, and even a small percentage of atypical responses may significantly affect the predictive accuracy of this test.
We strongly agree with Jacobson and colleagues that “the final pathological diagnosis of amyloidosis, without further information, is inadequate.” We state this point clearly in our review, and we believe that our algorithm will correctly identify the type of amyloidosis in most patients. Immunohistochemical studies may be highly specific in laboratories with skilled technicians performing large numbers of analyses. However, we have seen many misdiagnoses of the type of amyloidosis that were based on immunohistochemical analyses performed in the laboratories of referring hospitals. Thus, we cannot yet accept this approach as the gold standard.
The seminal and important work by Jacobson et al. on the variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans has shown that this genetic abnormality occurs more commonly than previously recognized.2 The phenotypic manifestation of cardiomyopathy is probably still quite rare. We acknowledge that an incidental monoclonal gammopathy of undetermined importance may coexist with a transthyretin isoleucine-122 cardiomyopathy (thereby presenting a confusing diagnostic challenge), but we would suggest that such cases are distinctly uncommon. No laboratory testing is foolproof, and no diagnostic algorithm can capture all possibilities. We nevertheless continue to feel comfortable with our suggested approach, which includes an overall clinical assessment of the patient's family history and diagnostic testing.
We appreciate the cautionary note of Dhodapkar et al. Our description of the results of high-dose intravenous melphalan and stem-cell support was tempered by the caveat that “the durability of remission remains to be determined, as does the impact of this approach on . . . survival.” We also stressed that this therapy should be used only in selected patients and that many patients with advanced AL amyloidosis are not suitable candidates. At our amyloidosis center, with more than 250 referrals per year, we are continually reviewing and refining our approach to the selection of patients for this treatment, as well as reviewing its results. We are committed to using the appropriate scientific channels to disseminate this information to the medical community. We are in full agreement that the results of new treatments should be disseminated in peer-reviewed journals, and a report on our further, positive experience with this approach is currently under review at a major peer-reviewed journal.
2 ReferencesRodney H. Falk, M.D.
Raymond L. Comenzo, M.D.
Martha Skinner, M.D.
Boston Medical Center, Boston, MA 02118-23931
Wright JR ,Calkins E ,Humphrey RL . Potassium permanganate reaction in amyloidosis: a histologic method to assist in differentiating forms of this disease. Lab Invest 1977;36:274-281
Web of Science | Medline2
Jacobson DR ,Pastore RD ,Yaghoubian R , et al. Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans. N Engl J Med 1997;336:466-473
Full Text | Web of Science | Medline
