Correspondence
Hereditary Amyloidosis
N Engl J Med 2002; 347:1206-1207October 10, 2002
- Article
To the Editor:
We concur with Lachmann et al. (June 6 issue)1 that therapeutic advances demand accurate typing of amyloid deposits.2 Our experience with 465 patients with sporadic, biopsy-proven, systemic amyloidosis indicates that immunoelectron-microscopical typing of amyloid deposits improves diagnostic accuracy and optimizes DNA analysis.3
The diagnosis of AL amyloidosis must not be presumed, and no patient should receive chemotherapy for a monoclonal disorder if the diagnosis has not been verified.4 Monoclonality was documented by high-resolution immunofixation5 in 96 percent of 446 patients who ultimately received a diagnosis of primary amyloidosis and by immunoelectron microscopy in the remaining 4 percent.
Since the presence of a monoclonal protein supports, but does not prove, the diagnosis of AL amyloidosis, we used immunoelectron microscopy to type the amyloid deposits in 134 consecutive patients with sporadic systemic amyloidosis who presented with a monoclonal protein. The diagnosis of AL amyloidosis was established in 129 patients, all of whom had a clinical presentation consistent with the diagnosis. Among five patients with a questionable history or presentation, amyloid typing disclosed AL amyloid in two patients, transthyretin in two, and apolipoprotein A-I in one. We found that ultrastructural immunohistochemical analysis unambiguously characterized the amyloid deposits, by colocalizing the specific protein with the fibrils, in all 37 patients (8 percent) who had sporadic amyloidosis without a monoclonal protein. It allowed typing of κ and λ light-chain deposits in all instances, whereas traditional immunohistochemical analysis was positive in only 38 percent of patients.1 The variable penetrance of the genetic defects indicates the need for confirmation by tissue typing. It seems more cost effective to focus the DNA analysis on specific genes by first typing the amyloid deposits with the use of ultrastructural immunohistochemical techniques.
5 ReferencesGiovanni Palladini, M.D.
Laura Obici, M.D.
Giampaolo Merlini, M.D.
University Hospital San Matteo, 27100 Pavia, Italy
gmerlini@unipv.it 1
Lachmann HJ ,Booth DR ,Booth SE , et al. Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. N Engl J Med 2002;346:1786-1791
Full Text | Web of Science | Medline2
Anesi E ,Palladini G ,Perfetti V ,Arbustini E ,Obici L ,Merlini G . Therapeutic advances demand accurate typing of amyloid deposits. Am J Med 2001;111:243-244
CrossRef | Web of Science | Medline3
Arbustini E ,Morbini P ,Verga L ,Merlini G . Light and electron microscopy immunohistochemical characterisation of amyloid deposits. Amyloid 1997;4:157-170
CrossRef | Web of Science4
Merlini G . Treatment of primary amyloidosis. Semin Hematol 1995;32:60-79
Web of Science | Medline5
Merlini G ,Marciano S ,Gasparro C ,Zorzoli I ,Bosoni T ,Moratti R . The Pavia approach to clinical protein analysis. Clin Chem Lab Med 2001;39:1025-1028
CrossRef | Web of Science | Medline
To the Editor:
The report by Lachmann et al. emphasizes the fallacy of relying on indirect evidence as a means to establish a diagnosis of AL (primary) amyloidosis. Although the type of amyloid present in a biopsy specimen can be inferred from the results of immunohistochemical analysis, it is well known that information gained using this technique can be misleading1 or the results misinterpreted if they are not evaluated by an expert in the field of amyloid pathology. Similarly, the detection in serum of a mutated amyloidogenic precursor protein (e.g., transthyretin, apolipoprotein A-I, lysozyme, or fibrinogen A α-chain) indicates only indirectly that the amyloid deposit is composed of like molecules.
Because more than 10 different proteins can be deposited systemically as amyloid,2 the particular form of amyloidosis in a patient must be determined for therapeutic and prognostic purposes. To obtain an accurate diagnosis, we believe that it is necessary to identify the exact nature of the material by chemical means (i.e., amino acid sequencing, mass spectroscopy of extracted fibrillar deposits, or both). Notably, as a result of the development of microanalytic techniques, we now can conduct such analyses readily, using formalin-fixed, paraffin-embedded fine-needle–biopsy samples.2,3 To make this diagnostic procedure more widely available, additional specialized reference laboratories should be created that can perform these analytic studies. Such an effort would be justified, given that diagnostic errors, especially in the case of AL amyloidosis, subject patients to inappropriate and costly therapy that can have dire, and possibly legal, consequences.
3 ReferencesAlan Solomon, M.D.
University of Tennessee Graduate School of Medicine, Knoxville, TN 37920
asolomon@mc.utmck. edu Per Westermark, M.D., Ph.D.
Uppsala University, SE 75185 Uppsala, Sweden1
Rocken C ,Schwotzer EB ,Linke RP ,Saeger W . The classification of amyloid deposits in clinicopathological practice. Histopathology 1996;29:325-335
CrossRef | Web of Science | Medline2
Kaplan B ,Murphy CL ,Ratner V ,Pras M ,Weiss DT ,Solomon A . Micro-method to isolate and purify amyloid proteins for chemical characterization. Amyloid 2001;8:22-29
CrossRef | Web of Science | Medline3
Murphy CL ,Eulitz M ,Hrncic R , et al. Chemical typing of amyloid protein contained in formalin-fixed paraffin-embedded biopsy specimens. Am J Clin Pathol 2001;116:135-142
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: We agree with Drs. Solomon and Westermark and Dr. Palladini and his colleagues that characterization of the type of amyloid fibril is paramount in patients with systemic amyloidosis and that this process is often inadequate. Indeed, we would go further and urge physicians to regard with caution results of immunohistochemical analysis that are apparently positive for AL amyloid. The expertise and sophisticated methods that Solomon and Westermark and Palladini et al. describe are laudable but available in few centers. In contrast, DNA screening for hereditary amyloidosis is widely available and can be performed without expert knowledge of amyloidosis and yield robust results. We were able to confirm that the mutations we identified were indeed the cause of the amyloid deposition in all patients in our study using light-microscopical immunohistochemical analysis.
There are pitfalls in virtually all of the methods used in the diagnosis and characterization of amyloidosis, ranging from those based on clinical features to the specialized techniques advocated by Solomon and Westermark and by Palladini et al. Our own practice is not to rely on the results of any single diagnostic test, but to use a broad, multidisciplinary diagnostic approach in all patients.
Philip N. Hawkins, M.B., B.S., Ph.D.
Helen J. Lachmann, M.B., B.Chir.
Mark B. Pepys, M.D., Ph.D.
Royal Free and University College Medical School, London NW3 2PF, United Kingdom
h.lachmann@rfc. ucl. ac. uk - Citing Articles (3)
Citing Articles
1
Charles L. Murphy, Shuching Wang, Daniel Kestler, Christopher Larsen, Don Benson, Deborah T. Weiss, Alan Solomon. (2010) Leukocyte Chemotactic Factor 2 (LECT2)-Associated Renal Amyloidosis: A Case Series. American Journal of Kidney Diseases 56:6, 1100-1107
CrossRef2
Laura Obici, Vittorio Perfetti, Giovanni Palladini, Remigio Moratti, Giampaolo Merlini. (2005) Clinical aspects of systemic amyloid diseases. Biochimica et Biophysica Acta (BBA) - Proteins & Proteomics 1753:1, 11-22
CrossRef3
Mariastella Graziani, Giampaolo Merlini, Concetta Petrini. (2003) Guidelines for the Analysis of Bence Jones Protein. Clinical Chemistry and Laboratory Medicine 41:3, 338-346
CrossRef
