Seeking Diagnostic Confidence in Typing Amyloidosis: Prospective Results with an Algorithm To Minimize Misdiagnosis of Immunoglobulin Light-Chain (AL) Amyloidosis. (2005)

Abstract In order to treat patients with symptomatic amyloidosis, the amyloidosis must be typed with confidence. Immunohistochemical techniques for light-chain isotype identification of amyloid are not reliable, and techniques to type fibrils extracted from clinical specimens are neither widely available nor validated. Retrospectively, investigators in the United Kingdom have shown that hereditary amyloidosis can be misdiagnosed as AL in 10% of cases because family history is often not relevant and because a monoclonal gammopathy (MG) and an hereditary variant can be present in the same patient (NEJM2002;346). The most common types of amyloidosis in the USA are AL and hereditary, the latter due to mutations in proteins such as transthyretin (TTR), fibrinogen A α-chain (FnAα), apolipoprotein AI or AII, and lysozyme. The genes for these proteins are not routinely examined in all cases of likely AL amyloidosis, and clinical genetics laboratories do not offer screening for all of them. The most common hereditary variant in the USA is the V122I transthyretin mutation found in 4% of African-Americans. In addition, a common presentation of both AL and hereditary amyloidosis is peripheral neuropathy. Furthermore, in the case of FnAα nephropathy, patients usually have isolated renal amyloid without marrow involvement. To minimize the risk of misdiagnosis of AL at our center, we prospectively tested four categories of patients with a tissue diagnosis of amyloidosis for hereditary variants whether or not MG was present: African-Americans, patients with dominant peripheral neuropathy (PN), patients with isolated renal amyloidosis (RA) without marrow involvement, and patients referred for hereditary testing or lack of MG. Testing was by PCR amplification and sequencing of genomic DNA. From 6/1/02 to 8/1/05, we evaluated 178 patients referred for amyloidosis, and 30% (n=54) were screened according to this algorithm: 20 African-Americans (16 with MG), 16 with PN (11 with MG), 7 with RA without marrow amyloid (all with MG), 7 referred for hereditary testing and 4 without MG. Of those with amyloidosis and monoclonal gammopathies, 6% (2/34) had both a monoclonal gammopathy and heterozygosity for a mutant TTR: a 45 year-old African-American man (V122I) with cardiac amyloid and a 59 year-old man (F64L) with polyneuropathy. Of the 9 African-American and PN patients without MG, 4 had mutant TTR. Of 7 sent for hereditary testing, 6 had mutant TTR, one of whom also was found to have undiagnosed stage I lambda light-chain myeloma. Of 4 without MG, 2 had senile cardiac amyloid, 1 AA and 1 had amyloid that could not be typed. For those with mutant TTR and MG, TTR tissue-staining resolved the type of amyloid. These results justify further study of screening for hereditary variants in patients with apparent AL, including those with AL associated with multiple myeloma. Myelotoxic therapies such as stem cell transplant are not appropriate treatments for patients with hereditary amyloidosis. These results also highlight the need for the development, validation and dissemination of reliable techniques for identifying fibrils extracted from tissue, and raise the question as to whether or not hereditary amyloid proteins increase the risk of developing MG.