Therapeutic advances demand better typing of amyloid deposits

Current treatments for systemic amyloidoses include high-dose chemotherapy with autologous peripheral stem-cell rescue for monoclonal immunoglobulin light chain amyloidosis and and liver transplantation for hereditary amyloidosis. Such radical and aggressive procedures demand unequivocal typing of amyloid deposits. The following case illustrates the possible pitfalls of the diagnostic process. A 70-year-old man was seen because of fatigue and weight loss, chronic diarrhea, exertional dyspnea. His symptoms had worsened slowly over the past 5 years. Bilateral carpal tunnel syndrome had been treated surgically 10 years earlier. The family history was uninformative. Physical examination revealed marked macroglossia with teeth indentation, peripheral edema, and hepatomegaly. Echocardiography showed restrictive cardiomyopathy with a thickened interventricular septum of 14 mm. Proteinuria and elevated serum creatinine were present. An abdominal fat biopsy specimen showed green birefringence after Congo red staining. High-resolution immunofixation did not detect monoclonal immunoglobulins in serum, whereas three faint but distinct urinary bands composed of kappa light chains were identified. Immunoelectron microscopy characterization of amyloid deposits on fat biopsy unexpectedly showed that fibrils did not stain with anti-kappa antibody but reacted only with anti-transthyretin antibody. Transthyretin gene sequencing revealed a new point mutation, producing a novel Tyr78Phe variant. This mutation was absent in 100 control subjects and is not listed among nonpathologic variants identified in population screening studies. Although there is a significant clinical overlap between monoclonal immunoglobulin light chain amyloidosis and transthyretin amyloidosis, macroglossia and renal failure are typically associated with the former. Both these findings, together with identifying urinary kappa light chain bands, supported the diagnosis of primary amyloidosis in this patient. The long disease history of our patient was rather unusual, however, for AL amyloidosis. Moreover, sensitive laboratory techniques permit detecting in healthy elderly patients trace amounts of urinary polyclonal free light chains with restricted electrophoretic heterogeneity forming few discrete bands, a finding that can be confused with Bence Jones protein, as in this case. A monoclonal protein is rather commonly found in patients older than 55 years; therefore, a nonpathogenic monoclonal protein can occur in older patients affected by hereditary amyloidosis. When clinical or biochemical data are atypical, immunoelectron microscopy reliably identifies the protein forming the amyloid fibrils and helps determine the diagnosis. Considering the relevant impact of amyloid typing on treatment strategy and prognosis, we propose that immunohistochemical characterization be considered in the diagnostic algorithm for systemic amyloidoses. We favor ultrastructural typing, which offers higher specificity than light microscopy immunostaining.