Figure 1.
Presenting features and diagnostic algorithm for AL amyloidosis. Amyloidosis can be suspected if elevated biomarkers of organ involvement are detected during follow-up of patients with MGUS or if suggestive symptoms arise. The first scenario is ideal and enables early presymptomatic diagnosis. Based on relative rates of progression, appropriate screening programs should detect 1 patient with MGUS progressing to AL amyloidosis for every 7 to 10 who develop multiple myeloma. In patients with MGUS in whom elevated NT-proBNP or BNP is found, cardiac magnetic resonance imaging can be used as a higher specificity confirmatory test. If symptoms of systemic amyloidosis arise in a patient in whom a preexisting monoclonal gammopathy is not known, the first step should be searching for a monoclonal component, particularly if heart involvement is suspected, so as not to delay diagnosis. Only the combination of immunofixation of both serum and urine and FLC measurement grant adequate diagnostic sensitivity to detect amyloidogenic monoclonal proteins. MS-based methods are under investigation. Patients with suspect cardiac amyloidosis without monoclonal components can have an attempted nonbiopsy diagnosis of ATTR amyloidosis with cardiac scintigraphy with bone tracers. Validated tracers are 99mTc-diphosphono-propanodicarboxylic acid, 99mTc-pyrophosphate, and 99mTc-hydroxymethylene diphosphonate. DNA analysis is necessary to differentiate between hereditary and wild-type ATTR amyloidosis and to rule out other rarer hereditary forms. All other patients require a tissue diagnosis. Amyloid deposits can be found in abdominal fat, minor salivary glands, and bone marrow, and most patients can be spared biopsy of the involved organ. However, if amyloidosis is deemed probable, for a prompt start of treatment, organ biopsy should not be deferred. Amyloid deposits are recognized as nonbranching fibrils of 7 to 10 nm in width, detected by light microscopy with green birefringence under polarized light after staining with Congo red or by electron microscopy. The diagnostic sensitivity of abdominal fat aspirate combined with bone marrow or minor salivary gland biopsy is ∼90% at referral centers, but the recognition of amyloid deposits is affected by the experience of the pathologist. With a few exceptions (eg, patients with a monoclonal component and periorbital purpura and/or macroglossia, or combination of amyloid heart and renal involvement with albuminuria), the clinical presentation of AL amyloidosis cannot reliably be differentiated from that of other types of systemic amyloidosis. Thus, amyloid tissue typing with adequate technology is mandatory. Standard light microscopy immunohistochemistry does perform satisfactorily, and patients should be referred to specialized centers for typing with adequate technology (immunohistochemistry with custom-made antibodies, IEM, or MS). Accurate clonal studies, biomarker-based staging, and assessment of comorbidities are necessary to design the therapeutic strategy. MRI, magnetic resonance imaging.

Presenting features and diagnostic algorithm for AL amyloidosis. Amyloidosis can be suspected if elevated biomarkers of organ involvement are detected during follow-up of patients with MGUS or if suggestive symptoms arise. The first scenario is ideal and enables early presymptomatic diagnosis. Based on relative rates of progression, appropriate screening programs should detect 1 patient with MGUS progressing to AL amyloidosis for every 7 to 10 who develop multiple myeloma. In patients with MGUS in whom elevated NT-proBNP or BNP is found, cardiac magnetic resonance imaging can be used as a higher specificity confirmatory test. If symptoms of systemic amyloidosis arise in a patient in whom a preexisting monoclonal gammopathy is not known, the first step should be searching for a monoclonal component, particularly if heart involvement is suspected, so as not to delay diagnosis. Only the combination of immunofixation of both serum and urine and FLC measurement grant adequate diagnostic sensitivity to detect amyloidogenic monoclonal proteins. MS-based methods are under investigation. Patients with suspect cardiac amyloidosis without monoclonal components can have an attempted nonbiopsy diagnosis of ATTR amyloidosis with cardiac scintigraphy with bone tracers. Validated tracers are 99mTc-diphosphono-propanodicarboxylic acid, 99mTc-pyrophosphate, and 99mTc-hydroxymethylene diphosphonate. DNA analysis is necessary to differentiate between hereditary and wild-type ATTR amyloidosis and to rule out other rarer hereditary forms. All other patients require a tissue diagnosis. Amyloid deposits can be found in abdominal fat, minor salivary glands, and bone marrow, and most patients can be spared biopsy of the involved organ. However, if amyloidosis is deemed probable, for a prompt start of treatment, organ biopsy should not be deferred. Amyloid deposits are recognized as nonbranching fibrils of 7 to 10 nm in width, detected by light microscopy with green birefringence under polarized light after staining with Congo red or by electron microscopy. The diagnostic sensitivity of abdominal fat aspirate combined with bone marrow or minor salivary gland biopsy is ∼90% at referral centers, but the recognition of amyloid deposits is affected by the experience of the pathologist. With a few exceptions (eg, patients with a monoclonal component and periorbital purpura and/or macroglossia, or combination of amyloid heart and renal involvement with albuminuria), the clinical presentation of AL amyloidosis cannot reliably be differentiated from that of other types of systemic amyloidosis. Thus, amyloid tissue typing with adequate technology is mandatory. Standard light microscopy immunohistochemistry does perform satisfactorily, and patients should be referred to specialized centers for typing with adequate technology (immunohistochemistry with custom-made antibodies, IEM, or MS). Accurate clonal studies, biomarker-based staging, and assessment of comorbidities are necessary to design the therapeutic strategy. MRI, magnetic resonance imaging.

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