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Diagnosis, amyloid typing, and risk stratification

Diagnosing AL amyloidosis involves 4 steps: proving systemic amyloid deposition, typing the deposits, assessing the monoclonal disease, and defining the extent of systemic damage including risk stratification/staging. Localized AL amyloidosis, resulting from in situ (eg, skin, airways, and urinary tract) production of LC, usually does not necessitate systemic therapy and should be differentiated from systemic amyloidosis, characterized by visceral involvement.

Demonstration of amyloid deposition in a tissue biopsy by Congo red staining remains the gold standard, although novel methods have been proposed.The most accessible site is periumbilical fat that can be easily and innocuously aspirated. Labial salivary gland biopsy is positive in >50% of patients with negative fat biopsy. If needed, target organs can be biopsied after careful assessment of hemostasis. Tissue deposits should be typed using mass spectrometry (the current gold standard), immuno–electron microscopy,or immunohistochemistry in specialized laboratories. Confirmation of fibril type is critical because a dozen proteins can cause systemic amyloidosis,each requiring distinct therapy. Even in patients with MGUS, cardiomyopathy caused by V122I mutant transthyretin (carrier rate of 4% in Afro-Caribbeans) or by wild-type transthyretin in elderly men with senile systemic amyloidosis, and amyloidosis reactive to chronic inflammation (AA) should be carefully considered in differential diagnosis. Gene sequencing is needed when familial amyloidosis is possible: such as in those with isolated neuropathic or cardiac disease (transthyretin amyloidosis), isolated renal involvement (fibrinogen amyloidosis), corneal lattice dystrophy, progressive bilateral facial paralysis and cutis laxa (gelsolin amyloidosis), dry mouth/gastrointestinal/kidney/liver involvement (lysozyme amyloidosis), and renal/liver/cardiac involvement in relatively asymptomatic patients (apolipoprotein-A1 amyloidosis). Amyloid typing and gene sequencing are available at all major referral centers.

The identification of amyloidogenic monoclonal proteins requires serum and urine immunofixation combined with FLC quantification. Half of all amyloidogenic PC clones produce LC only, with typically modest bone marrow infiltrate (median 5% to 10%). The λ clones dominate κ ones by 4:1, unlike the 2:3 ratio in myeloma. Fluorescence in situ hybridization of bone marrow PC and investigations to rule out symptomatic myeloma, including skeletal survey, should be done at baseline.

Assessment of amyloid-related organ damage is the next step. Echocardiography, including tissue Doppler and strain imaging, defines baseline cardiac function, in addition to widely available and well-standardized cardiac biomarkers. Cardiac magnetic resonance imaging is useful in diagnosing and possibly monitoring amyloid deposits. Renal involvement is best evaluated by eGFR and albuminuria. Liver function tests and size document involvement. Whole body imaging techniques like serum amyloid P component scintigraphy are useful, where available, for diagnosis and monitoring.^99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid or pyrophosphate scans help in differentiating cardiac AL from transthyretin amyloidosis (both mutated and wild type) and may spare cardiac biopsy. Simple parameters like poor performance status, New York Heart Association class ≥3, and low systolic blood pressure (<100 mm Hg) are useful bedside indicators of poor outcome. Because cardiac damage determines survival and treatment tolerability, the Mayo staging system using NT-proBNP (>332 ng/L) and cardiac troponin-T (cTnT)/troponin-I (cTnT, >0.035 ng/mL; cardiac troponin-I, >0.1 ng/mL), or more recently high-sensitivity cTnT (>0.077 ng/mL), is the most robust method for risk stratification. Stage III patients have a median survival of 3.5 to 8 months. High FLC levels predict poor outcome and early mortality and have been incorporated in the Mayo staging system.Renal function (especially when eGFR <30 mL/min) affects cardiac biomarkers concentration, and the Mayo staging is not directly applicable for patients in renal failure. BNP is more useful than NT-proBNP in these patients.