Diagnostic Challenges in Amyloid Light-Chain Amyloidosis

ABSTRACT Amyloid light-chain (AL) amyloidosis is a rare plasma cell disorder characterized by the extracellular deposition of misfolded immunoglobulin light chains, resulting in organ dysfunction and high mortality. Delayed and missed diagnoses are common owing to nonspecific, heterogeneous symptoms. Evidence shows that racial and ethnic minorities, individuals with low socioeconomic status, and patients without access to specialized centers are more likely to experience delayed diagnoses and reduced treatment access. This introduces the potential for populations affected by AL amyloidosis to be excluded from clinical cohorts. From a laboratory perspective, diagnosis relies heavily on serum and urine free light-chain assays. Reference intervals present an ongoing challenge as recommendations shift from population-specific to population-inclusive models and as organ dysfunction confounds urine-based assays. Refinement of reference intervals using diverse cohorts, development of novel assays targeting amyloidogenic light chains, risk-based stratification approaches, and artificial intelligence–based predictive models show promise for earlier disease recognition. Addressing diagnostic delays while minimizing unnecessary interventions requires coordinated improvements in laboratory testing, provider education, infrastructure, and population-based research.