Clinical Features of Systemic Amyloidosis: A Scoping Review

• This scoping review maps the earliest clinical signs of AL, ATTRwt, and ATTRv amyloidosis to improve early recognition and diagnosis.

• Distinct red flags across organ systems highlight missed diagnostic opportunities and specialty-specific presentation patterns

Systemic amyloidosis is a rare, multisystem disorder that is often challenging to diagnose due to vague and non-specific symptoms that frequently overlap with other disorders. By the time patients are diagnosed, irreversible organ impairment from amyloid deposition has occurred, contributing to substantial morbidity and mortality. While developing the American Society of Hematology (ASH) guidelines on systemic amyloidosis, we identified a critical knowledge gap in the recognition of the clinical presentation of its most common subtypes. Therefore, we conducted a scoping review of 117 studies following PRISMA-ScR guidelines to identify clinical "red flags" for light chain (AL) and transthyretin (ATTRwt, ATTRv) amyloidosis. Studies were identified from the comprehensive systematic review through the ASH amyloidosis diagnosis guideline panel, data mining, and grey literature review. Data were extracted and synthesized by systems to characterize the earliest and most frequently overlooked clinical red flags for the different types of amyloidosis. Shortness of breath and fatigue, the earliest symptoms of AL amyloidosis, contrast with the carpal tunnel syndrome occurring years before ATTRwt cardiac amyloidosis is diagnosed. Weight loss, unexplained abdominal pain, and early satiety were overlooked red flags for AL amyloidosis, compared to the preceding arrhythmias often missed in evaluation for ATTRwt amyloidosis. Sensory loss was the predominant neuropathic presentation for AL amyloidosis compared to the painful length-dependent neuropathy of ATTRv amyloidosis. Awareness of the early symptoms and distinct patterns across subtypes can enhance cross-specialty awareness and support earlier diagnosis and intervention of AL and ATTR amyloidosis.