Who can perform a workup for amyloidosis?

Who Can Perform a Workup for Amyloidosis

The workup for amyloidosis should be initiated by internists or primary care physicians when clinical suspicion arises, but requires collaboration with hematologists and cardiologists for definitive diagnosis and management, with ultimate referral to specialized amyloidosis centers whenever possible. 1, 2

Initial Clinical Recognition and Screening

Any physician can and should initiate the diagnostic workup when encountering red flag symptoms, including unexplained proteinuria, restrictive cardiomyopathy, peripheral neuropathy with autonomic features, bilateral carpal tunnel syndrome, hepatomegaly, macroglossia, or periorbital purpura. 1

Role of Primary Care Physicians and Internists

• Internists play a critical role in suspecting the disease early, which is essential since effective treatments exist but must be started before irreversible organ damage occurs. 2
• Primary care physicians should initiate basic screening tests including CBC with differential, BUN, serum creatinine, electrolytes, and most importantly, comprehensive monoclonal protein screening. 1
• The monoclonal protein screen must include all three tests simultaneously: serum free light chain assay (sFLC) with kappa/lambda ratio, serum immunofixation electrophoresis (SIFE), and urine immunofixation electrophoresis (UIFE). 1, 3, 4
• Standard protein electrophoresis (SPEP/UPEP) alone is inadequate because it fails to detect a monoclonal spike in nearly 50% of AL amyloidosis cases. 1, 3

Essential Specialist Involvement

Hematologist as Primary Coordinator

A hematologist should serve as the primary specialist directing the workup and treatment of amyloidosis, particularly for AL amyloidosis where plasma cell-directed therapy is required. 3

• Hematologists are essential for interpreting abnormal monoclonal protein screens, distinguishing between AL amyloidosis, monoclonal gammopathy of uncertain significance (MGUS), and multiple myeloma. 1
• They perform and interpret bone marrow biopsies to demonstrate clonal proliferation of lambda or kappa-producing plasma cells, which is mandatory for AL amyloidosis diagnosis. 1, 3
• Hematologists coordinate tissue biopsy procedures, including abdominal fat pad aspiration (84% sensitivity for AL-CM) or bone marrow biopsy (69% sensitivity for systemic AL amyloidosis). 1

Cardiologist Involvement

Cardiologists are essential because cardiac involvement is the main driver of disease prognosis and mortality in amyloidosis. 3, 5

• Cardiologists perform and interpret cardiac imaging studies including echocardiography showing increased left ventricular wall thickness, cardiac MRI with gadolinium showing late gadolinium enhancement, and nuclear scintigraphy (PYP scan) for ATTR diagnosis. 1, 6
• They collaborate with hematologists for monitoring cardiotoxicity of AL amyloidosis therapies and assessing cardiovascular fitness for high-dose melphalan with stem cell transplantation. 1
• For ATTR cardiac amyloidosis, cardiologists can make a noninvasive diagnosis using nuclear scintigraphy without tissue biopsy, provided monoclonal protein screening is negative. 1

Additional Specialists Based on Organ Involvement

• Nephrologists manage kidney involvement, interpret serum free light chain concentrations in the context of renal dysfunction, and address proteinuria. 3
• Neurologists evaluate peripheral or autonomic nervous system involvement, particularly in hereditary ATTR amyloidosis. 1
• Gastroenterologists address GI tract involvement including malabsorption, diarrhea, and pseudo-obstruction. 1, 7

Critical Diagnostic Steps Requiring Specialized Expertise

Tissue Biopsy and Amyloid Typing

Tissue biopsy with Congo red staining is mandatory for diagnosis, showing characteristic apple-green birefringence under polarized light. 3, 7, 6

• Mass spectrometry (LC-MS/MS) is the gold standard for amyloid typing with 88% sensitivity and 96% specificity, and should be performed at specialized centers. 1, 3, 6
• Accurate typing is absolutely essential before initiating treatment because AL and ATTR amyloidosis require completely different therapeutic approaches. 3, 6, 8
• Immunohistochemistry and immunofluorescence have limitations in specificity and sensitivity, making mass spectrometry preferable. 6

Genetic Testing

Genetic mutational analysis must be performed to identify hereditary forms, especially in African-Americans and patients with peripheral neuropathy. 1

Referral to Specialized Centers

Patients should be referred to specialized amyloidosis centers whenever possible because the workup requires adequate technology and expertise. 2, 5

• Specialized centers have access to mass spectrometry for definitive amyloid typing. 6, 8
• They provide multidisciplinary teams including hematologists, cardiologists, nephrologists, neurologists, and transplant specialists working collaboratively. 1, 3
• Fragmented care without coordination between specialists leads to suboptimal treatment outcomes. 3

Common Pitfalls to Avoid

• Delayed diagnosis occurs when physicians fail to consider amyloidosis due to nonspecific and vague symptoms; early specialist referral is critical. 1, 3, 2
• Using standard protein electrophoresis alone misses approximately 50% of AL amyloidosis cases; always order the complete three-test monoclonal protein screen. 1, 3
• Overlooking cardiac involvement is a critical error since heart involvement drives prognosis and mortality. 3, 5
• In 10-40% of ATTR-CM patients, an abnormal monoclonal protein screen may represent concomitant MGUS rather than AL amyloidosis, requiring hematologist interpretation. 1
• Failing to perform mass spectrometry for amyloid typing can lead to misdiagnosis, as over 10% of patients with monoclonal gammopathy can have ATTR deposits. 1