What are AL (Amyloid Light-chain) amyloidosis and ATTR (Amyloid Transthyretin) amyloidosis?

AL and ATTR Amyloidosis: Distinct Types of Systemic Amyloidosis

AL (Amyloid Light-chain) amyloidosis and ATTR (Amyloid Transthyretin) amyloidosis are two major types of systemic amyloidosis characterized by abnormal protein deposition in tissues and organs, with distinct pathophysiology, clinical manifestations, and treatment approaches. 1

AL Amyloidosis

AL amyloidosis is characterized by:

• Results from abnormal production of immunoglobulin light chains by bone marrow plasma cells that form amyloid deposits 1
• Previously known as primary amyloidosis 1
• Lambda isotype occurs in 75-80% of cases, kappa isotype in the remaining cases 1
• Often associated with multiple myeloma (10-15% of patients with multiple myeloma have AL amyloidosis, and 10% of AL amyloidosis cases are associated with multiple myeloma) 1
• Primarily affects the heart and kidneys, causing restrictive cardiomyopathy and proteinuria respectively 1
• Can also involve soft tissues, liver, GI tract, autonomic and peripheral nervous systems, and lymph nodes 1
• Distinctive clinical manifestations include macroglossia (enlarged tongue), submandibular gland enlargement, periorbital purpura, and coagulopathy from acquired factor X deficiency 1
• Treatment focuses on targeting the underlying plasma cell dyscrasia using chemotherapy agents, including proteasome inhibitors, immunomodulators, and monoclonal antibodies 1, 2
• Approximately 20% of patients may be eligible for autologous stem cell transplantation 1

ATTR Amyloidosis

ATTR amyloidosis is characterized by:

• Caused by amyloid deposits made up of transthyretin (TTR) protein 1

• Occurs in two forms: hereditary (variant) or acquired (wild-type) 1

• Hereditary ATTR amyloidosis (ATTRv):

  • Caused by mutations in the TTR gene 1
  • Can manifest as familial amyloid polyneuropathy (primarily affecting nerves) or familial amyloid cardiomyopathy (primarily affecting the heart) 1
  • Requires genetic testing and counseling for relatives of affected patients 1

• Wild-type ATTR amyloidosis (ATTRwt):

  • Involves normal "wild-type" TTR protein that misfolds due to aging 1
  • Formerly known as senile amyloidosis 1
  • Primarily affects the heart 3
  • Often associated with carpal tunnel syndrome, spinal stenosis, and biceps tendon rupture 3

• Treatment options include TTR stabilizers (tafamidis), RNA-interference agents (patisiran, inotersen), and in selected cases, heart transplantation 4, 5, 2

Diagnostic Approach

• Clinical suspicion should be raised with:

  • Unexplained heart failure with preserved ejection fraction
  • Unexplained proteinuria
  • Peripheral/autonomic neuropathy
  • Characteristic organ involvement patterns 1, 2

• Diagnostic workup includes:

  • Monoclonal protein screening (serum and urine immunofixation, serum free light chain assay) 1
  • Cardiac imaging (echocardiography, cardiac MRI, nuclear scintigraphy) 1, 3
  • Tissue biopsy (endomyocardial, abdominal fat pad, affected organ) with Congo red staining 1
  • Amyloid typing via immunohistochemistry or mass spectrometry 1, 6
  • TTR gene sequencing in confirmed ATTR cases 1

Important Clinical Distinctions

• Cardiac involvement is the main determinant of prognosis in both types 1, 7
• Biomarkers like natriuretic peptides and troponins are important for risk stratification 7
• Musculoskeletal manifestations (biceps tendon rupture, spinal stenosis) are more characteristic of ATTR amyloidosis 1, 3
• Early diagnosis is crucial as both types now have effective treatments that can significantly improve survival 2, 8
• False positive immunostaining can occur, making mass spectrometry important for definitive typing in some cases 6

Treatment Considerations

• AL amyloidosis: Therapy targets the underlying plasma cell clone 1, 2
• ATTR amyloidosis: Treatment aims to stabilize TTR protein or reduce its production 4, 5, 2
• Both conditions require multidisciplinary management involving cardiologists, hematologists, neurologists, and other specialists 1, 8
• Early treatment initiation before irreversible organ damage occurs is critical for improving outcomes 1, 2