What are the abbreviations for AL (Amyloid Light chain) and ATTR (Amyloid Transthyretin) amyloidosis and what are the differential diagnoses between these two types of amyloidosis?

AL and ATTR Amyloidosis: Abbreviations and Differential Diagnosis

AL stands for Amyloid Light chain (immunoglobulin light chain amyloidosis) and ATTR stands for Amyloid Transthyretin amyloidosis—these two entities require fundamentally different treatments (chemotherapy/transplant for AL versus targeted therapies like tafamidis for ATTR), making accurate differentiation critical for patient survival. 1

Abbreviations and Definitions

AL Amyloidosis

• AL = Amyloid Light chain (immunoglobulin light chain amyloidosis) 2
• Results from abnormal production of immunoglobulin light chains by bone marrow plasma cells that misfold and form amyloid deposits 2
• Lambda isotype occurs in 75-80% of cases, kappa isotype in the remaining 20-25% 2
• Associated with multiple myeloma in 10-15% of patients with myeloma, and 10% of AL cases have concurrent myeloma 2

ATTR Amyloidosis

• ATTR = Amyloid Transthyretin 1, 2
• Caused by amyloid deposits made up of transthyretin (TTR) protein, a liver-synthesized thyroxine and vitamin A transporter 1, 2
• Two forms exist: wild-type (previously called senile amyloidosis, age-related) and hereditary/variant (caused by autosomal dominant TTR gene mutations) 1, 2

Key Differential Diagnostic Features

Clinical Presentation Differences

Organ Involvement Patterns:

• AL amyloidosis primarily affects heart and kidneys, causing restrictive cardiomyopathy and nephrotic-range proteinuria 1, 2
• ATTR amyloidosis predominantly involves the heart (both forms) and peripheral/autonomic nervous system (especially hereditary form) 1, 2
• AL commonly presents with organomegaly (hepatomegaly, macroglossia, enlarged salivary glands), which is less typical in ATTR 1

Age and Demographics:

• Wild-type ATTR typically affects older adults (age-related) 1
• Hereditary ATTR can present at younger ages depending on the specific mutation 2
• AL can occur across a broader age range, often associated with plasma cell disorders 2

Laboratory Differentiation

Critical First Step - Monoclonal Protein Screening:

• Obtain simultaneously: serum free light chains (sFLC), serum immunofixation electrophoresis (SIFE), and urine immunofixation electrophoresis (UIFE) 3
• Standard SPEP/UPEP alone misses up to 50% of AL cases due to low monoclonal protein levels 3
• AL amyloidosis: Positive monoclonal protein (free light chains, immunofixation) with abnormal kappa:lambda ratio 3, 4
• ATTR amyloidosis: Negative or low-level monoclonal protein studies 1, 5

Critical Pitfall: Over 10% of patients with monoclonal gammopathy (MGUS) can have ATTR deposits, making tissue diagnosis essential when both PYP is positive AND monoclonal protein studies are abnormal 5, 6

Imaging Differentiation

Nuclear Scintigraphy (99mTc-PYP):

• Positive PYP scan (Grade 2-3 uptake, heart-to-contralateral lung ratio >1.5 at 1 hour): Confirms ATTR when monoclonal protein studies are negative 5
• Negative PYP scan: Suggests AL amyloidosis (PYP does not bind AL deposits) 5, 7
• CRITICAL: If ANY monoclonal protein is present (even MGUS), PYP scan alone is insufficient—endomyocardial biopsy with mass spectrometry is required to definitively distinguish AL from ATTR or coexisting disease 5, 3, 6

Tissue Diagnosis - The Gold Standard

When Tissue Biopsy is Mandatory:

• Any patient with positive monoclonal protein AND positive PYP scan requires endomyocardial biopsy 5, 3
• Suspected concomitant AL and ATTR cardiac amyloidosis 3, 6
• Discordant clinical and laboratory findings 3

Typing Methods:

• Mass spectrometry (LC-MS/MS): Gold standard with 88% sensitivity and 96% specificity for identifying the amyloidogenic protein 3, 8
• Immunohistochemistry can produce false-positive light chain staining in ATTR patients, making mass spectrometry essential 8
• Congo red staining confirms amyloid presence but does not identify the type 3

Bone Marrow Biopsy:

• Required in AL amyloidosis to demonstrate clonal proliferation of lambda or kappa-producing plasma cells 3
• Excludes multiple myeloma or B-cell lymphoproliferative disorders 3
• Not needed for ATTR diagnosis 2

Prognostic Biomarkers

Both AL and ATTR:

• NT-proBNP and troponin are powerful prognostic indicators in both types 1, 4
• Multiple staging systems exist using these cardiac biomarkers 1

AL-Specific:

• Free light chains (dFLC) and kidney function are uniquely prognostic for AL 1, 4

ATTR-Specific:

• Kidney function (eGFR <45 mL/min/1.73 m²) indicates worse prognosis in ATTR 1

Treatment Implications - Why Differentiation Matters

AL Amyloidosis Treatment:

• Chemotherapy targeting plasma cell clone (bortezomib-based regimens, anti-CD38 antibodies like daratumumab) 1, 2, 7
• Autologous stem cell transplantation in eligible patients 1, 7

ATTR Amyloidosis Treatment:

• TTR stabilizers (tafamidis) 1, 7, 9
• RNA-interference agents (patisiran, inotersen) 7, 9
• Gene silencing therapies 9

The fundamental difference: AL requires chemotherapy/transplant to eliminate the plasma cell clone, while ATTR requires targeted therapies to stabilize or reduce TTR protein—using the wrong treatment approach will not improve outcomes and delays appropriate therapy 1, 7