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PubMed This is a summary of 22 peer-reviewed journal articles Updated
Hematology

The Biology of AL Amyloidosis: AL vs. ATTR

At a Glance

AL amyloidosis is caused by abnormal plasma cells in the bone marrow that produce toxic light chain proteins. These proteins misfold and build up in organs. It is biologically completely different from ATTR amyloidosis and requires entirely different treatments like chemotherapy.

Understanding the biology of AL amyloidosis is key to understanding why your treatment works the way it does. While the name “amyloidosis” is used for several different diseases, they are biologically very different and require “diametrically opposed” treatment strategies [1][2].

The Biological Engine: Plasma Cells and Light Chains

AL amyloidosis begins with a “dyscrasia,” or a malfunction, in your plasma cells—white blood cells in your bone marrow that usually protect you by making antibodies [3]. In this condition, a group of abnormal (clonal) plasma cells begins overproducing one specific piece of an antibody called a monoclonal light chain [4][5].

These light chains are unstable. Instead of staying dissolved in your blood, they “misfold” and clump together to form amyloid fibrils [4][6]. These fibrils deposit in your organs, but the light chains themselves are also “toxic.” In the heart, for example, circulating light chains can directly damage cells by causing oxidative stress and mitochondrial dysfunction, even before large amounts of fibrils have built up [7][8].

AL vs. ATTR: Two Different Diseases

A common point of confusion is the difference between AL (light-chain) and ATTR (transthyretin) amyloidosis. They may look similar on some scans, but their “engines” are completely different:

Feature AL Amyloidosis ATTR Amyloidosis
Source Plasma cells in the bone marrow [3] The liver (primarily) [5]
Protein Immunoglobulin Light Chains [4] Transthyretin (TTR) [9]
Treatment Chemotherapy / Immunotherapy [1] TTR stabilizers or “silencers” [2]
Progression Often rapid and aggressive [10] Typically slower and more gradual [10]

It is possible—though rare—for a patient to have dual pathology, where both AL and ATTR proteins are present at the same time [11][12]. This is most common in elderly patients, and sophisticated testing like Mass Spectrometry is often needed to tell them apart [13][11].

The Connection to Multiple Myeloma

AL amyloidosis is closely related to Multiple Myeloma, another bone marrow disorder [14]. Both involve abnormal plasma cells producing monoclonal proteins. The main difference is often the “concentration” and the “behavior” of the protein:

  • Multiple Myeloma is defined by a high volume of plasma cells (often 10% or more of the bone marrow) and can cause bone damage or high calcium levels [15][14].
  • AL Amyloidosis is defined by the toxicity of the light chains. Even a very small number of abnormal plasma cells can produce enough light chains to cause severe organ failure [4][16].

Some patients meet the diagnostic criteria for both conditions simultaneously [14][17].

Common “Misdiagnosis Traps”

Because AL amyloidosis is rare, it is frequently misdiagnosed as more common conditions. Doctors may initially suspect:

  • Idiopathic Nephrotic Syndrome: Unexplained protein in the urine [18].
  • Hypertrophic Cardiomyopathy: Unexplained thickening of the heart walls [19].
  • Standard Peripheral Neuropathy: Numbness or tingling attributed to age or diabetes [20].

If you have these symptoms and they are not responding to standard treatments, specialists look for a “monoclonal protein” in the blood or urine to check for AL amyloidosis [21][22].

Common questions in this guide

What is the main difference between AL and ATTR amyloidosis?
AL amyloidosis begins in the bone marrow and is caused by abnormal light chain proteins. ATTR amyloidosis primarily originates in the liver and involves the transthyretin protein. Because their biological engines are different, they require completely opposite treatment approaches.
How is AL amyloidosis related to multiple myeloma?
Both are bone marrow disorders involving abnormal plasma cells. Multiple myeloma is characterized by a high volume of these cells causing bone damage, while AL amyloidosis can occur with very few abnormal cells but causes severe organ damage due to toxic light chains.
Why is AL amyloidosis frequently misdiagnosed?
Because it is a rare disease, the symptoms mimic much more common conditions. It is frequently mistaken for standard heart failure, idiopathic kidney disease, or standard peripheral neuropathy until those conditions fail to respond to standard treatments.
How do doctors confirm I have AL amyloidosis and not ATTR?
Doctors use sophisticated testing, most notably mass spectrometry, to analyze the proteins in your tissue. This precise testing confirms exactly which type of amyloid protein is present, ensuring you don't receive treatment for the wrong disease.
Can the light chains damage my heart before amyloid builds up?
Yes. In AL amyloidosis, the circulating light chains are inherently toxic. They can cause direct damage to heart cells by creating oxidative stress and cellular dysfunction, even before large amounts of amyloid fibrils have physically built up.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Was my diagnosis confirmed by Mass Spectrometry to be 100% sure it is AL and not ATTR?
  2. 2.What is my bone marrow plasma cell percentage, and does it meet the criteria for a Multiple Myeloma diagnosis as well?
  3. 3.What is the 'difference between involved and uninvolved free light chains' (dFLC) in my blood right now?
  4. 4.If I have a 'monoclonal gammopathy' but my heart or kidneys aren't getting better, could I have both AL and ATTR amyloidosis?
  5. 5.Are my heart symptoms caused by the physical buildup of amyloid or the direct toxic effects of the light chains?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

References (22)
  1. 1

    Cardiac Care of Patients with Cardiac Amyloidosis.

    Itzhaki Ben Zadok O, Kornowski R

    Acta haematologica 2020; (143(4)):343-351 doi:10.1159/000506919.

    PMID: 32408301
  2. 2

    Diagnosing AL and ATTR Amyloid Cardiomyopathy: A Multidisciplinary Approach.

    Aus dem Siepen F, Hansen T

    Journal of clinical medicine 2024; (13(19)) doi:10.3390/jcm13195873.

    PMID: 39407933
  3. 3

    Long-term outcome of patients with AL amyloidosis treated with high-dose melphalan and stem cell transplantation: 20-year experience.

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    Acta haematologica 2019; (141(2)):93-106 doi:10.1159/000495455.

    PMID: 30650422
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    Dissection of the amyloid formation pathway in AL amyloidosis.

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    Nature communications 2021; (12(1)):6516 doi:10.1038/s41467-021-26845-0.

    PMID: 34764275
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    Amyloid Light Chain Proteins in Cardiovascular Disease: Pathogenesis and Emerging Therapies for Cardiac Amyloidosis.

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    Pharmaceutical research 2025; doi:10.1007/s11095-025-03965-6.

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    Successes in translation.

    Westermark P, Merlini G

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    Prognostic impact of light-chain and transthyretin-related categories in cardiac amyloidosis: A systematic review and meta-analysis.

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    Prognostic Impact of Bone Marrow Plasma Cell Percentage in Patients With Systemic Light-Chain Amyloidosis: A Systematic Review and Meta-Analysis.

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This page explains the biological mechanisms of AL amyloidosis for educational purposes only. It does not replace professional medical advice. Always consult your hematologist or oncologist regarding your specific diagnosis and treatment.

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