Sharmila Dorbala, MD, MPH, MASNC

Differentiating Between Light Chain and Transthyretin Amyloidosis

Summary for Physicians: The Importance of Differentiating Between Light Chain Amyloidosis and Transthyretin Amyloidosis

 (ATTR amyloidosis) is crucial for proper diagnosis, treatment planning, and patient management. Both are types of systemic amyloidosis but have different etiologies, clinical presentations, and treatment strategies. Here’s why this distinction is important:

Different etiologies and pathophysiologies

: AL amyloidosis results from the production of abnormal immunoglobulin light chains, typically by plasma cell dyscrasias such as multiple myeloma. These misfolded proteins accumulate as amyloid fibrils in organs, most commonly the heart, kidneys, liver, and nervous system.

: ATTR amyloidosis occurs due to the deposition of misfolded transthyretin (TTR) protein, either due to hereditary mutations in the TTR gene (familial ATTR) or age-related amyloid deposition in the absence of a mutation (wild-type ATTR). The affected organs primarily include the heart and nervous system.

: Understanding the underlying cause of amyloidosis is essential for determining the appropriate therapeutic approach. AL amyloidosis requires treatments that address the underlying plasma cell disorder, whereas ATTR amyloidosis requires different disease-modifying therapies targeting the TTR protein.

: Treatment focuses on managing the underlying plasma cell disorder. This often involves chemotherapy, stem cell transplantation, or novel therapies such as immunomodulatory agents (eg, daratumumab, bortezomib). The goal is to reduce or eliminate the production of the abnormal light chains.

: Treatment for ATTR amyloidosis includes therapies such as TTR stabilizers (eg, tafamidis), RNA interference (eg, patisiran, inotersen), and gene silencing. These therapies aim to stabilize the TTR protein and prevent further amyloid deposition.

: Administering the wrong treatment for either condition could lead to suboptimal results or even worsen the patient’s condition. Therefore, accurate diagnosis is critical to ensure the correct therapeutic pathway is pursued.

: AL amyloidosis is often associated with more aggressive disease and a poorer prognosis, particularly if it is diagnosed late. Early intervention is crucial to prevent organ damage and improve survival.

: Although ATTR amyloidosis (especially wild type) tends to have a more indolent course, early intervention with TTR-stabilizing therapies can significantly improve outcomes, particularly for heart failure and neurological symptoms.

: A correct diagnosis of either AL or ATTR amyloidosis will lead to better disease monitoring and prognosis prediction, as well as timely intervention to improve quality of life and survival.

: Diagnosis is confirmed by the detection of light chain protein deposits in tissues, typically using 

. In cases of familial ATTR, genetic testing can reveal specific mutations.

: Accurate diagnostic testing using appropriate tools for each type of amyloidosis is essential for confirming the diagnosis and differentiating between these 2 conditions.

: Differentiating between AL amyloidosis and ATTR amyloidosis is vital for determining the correct treatment, optimizing patient outcomes, and providing an accurate prognosis. Both conditions have distinct underlying causes, therapeutic approaches, and prognoses, making accurate diagnosis and tailored treatment critical for effective management.

Videos

Panelists discuss how differentiating between light chain amyloidosis and transthyretin amyloidosis is crucial for accurate diagnosis, appropriate treatment selection, and optimal patient management, given their distinct etiologies, therapeutic approaches, and prognoses.

Increasing Awareness Around ATTR-CM

Summary for Physicians: The Call to Action for ATTR-CM Awareness and Its Classification as a Rare Disease (Brito et al 2023)

The Call to Action for Raising Awareness for ATTR-CM (Brito et al 2023)

: The call to action to raise awareness about 

 (ATTR-CM) stems from the realization that this condition is frequently underdiagnosed or misdiagnosed despite its growing prevalence and devastating impact on patients. ATTR-CM can easily be mistaken for other common cardiac conditions such as heart failure with preserved ejection fraction, which leads to delays in diagnosis and appropriate treatment.

: ATTR-CM is often diagnosed too late, after irreversible damage has occurred. Early recognition is critical, as recent advancements in diagnostic tools (eg, 99mTc-PYP scintigraphy) and disease-modifying therapies (eg, tafamidis, patisiran, and inotersen) can significantly improve patient outcomes when started early.

: The increasing recognition of the disease, especially in the aging population, has prompted the need for greater awareness. Both hereditary (mutated 

 gene) and wild-type ATTR (mostly seen in older adults) contribute to the disease burden. As the population ages, ATTR-CM is expected to be more common than previously recognized.

: Raising awareness among health care providers, especially cardiologists, can lead to faster diagnosis, earlier treatment initiation, and better management, ultimately improving quality of life and survival for affected patients.

 emphasized by Dr Abou Ezzeddine and Brito et al, highlights the importance of increased awareness, faster diagnosis, and early therapeutic intervention to optimize patient outcomes in ATTR-CM.

Is ATTR-CM Still Considered a Rare Disease?

: Although ATTR-CM was historically classified as a rare disease, this is increasingly being questioned, especially with the rise in awareness and the availability of diagnostic tools. It is becoming clear that ATTR-CM is not as rare as once thought, particularly in aging populations.

: Advances in imaging techniques, genetic testing, and biomarker identification have led to increased recognition of ATTR-CM. As more clinicians consider this diagnosis in patients with unexplained heart failure, the number of diagnosed cases grows.

: Wild-type ATTR-CM, which primarily affects older individuals, is much more common than previously acknowledged. This form of the disease is now recognized as a significant cause of heart failure in older populations, suggesting that ATTR-CM may be more prevalent than we once thought, especially in older patients.

: The introduction of diagnostic imaging methods (eg, 99mTc-PYP scintigraphy) and genetic testing has enabled clinicians to detect the disease earlier, even in asymptomatic or mildly symptomatic patients, further contributing to the apparent rise in prevalence.

: ATTR-CM, although still classified as a rare disease by traditional definitions, is likely more common than previously recognized, especially in older populations. With better diagnostic tools and increasing awareness, the condition may no longer be considered rare, and more patients will benefit from timely diagnosis and intervention.

Panelists discuss how increasing recognition of transthyretin amyloid cardiomyopathy (ATTR-CM), fueled by advancements in diagnostic tools and greater awareness, is challenging its classification as a rare disease, particularly in aging populations, and emphasizing the need for earlier diagnosis and intervention.

Sharmila Dorbala, MD, MPH, MASNC

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