Letter to the editor regarding the article “Prevalence and prognostic value of different iron deficiency definitions in light chain cardiac amyloidosis patients”

Abstract

We read with great interest the study by Li et al., which investigated the prevalence and prognostic implications of different iron deficiency (ID) definitions in light chain cardiac amyloidosis (AL-CM) patients.¹ This study provides valuable insights into the role of iron metabolism in AL-CM and challenges the applicability of current heart failure (HF)-based ID definitions in this patient population. The authors demonstrate that TSAT <20% and serum iron <13 μmol/L, rather than guideline-defined ID, are independent predictors of all-cause mortality. These findings underscore the potential need to revise ID criteria in AL-CM and have implications for clinical risk stratification.

However, despite these strengths, several methodological concerns and limitations should be considered when interpreting the findings. First, the study is limited by its single-centre, retrospective design, which inherently introduces selection bias. The relatively small sample size (n = 149) may not be fully representative of the broader AL-CM population, particularly given regional differences in iron metabolism, treatment strategies, and underlying genetic or inflammatory profiles. A multicentre validation of these findings would be necessary before integrating TSAT or serum iron-based ID definitions into routine clinical practice.

Another major concern is the use of ferritin as a sole criterion in the guideline-based ID definition. Ferritin is an acute-phase reactant, and its levels can be elevated in AL-CM due to chronic inflammation, hepatic involvement or amyloid-related metabolic changes. This could explain why guideline-defined ID was not predictive of mortality, as ferritin-based classification may overlook functionally iron-deficient patients with AL-CM. Incorporating additional markers such as hepcidin or soluble transferrin receptor could help refine ID assessment in this cohort.

Additionally, the study does not fully address the potential impact of confounding factors such as nutritional status, renal function and chemotherapy regimens on iron metabolism and patient outcomes. AL-CM patients often have multifactorial anaemia, and distinguishing true ID from inflammation-induced dysregulation remains a challenge. Future studies should explore the dynamic interplay between iron homeostasis, disease progression and systemic inflammation.

Lastly, while the study suggests that ID defined by TSAT and serum iron is associated with worse outcomes, it does not establish whether iron supplementation could improve prognosis in AL-CM patients. Given the success of intravenous iron therapy in HF trials,² it would be crucial to investigate whether iron repletion strategies are beneficial in AL-CM, or if disease-specific mechanisms make ID a bystander rather than a modifiable risk factor.

In conclusion, Li et al. contribute to an important discussion regarding ID classification in AL-CM, but further research is needed to validate their proposed ID definitions, clarify the role of iron in disease pathogenesis and determine whether targeted iron interventions could alter clinical outcomes. Until such data become available, clinicians should interpret ID biomarkers in AL-CM with caution, considering the broader inflammatory and metabolic context.

None declared.