Screening and Diagnosis of ID in HF

One of the main challenges in diagnosing ID is the distinction between functional and absolute iron deficiency.^1,4,11 Iron deficiency can be absolute, when total body iron is decreased, or functional, when total body iron is normal or even increased, but iron is not available or not sufficient because it has been trapped in the iron storage pool.¹¹ This interplay between the iron storage pool (consisting of liver, spleen, and lymph nodes) and functional pool (consisting of red blood cells, bone marrow, and cardiac and skeletal muscle) makes it very challenging to diagnose ID.^1,11 In diseases like heart failure, due to complex pathophysiological mechanisms, the body often does not have enough iron to utilize for homeostasis despites normal iron levels within the storage pools, and more often ID in HF is functional rather than absolute.^11,12 Furthermore, although ID can decrease hemoglobin synthesis, it is only classified as anemia once hemoglobin levels fall below a certain level.¹² As such, screening for anemia is not enough, and the diagnosis of iron deficiency without anemia is a critical one to make, particularly in HF patients.¹² The gold standard for ID diagnosis is bone marrow aspiration with Prussian Blue staining, but this approach is not well-suited for everyday practice.⁵ Several biomarkers which are detected in the blood and secreted by tissues that utilize or store iron have been proposed to measure ID.¹¹ Two commonly-used markers for ID are serum ferritin, an intracellular protein that stores iron, and transferrin saturation (TSAT), a marker of how much serum iron is bound to transferrin, which is a molecule that carries iron to the storage and functional pools.^11,12 However, serum ferritin is a poor measure of iron deficiency in patients with heart failure, and many patients with normal serum ferritin (defined by many as greater than 100 µg/L) have iron deficiency. Inflammation or oxidative stress may also artificially increase ferritin concentrations, regardless of actual iron status. In contrast to other clinical settings, the ferritin threshold defining deficient iron storage is increased to 100 µg/L in heart failure patients to take account of the chronic inflammatory state.¹¹ As such, it is recommended that in chronic inflammatory conditions, including HF, when ferritin levels may be elevated, that TSAT levels must be used. These two markers, serum ferritin and TSAT make up the current definition of ID that is used in most heart failure trials: ferritin <100 µg/L or 100-299 µg/L with TSAT <20%.¹ This forms the basis for the diagnostic algorithm for ID in HF and for the potential initiation of iron repletion treatment to correct ID regardless of anemia status (Figure 1).¹ While acknowledging the limitations of this diagnostic approach and the need for an improved definition of ID, authors of the 2023 Scientific Statement on ID in HF from the Heart Failure Society of America endorsed it as a valid approach until optimal markers are identified.⁵