Photo Credit: Rodrusoleg
A group of cardiology experts has proposed to redefine iron deficiency in heart failure.
According to a review article in Circulation, iron deficiency was widely considered the cornerstone of the differential diagnosis in patients with anemia. This condition, in the current era, is often related to gastrointestinal disorders, poor dietary intake, chronic kidney disease (CKD), or medications that inhibit iron absorption. Recently, it has become apparent that a proportion of patients with heart failure (HF) are also iron deficient. This has led to several double-blind, placebo-controlled trials of oral and intravenous (IV) iron supplementation in patients with reduced ejection fraction.
The definitions of iron deficiency and eligibility criteria used in these HF trials were largely informed by earlier experiences with profoundly anemic patients on hemodialysis. However, most patients with HF at risk of iron deficiency do not have significant anemia or advanced CKD. The goals of treating iron deficiency in renal anemia differ from those guiding the treatment of cardiomyopathy.
Identifying Iron Deficiency in Patients with HF
Iron deficiency in patients with HF can be classified as absolute or functional. Absolute iron deficiency is defined by the depletion of total body iron stores, often related to blood loss, poor dietary iron intake, or malabsorption. Functional iron deficiency, on the other hand, is characterized by adequate total body iron stores but an impairment in the mechanism by which these stores are mobilized to deliver iron to target tissues, such as erythroblasts for erythropoiesis or cardiomyocytes and skeletal muscles for maintaining contractile function.
Mechanisms Leading to Depleted Total Body Iron Stores in HF Patients
Patients with HF may experience absolute iron deficiency through various mechanisms. They often receive antiplatelet or anticoagulant drugs, which can cause occult gastrointestinal blood loss. Additionally, the use of proton pump inhibitors, which reduce the gastric acidity necessary for iron absorption, polyphenols in coffee, which impair iron absorption in the duodenum, and calcium channel blockers, which interfere with the uptake of iron by enterocytes, can all contribute to iron deficiency. Hepcidin increases, potentially resulting from hepatic congestion due to increased central venous pressures, may limit duodenal absorption of dietary iron. Elderly patients with HF may have poor dietary iron intake due to anorexia or suffer iron loss due to gastrointestinal malignancy.
Diagnosis of Absolute Iron Deficiency
The diagnosis of absolute iron deficiency is not conventionally made by measuring circulating iron or through bone marrow examination but rather by finding a serum ferritin level of less than 15 to 20 μg/L. Ferritin acts as an intracellular nanocage, storing excess cytosolic iron in a nonreactive form to be made available when needed. When levels of biologically reactive cytosolic iron within erythroid precursors are diminished, iron is released from ferritin through ferritin degradation, intensified when cytosolic iron is depleted. Although it is impossible to measure the labile intracellular pool of highly reactive catalytic iron in humans, the expression of ferritin inside cells can be estimated, as it is actively and proportionately secreted into the bloodstream, primarily from macrophages. Very low serum levels of ferritin imply accelerated degradation of intracellular ferritin within the reticuloendothelial system, occurring when cytosolic iron levels are depressed. Consequently, absolute iron deficiency is identified by a serum ferritin level <15 to 20 μg/L, generally in combination with hypochromic microcytic anemia.
Transferrin Saturation (TSAT)
TSAT is a key parameter in evaluating iron deficiency. TSAT is calculated by dividing the serum iron level by the total iron-binding capacity (TIBC) and multiplying by 100 to express it as a percentage. TSAT indicates the iron available in the bloodstream for erythropoiesis and other cellular functions. A TSAT below 20% suggests insufficient iron is available to meet the body’s needs despite the presence of iron stores. In the context of HF, TSAT is particularly useful as it helps identify functional iron deficiency, where iron stores are adequate but iron mobilization to the bloodstream is impaired. The current guideline for diagnosing iron deficiency in HF includes a serum ferritin level of less than 100 μg/L regardless of TSAT or a serum ferritin level of 100 to 299 μg/L with a TSAT of less than 20%. However, this definition has been criticized as it may not accurately reflect true iron deficiency states, particularly in the presence of inflammation, which can elevate ferritin levels independently of iron stores. A more accurate definition would prioritize TSAT less than 20% as a critical marker of iron deficiency in HF patients.
The Recommendation
“We propose that the current ferritin-driven definition of iron deficiency in HF be abandoned and that a definition based on hypoferremia (TSAT <20%) be adopted,” the authors expressed.
