Re-defining iron deficiency in patients with heart failure

ABSTRACT

Introduction

Iron deficiency (ID) is common in patients with chronic heart failure (CHF) and is associated with worse symptoms and prognosis regardless of whether anemia is also present. However, randomized controlled trials (RCT) of intravenous (IV) iron in patients with CHF have produced inconsistent results. This review considers the past, present, and future of defining and treating ID in patients with CHF.

Areas covered

The current guideline definition of ID is a serum ferritin <100 µg/L or serum ferritin 100–299 µg/L and transferrin saturation (TSAT) <20% derived from trials of IV iron in patients with end-stage renal failure. Ferritin synthesis and secretion is promoted by inflammatory cytokines which are raised in patients with CHF; thus, using ferritin to define iron deficiency in patients with CHF may be flawed. Observational data suggest that the current definition of iron deficiency in CHF does not identify a high-risk population.

Expert Opinion

Alternative indicators of ID such as low serum iron concentrations or TSAT may better identify patients with ID who are at greater risk of adverse outcome and thus, possibly, more likely to benefit from IV iron.

KEYWORDS:

• Iron deficiency
• heart failure
• IV iron
• ferritin
• transferrin saturations
• serum iron
• prognosis
• outcome

Article highlights

• Iron deficiency, defined as serum ferritin <100 µg/L or ferritin 100–299 µg/L and transferrin saturations (TSAT) <20%, is common in patients with heart failure (HF) and is associated with poorer quality of life and reduced longevity.

• Iron is essential to normal physiology thus it is, perhaps, surprising that all trials of iron replacement in patients with HF and iron deficiency to date have shown only modest symptomatic benefit, and no mortality benefit.

• HF is associated with high circulating levels of inflammatory cytokines – such as tumor necrosis factor alpha and interleukin 6—which also stimulate ferritin synthesis and secretion. Low serum ferritin may be an inaccurate marker of iron deficiency in patients with HF.

• Observational data suggest that ferritin is not strongly associated with outcome in patients with HF therefore the current definition of iron deficiency does not identify an at-risk population – potentially explaining the modest benefits of IV iron seen in randomized controlled trials.

• Alternative markers of iron deficiency, such as low serum iron, may better identify patients with iron deficiency who are at greatest risk of adverse outcome and, therefore, have the most to gain from iron replacement therapy.

• Reassessment of trial data using alternative definitions of iron deficiency will help clarify which patients with HF have the most to gain from iron replacement therapy.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Notes

1. Ferrous iron (non-heme bound) within erythroblasts reacts with potassium ferrocyanide forming ferric ferrocyanide which has a deep blue pigment.

Additional information

Funding

This paper was not funded.