Limitations of Serum Ferritin in Diagnosing Iron Deficiency in Inflammatory Conditions

Abstract

Patients with inflammatory conditions such as inflammatory bowel disease (IBD), chronic heart failure (CHF), and chronic kidney disease (CKD) have high rates of iron deficiency with adverse clinical consequences. Under normal circumstances, serum ferritin levels are a sensitive marker for iron status but ferritin is an acute-phase reactant that becomes elevated in response to inflammation, complicating the diagnosis. Proinflammatory cytokines also trigger an increase in hepcidin, which restricts uptake of dietary iron and promotes sequestration of iron by ferritin within storage sites. Patients with inflammatory conditions may thus have restricted availability of iron for erythropoiesis and other cell functions due to increased hepcidin expression, despite normal or high levels of serum ferritin. The standard threshold for iron deficiency (<30 μg/L) therefore does not apply and transferrin saturation (TSAT), a marker of iron availability, should also be assessed. A serum ferritin threshold of <100 μg/L or TSAT < 20% can be considered diagnostic for iron deficiency in CHF, CKD, and IBD. If serum ferritin is 100-300 μg/L, TSAT < 20% is required to confirm iron deficiency. Routine surveillance of serum ferritin and TSAT in these at-risk groups is advisable so that iron deficiency can be detected and managed.

Figure 1

Normal iron homeostasis in the reticuloendothelial macrophage. Macrophages phagocytose aged or damaged red blood cells, using heme oxygenase 1 to release iron from heme, a recycling process that accounts for approximately 90% of the body's daily iron needs. Iron is rapidly released to circulating transferrin or, when present in excess, stored in ferritin. When required, ferritin is degraded in the lysosomes via a process called ferritinophagy and the iron is released. Iron(II) is exported from the macrophage via ferroportin in the cell membrane in a process coupled to reoxidation from iron(II) to iron(III) by membrane-bound ceruloplasmin. Iron(III) is then loaded onto transferrin for transport in the plasma.

Figure 2

The role of hepcidin in systemic iron homeostasis. (a) In healthy individuals, hepcidin production increases in response to increasing levels of transferrin-bound serum iron and iron stores. Hepcidin internalizes and degrades the iron transporter ferroportin, restricting the export of iron from enterocytes and from iron stores in hepatocytes and macrophages, to restore normal iron levels. (b) In inflammatory conditions, hepcidin production increases in response to inflammatory cytokines such as IL-6, disrupting the usual homeostatic mechanisms. Ferroportin is internalized and degraded, reducing transmembrane export of iron, and the availability of iron to bind to transferrin is restricted.