Iron deficiency across chronic inflammatory conditions: International expert opinion on definition, diagnosis, and management

Abstract

Iron deficiency, even in the absence of anemia, can be debilitating, and exacerbate any underlying chronic disease, leading to increased morbidity and mortality. Iron deficiency is frequently concomitant with chronic inflammatory disease; however, iron deficiency treatment is often overlooked, partially due to the heterogeneity among clinical practice guidelines. In the absence of consistent guidance across chronic heart failure, chronic kidney disease and inflammatory bowel disease, we provide practical recommendations for iron deficiency to treating physicians: definition, diagnosis, and disease-specific diagnostic algorithms. These recommendations should facilitate appropriate diagnosis and treatment of iron deficiency to improve quality of life and clinical outcomes.

Figure 1

The pathophysiology of iron deficiency in chronic inflammation. Increased cytokine levels in all conditions, and decreased renal clearance in CKD and CHF, result in enhanced hepcidin levels. High hepcidin levels bind, internalize and degrade ferroportin on the lateral membrane of duodenal enterocytes and spleen macrophages. Iron remains trapped in enterocytes, which are then shed in the gut. Iron is also sequestered into macrophages, which are responsible for destroying senescent red blood cells and recycling their iron. Serum ferritin levels are regulated by the iron content of macrophages and increase in inflammation (apoferritin as an acute‐phase protein). A decrease in circulating iron leads to lower amounts of iron bound to the iron carrier protein, transferrin, and subsequently to a decline in transferrin saturation and low iron supply to all organs. Furthermore, cytokines may also have negative effects on erythropoietin production in the kidney and erythroid cell maturation, while also increasing macrophage iron retention. Note that the increased iron losses that can occur in specific chronic inflammatory conditions are not illustrated here. Plus and minus signs represent increase/enhancement and decrease, respectively. EPO, erythropoietin; FPN, ferroportin; IL, interleukin; TNF, tumor necrosis factor; TSAT, transferrin saturation

Figure 2

Diagnostic algorithm: iron deficiency in chronic heart failure. *Look for other causes of anemia and treat accordingly. Hb, haemoglobin; IV, intravenous; NYHA, New York Heart Association; SF, serum ferritin; TSAT, transferrin saturation

Figure 3

Diagnostic algorithms: iron deficiency in (A) non‐dialysis and (B) dialysis chronic kidney disease. *If iron stores are normal but Hb is low, look for other causes of anemia and treat accordingly. **When prescribing ESA therapy, iron should always be administered. ESA, erythropoiesis‐stimulating agent; Hb, haemoglobin; IV, intravenous; SF, serum ferritin; TSAT, transferrin saturation

Figure 4

Diagnostic algorithm: iron deficiency in inflammatory bowel disease. *Look for other causes of anemia and treat accordingly. CRP, C‐reactive protein; Hb, haemoglobin; IV, intravenous; SF, serum ferritin; TSAT, transferrin saturation