The Fascinating but Deceptive Ferritin

Abstract

Although the emergence of erythropoiesis-stimulating agents has revolutionized the anemia management of chronic kidney disease (CKD) in the past two decades, strategies to assess iron (Fe) status and to provide Fe supplementation have remained indistinct. The reported cases of hemochromatosis in dialysis patients from the pre-erythropoiesis-stimulating agent era along with the possible associations of Fe with infection and oxidative stress have fueled the "iron apprehension." To date, no reliable marker of Fe stores in CKD has been agreed on. Serum ferritin continues to be the focus of attention. Almost half of all maintenance hemodialysis patients have a serum ferritin >500 ng/ml. In this ferritin range, Fe supplementation currently is not encouraged, although most reported hemochromatosis cases had a serum ferritin >2000 ng/ml. The moderate-range hyperferritinemia (500 to 2000 ng/ml) seems to be due mostly to non-Fe-related conditions, including inflammation, malnutrition, liver disease, infection, and malignancy. Recent epidemiologic studies have shown that a low, rather than a high, serum Fe is associated with a poor survival in maintenance hemodialysis patients. In multivariate adjusted models that mitigate the confounding effect of malnutrition-inflammation, serum ferritin <1200 ng/ml and Fe saturation ratio in 30 to 50% range are associated with the greatest survival in maintenance hemodialysis patients. Although ferritin is a fascinating molecule, moderate hyperferritinemia is a misleading marker of Fe stores in patients with CKD. It may be time to revisit the utility of serum ferritin in CKD and ask ourselves whether its measurement has helped us or has caused more confusion and controversy.

Combined High Serum Ferritin and Low Iron Saturation in Hemodialysis Patients

“…Such alterations are usually parallel to increased hepcidin activity (40,41). Inflammation-induced hyperferritinemia may result in a so-called "functional iron deficiency," which can block iron mobility and, hence, be useful in "acute" inflammation by iron containment in the reticuloendothelial system but harmful under "chronic" inflammation by leading to refractory anemia, such as in CKD or other chronic disease states (7). The results of our study are consistent with the role of inflammation in confounding such iron markers, especially ferritin.…”

“…Serum iron, ISAT, and ferritin are the most commonly used laboratory indicators in the diagnosis and management of iron deficiency anemia in CKD patients (7). However, in addition to iron stores, such non-iron-related factors as inflammation and nutritional status may have a bearing on variability of iron markers, especially serum ferritin variability (42).…”

“…Whereas serum ferritin is the main storage molecule for iron (7), it also is an acute phase reactant; i.e., its serum concentration tends to increase moderately in the presence of inflammation (3,7,8), which occurs commonly in MHD patients (9). Moreover, inflammation is closely related to protein-energy wasting in dialysis patients (10) and the simultaneous combination of these two conditions, also referred to as malnutrition-inflammationcachexia syndrome (MICS), is observed frequently in CKD patients (9).…”

Iron Metabolism, Iron Deficiency, Thrombocytosis, and the Cardiorenal Anemia Syndrome

“…More than 50% of the dialysis patient population in the U.S. have a ferritin level Ͼ500 ng/ml. Significantly higher mortality occurs only at a serum ferritin level Ͼ1,200 ng/ml [46].…”

“…Treatment with EPO can cause functional iron deficiency [34,45], and this can lead to thrombocytosis [45,46], which could predispose to a greater risk for cardiovascular events [46].…”