Is Serum Iron and Iron Binding Capacity Important for Diagnosis of Iron Deficiency?

Diagnosis of iron deficiency remains a common diagnostic dilemma. While gold standard bone marrow biopsies are impractical and invasive, serum ferritin is the most sensitive and specific test available.² Some recent studies define iron deficiency by transferrin saturations (serum iron/TIBCx100) less than 20% without concurrently low ferritin (<100 ng/mL).¹ A literature search shows there is no substantial data to support the practice of assuming iron deficiency with low iron saturations in the absence of a ferritin <100 ng/mL. Published data have documented a sensitivity and specificity of 98% with serum ferritin levels <41 ng/mL in patients without inflammation.³ Data with inflammation reveals that ferritin levels over 100 ng/mL exclude diagnosis of iron deficiency for the majority of patients.^2-4  In patients with liver disease, no serum test has been shown to be accurate. ⁵ Unnecessary treatment with iron confers significant risks. Iron treatment in patients with ferritin levels >100ng/mL has been linked to adverse outcome and impaired immunity in a non-dialyzed population.⁶ Prioritizing transferrin saturation over serum ferritin as diagnostic test for iron deficiency may lead to inaccurate diagnosis and unnecessary treatment with iron. To determine the rate of potential misdiagnosis in iron deficiency based on low iron saturations, we performed an analysis of unselected iron panels over a year.

Analysis involved a retrospective review of 2,846 unselected patients. Records were reviewed to correlate iron saturations with ferritin levels at the San Diego Veteran's Affairs Hospital from December 2008-December 2009. The study was approved by the UCSD Internal Review Board. Low iron saturations were compared to ferritin levels of <15, <30, <45, <60, <100 and >100 ng/mL using Spearman Correlation Coefficients. Low iron saturation is defined as less than 20%.

502 patients (47%) with low iron saturations (<20%) had ferritin levels over 100 ng/mL. 151 patients (30%) with ferritin levels under 40 ng/mL had elevated iron saturations. Ferritin values <30ng/mL, and ferritin levels >100ng/mL(spearman correlation, 0.18/p-value 0.006, 0.2/p-value <0.0001) have the strongest correlation to iron saturation levels. Ferritin levels between 30 and 60ng/mL do not have any statistical correlation to iron saturation levels. (Figure 2)

From our data, relying on iron saturations in lieu of ferritin levels could result in a high rate of misdiagnosis. For patients who are ill or have inflammation, relying on low iron saturation despite a ferritin over 100 ng/mL, may result in potential misdiagnosis in up to 47% of patients. Ferritin levels less than 30 ng/mL are sufficient for diagnosis of iron deficiency, without additional testing of iron level and TIBC for most patients.^2,3  Ferritin levels >100 ng/mL are sufficient for excluding iron deficiency in most patients, except for liver cirrhosis/hepatitis patients.^2-5 Ferritin levels above 100 ng/mL and below 30 ng/mL have a statistically significant correlation to iron saturation levels, raising the question whether additional iron studies are warranted in these patients. If ferritin levels between 30 ng/mL and 60 ng/mL do not have statistical correlation with iron saturation levels, perhaps a serum transferrin receptor quantification or bone marrow exam would provide more conclusive evidence in this group. Ordering only serum ferritin or algorithmic testing, instead of a traditional iron panel, will eliminate excess testing and improve accurate diagnosis.

No relevant conflicts of interest to declare.