Evaluation of Abnormal Ferritin with Normal Transferrin Saturation

Introduction to Ferritin and Transferrin Saturation

Ferritin is a storage protein for iron and an acute phase reactant that can be elevated in inflammatory conditions, while transferrin saturation reflects iron that is readily available for erythropoiesis 1
Normal transferrin saturation (typically <45-50%) with elevated ferritin is not consistent with hereditary hemochromatosis, which typically presents with both elevated transferrin saturation and ferritin 2, 3
In healthy individuals, transferrin is normally not saturated more than 50% with iron under normal physiological conditions 4

An isolated elevated ferritin with normal transferrin saturation is commonly seen in inflammatory conditions (as ferritin is an acute phase reactant) 1
The American Association for the Study of Liver Diseases guidelines state that "a variety of disease conditions unrelated to iron overload may cause a nonspecific rise in serum ferritin, and in the absence of an elevated transferrin saturation, this rise may be nonspecific" 2
For patients with suspected iron metabolism disorders, both transferrin saturation and ferritin should be measured together as the first step in testing 3
The EASL guidelines recommend that "individuals with clinical and biochemical signs of hemochromatosis, elevated transferrin saturation and high serum ferritin concentrations, or otherwise unexplained persistently elevated transferrin saturation should be genetically tested for hemochromatosis" 3

If the patient has other symptoms or risk factors, consider evaluating for inflammatory conditions (check CRP, ESR) 1
In patients with liver disease, check liver enzymes and abdominal ultrasound 5
In patients with unexplained hyperferritinemia, MRI may be used to quantify hepatic iron concentrations if clinically indicated 3
For patients with isolated ferritin elevation and normal transferrin saturation, periodic monitoring of iron studies (ferritin and transferrin saturation) is recommended 2
The British Society of Gastroenterology recommends that iron deficiency should be confirmed by iron studies prior to investigation, with serum ferritin being the single most useful marker, but other blood tests (e.g., transferrin saturation) can be helpful if a false-normal ferritin is suspected 7