REVIEWFerritin for the clinician
Introduction
Ferritin, an iron storage protein, is the primary iron storage mechanism and is critical to iron homeostasis. Ferritin makes iron available for critical cellular processes while protecting lipids, DNA, and proteins from the potentially toxic effects of iron. Alterations in ferritin are seen commonly in clinical practice, often reflecting perturbations in iron homeostasis or metabolism. It is increasingly recognized that ferritin also plays a role in a multitude of other conditions, including inflammatory, neurodegenerative, and malignant diseases.
Section snippets
Ferritin in the context of iron homeostasis
In humans, the majority of iron is integrated within the globin proteins that facilitate the transport of oxygen throughout the body. Iron is also critical in converting oxygen into useable cellular energy by serving as a key component in the electron transfer chain. In addition to its role in respiration, iron is also utilized as an enzymatic co-factor in numerous other reactions. One such reaction is the conversion of ribose nucleotides to deoxyribose nucleotides, an iron-dependent process
Ferritin structure
Ferritin is an iron-binding protein that exists in both intracellular and extracellular compartments (reviewed in.9) Apoferritin forms a roughly spherical container within which ferric iron is stored as a ferrihydrite mineral, as shown in Fig. 1. (Apoferritin refers to the iron-free form of the protein; the iron-containing form is termed holoferritin or simply ferritin). The apoferritin shell is composed of 24 subunits. The subunits are of two types, termed H and L. The ratio of these subunits
Ferritin function
Ferritin serves as a critical component of iron homeostasis, as shown in Fig. 2. Its primary role is in iron sequestration in which it functions as a ferroxidase, converting Fe(II) to Fe(III) as iron is internalized and sequestered in the ferritin mineral core.
Iron is toxic in cellular systems because of its capacity to generate reactive species which can directly damage DNA and proteins. Ferritin captures and buffers the intracellular iron pool, and thus is a key component in organism
Ferritin in iron deficiency
Clinically, serum ferritin is most commonly obtained in combination with other iron parameters to gauge the iron status of a specific patient. Of the various laboratory values within an iron panel, the serum ferritin is the most useful in diagnosing iron deficiency. Though bone marrow biopsy with iron staining remains the gold standard, a low serum ferritin (<12 μg/L) is highly specific for iron depletion. Only two conditions other than iron deficiency are known to lower serum ferritin;
Iron overload conditions
Ferritin is also clinically useful in the identification and treatment of iron overload. Because iron is primarily regulated at the site of absorption and there is no physiologic process to excrete excess iron, most cases of iron overload occur as a result of abnormal iron absorption or excess iron administration (usually the result of repeated red cell transfusions). Excess iron collects within the liver and heart where it causes chronic free-radical induced injury. Over time, this tissue
Other measures of iron stores
The monitoring of iron overload was recently reviewed.26, 29, 30 New approaches include biomagnetic susceptometry and magnetic resonance imaging, which offer a noninvasive measure of iron deposition in the heart and liver.
Still’s disease
Adult onset Still’s disease is a systemic inflammatory disorder characterized by fever, arthritis, and rash that typically affects young women.37, 38 Elevated serum ferritin levels were seen in 89% of these patients in a recent series, nearly half of whom had levels greater than five times normal, though this did not correlate with time to disease remission or the presence of chronic or deforming arthritis.38 Another recent case control study established that an exaggerated ferritin response
Hemophagocytic syndrome
Hemophagocytic syndrome (also known as macrophage activation syndrome or lymphohistiocytic syndrome) is a heterogeneous group of disorders with a final common pathway consisting of hypertriglyceridemia, hyperferritinemia, pancytopenia, and multiple organ failure which is highly fatal.40 The syndrome is strongly associated with autoimmune disorders, particularly systemic lupus erythematosis and Still’s disease, and viral infections, particularly Epstein–Barr virus. Ingestion of red blood cells
Ferritin in selected neurologic disorders
Several iron disorders that affect movement and other neurologic functions have been well characterized, and have been the subject of recent comprehensive reviews.47, 48 We present those which are most common (Parkinson’s disease and restless legs syndrome) and those whose pathophysiology is most directly linked to abnormalities in ferritin.
Coronary artery disease
Coronary artery disease is a leading cause of death in developed countries. The relationship between iron overload and increased risk for developing cardiovascular disease was recently reviewed.63 Epidemiologic studies have shown a correlation between elevated serum ferritin and an increased risk of coronary artery disease and myocardial infarction.64 This association was first reported by Salonen et al. in the Finnish Kuopio Ischaemic heart disease risk factor study (KIHD) of greater than 1900
Breast cancer
The idea that excess iron can potentiate carcinogenesis is an intriguing one. Free iron can induce oxidative stress and DNA damage. Animal models have shown that excess free iron is carcinogenic. Kabat and Rohan recently reviewed the evidence for the role of excess iron in breast carcinogenesis.69 Oxidative stress is induced by a reactive oxygen species, the formation of which is mediated by free iron. Ferric iron (Fe3+) released from ferritin and hemosiderin is reduced to ferrous iron (Fe2+)
Practice points
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Low serum ferritin is highly specific for iron deficiency anemia in otherwise healthy patients, as virtually no other clinically significant conditions will result in very low levels. In patients with underlying inflammation or infection, the use of ferritin with other markers of iron deficiency, especially soluble transferrin receptor, allows the clinician to distinguish between anemia of inflammation and iron deficiency anemia.
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Ferritin levels are not particularly useful in end-stage renal
Acknowledgements
Supported in part by Grants from the National Institutes of Health (R01DK71892, SVT; R37 DK42421, FMT) and a predoctoral fellowship from the American Heart Association (LGC).
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