Causes and Significance of Markedly Elevated Serum Ferritin Levels in an Academic Medical Center

Charles Moore, Jr, MD; Michelle Ormseth, MD; Howard Fuchs, MD

Disclosures

J Clin Rheumatol. 2013;19(6):324-328. 

In This Article

Discussion

Serum ferritin level is a nonspecific indicator of systemic illness and can be elevated through a variety of mechanisms, which may overlap or coexist. Systemic inflammation plays a key role in the initiation and perpetuation of hyperferritinemia. Serum ferritin has been widely accepted as an acute-phase reactant and is nonspecifically elevated in a wide variety of inflammatory states including infection, malignancy, and autoimmune diseases. It is particularly elevated in cases of AOSD and HLH, and in fact, the diagnosis of both syndromes rests partially on the presence of a markedly elevated serum ferritin level.[7] Diagnostic criteria for HLH include a serum ferritin level greater than 500 μg/L as a minor criterion,[8] and an elevated serum ferritin level is seen in approximately 90% of patients with AOSD/SJIA.[9] In both of these syndromes, serum ferritin levels can exceed 20,000 μg/L.[10] Several groups have established a role for glycosylated ferritin in the diagnosis of inflammatory causes of hyperferritinemia. Fardet et al.[11] found significantly lower levels of glycosylated ferritin in patients with hemophagocytic syndrome, and Fautrel et al.[12] found that diagnostic criteria for AOSD, which included a glycosylated ferritin fraction of 20% or less, resulted in improved sensitivity and specificity. This assay, however, is as yet not widely used or available, and glycosylated ferritin levels were not available to us in this analysis.

Serum ferritin and systemic iron handling are affected by inflammatory pathways involving the up-regulation of hepcidin. Ferroportin is a cellular membrane protein that allows the egress of iron from enterocytes into the circulation. It is present as well on cells of the reticuloendothelial system, particularly macrophages. Hepcidin binds to and inactivates ferroportin, causing its internalization and degradation within the cell, the net effect of which is to decrease iron absorption from the gut and to limit the amount of iron made available to the circulation, sequestering iron within the reticuloendothelial system.[13] Hepcidin production within the liver is stimulated by proinflammatory cytokines, particularly IL-6,[14] and it is this constellation of findings (decreased serum iron, increased ferritin, and increased hepcidin levels) that is seen in anemia of chronic inflammation. It is likely that this mechanism at least partially underlies the hyperferritinemia seen in patients with chronic infections, chronic kidney disease, autoimmune disease, and malignancies.

In our patient population, there were very few patients with HLH/MAS or AOSD/SJIA. This may attest to the relative rarity of these diseases, even in a large tertiary medical center. The ferritin cutoff of 1000 μg/L was chosen based on previous work showing that a cutoff of greater than 5 times the upper limit of normal is suggestive of AOSD,[15] but it is possible that this value was too high to pick up more of these patients. For example, in a Japanese cohort of patients with AOSD, 6 of 34 patients had normal ferritin levels, and 6 patients with elevated hyperferritinemia had levels less than 5 times the upper limit of normal.[16] Although our patients with established Still's disease or HLH/MAS had markedly elevated serum ferritin levels as one would expect, many more patients with extreme hyperferritinemia had an alternative diagnosis, such as malignancy or infection.

Five of our patients we were unable to clearly categorize. Three of these had undergone solid organ transplantation and were receiving chronic immune suppressive therapy. Although all 3 had normal graft function, it is possible that they all had some level of chronic inflammation, which would account for their elevated serum ferritin level. Iron indices and acute-phase reactants in these patients either were not available or were not indicative of anemia of chronic inflammation. There are data in patients undergoing stem cell transplant for hematologic malignancies showing a poorer prognosis in those with pretransplant iron overload and hyperferritinemia.[17] We are not aware of data showing the significance of hyperferritinemia in posttransplant patients with otherwise normal graft function. The 2 remaining patients in this category clearly demonstrated the strong likelihood of an underlying inflammatory process (fever, weight loss, pleural effusions) but, unfortunately, remained undiagnosed.

There are weaknesses in an analysis of this kind. Most prominently, it can be difficult to assign a single diagnosis to a multifactorial outcome. A markedly elevated serum ferritin level can arise from a wide variety of overlapping conditions, and it may be difficult to assign a primary cause in a patient with, for instance, both acute hepatic and chronic renal failure. We attempted to minimize the somewhat arbitrary nature of this assignment by using a simple algorithm, with disease states most associated with hyperferritinemia at the top and those where this association is less profound at the bottom. In this way, we feel we maximized our chances of correctly assigning the most likely etiology causing the highest burden of hyperferritinemia, even in patients with several conditions.

An additional difficulty arises from the nature of retrospective review of patient cases and the limitations of the data available. Up to a quarter of patients with apparent sepsis, for example, do not have documented infection.[18] It is possible that there are cases of autoimmune inflammatory disease in our cohort who were incorrectly diagnosed as "culture-negative" sepsis. These patients would not, in general, come to the attention of a rheumatologist, and it is possible that alternative diagnoses may not have been entertained.

Having a higher ferritin cutoff value is typically considered more valuable in predicting the presence of an underlying inflammatory disease. We used a cutoff value greater than 1000 μg/L. We did this because these values are more commonly encountered in the clinical setting, making our analysis more broadly applicable. Although patients in our study with inflammatory conditions such as AOSD or MAS/HLH did have significantly higher serum ferritin levels than those without, the majority of patients with serum ferritin levels greater than 10,000 μg/L carried diagnoses similar to the cohort as a whole.

Finally, our patient population is taken from a tertiary academic medical center and may not reflect a range of diseases or conditions that would more typically be encountered in general practice. In particular, our patients include a significant number of transplant patients, both solid and hematologic. It is possible that the causes of marked hyperferritinemia in a nonacademic medical center would trend more toward malignant and infection causes.

In conclusion, although a markedly elevated serum ferritin level may occur in the presence of an inflammatory disease, it is far more likely to accompany nonrheumatologic conditions such as malignancy, infection, or liver disease. In addition, there are patients with indolent levels of chronic inflammation who may appear well yet have extremely high ferritin levels.

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