High serum ferritin alone as a predictor of mortality and hemophagocytic lymphohistiocytosis

Abstract We report here utility of high serum ferritin alone as a predictor of mortality and diagnosis of hemophagocytic lymphohistiocytosis (HLH). We compared mortality in patients with high serum ferritin >5000 ng/mL versus <5000 ng/mL and looked for presence of HLH. Mortality was significantly higher (P‐value .0048) in patients with serum ferritin levels >5000 ug/dL. Of 21 patients with high serum ferritin, a median of three criteria were fulfilled to diagnose HLH. All patients had features of immune‐activation, and 76.2% patients had features of immune‐pathology favoring diagnosis of HLH. Serum ferritin can aid in prediction of mortality and help in the early diagnosis of HLH.


INTRODUCTION
Serum ferritin levels are high in hemophagocytic lymphohistiocytosis (HLH), and higher the ferritin values more likely is the diagnosis of HLH [1]. The clinical symptoms of HLH are common and similar to other infections, autoimmune conditions immunodeficiencies, and malignancies and therefore it may be difficult to clinch the diagnosis [2]. Timely diagnosis is crucial as suggested by more than 90% fatality rate in patients before the advent and use of immunomodulating drugs [1]. Ferritin is thought to play a role in the rapid detoxification of iron and facilitates iron nucleation, mineralization, and long-term iron storage [3]. It is also a part of positive regulation of transcription in response to oxidative stress and proinflammatory cytokine signaling through nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) pathway [4]. These functions of ferritin suggest that it might serve as a cytoprotective protein, minimizing oxygen free radical formation [3]. Small quantities of ferritin are also present in human serum and are elevated in conditions of iron overload and inflammation [5]. Measurement of ferritin levels does not require a specialized laboratory and is cheaper, and the report can be availed on the same day. Interleukin-2 receptor alpha chain (IL-2Ra) levels, on the other hand, requires a focused laboratory and is expensive and cumbersome to perform even though it is a sensitive test for diagnosis of HLH [6,7]. In this retrospective study, we report here utility of high serum ferritin alone as a predictor of mortality and diagnosis of HLH.

ICU admissions
Ten of the 21 (47.6%) patients required ICU admission and prolonged hospital stay, and six out of 10 (60%) died.
Cytopenias (bi or pan) were present in 14 of 21 (66%) patients. patients. Deranged liver function was used as a supportive evidence of immunopathological involvement suggesting HLH in these patients.
As per medical records none of the patients had documented central nervous system involvement, and no lumbar punctures were performed.

Treatment for HLH
Only nine of 21 (42.8%) patients received treatment mostly with steroids except one patient who received additional treatment with cyclosporine and etoposide.

DISCUSSION
Serum ferritin level has been included as a diagnostic criterion in HLH 2004 (>500 ng/mL). It is a simple and inexpensive test. In our patients only six criteria out of eight (as per HLH 2004 criteria [8]) were available to be tested as investigations like soluble CD25 and NK cell activity were not available. However, among the available tests also, not all were ordered due to lack of recognition of HLH as 138 LETTER an entity. Even though all criteria were not met among these patients, there was a higher rate of ICU admissions and mortality in patients with serum ferritin levels above 5000 ng/mL compared to those with ferritin levels below 5000 ng/mL. Despite the fact that our patients had clinical symptoms of HLH, due to lack of data we needed an alternative system to help in the diagnosis. In a study by Jordan et al, it had been discussed the diagnosis of HLH can be challenging, and the key is to consider underlying immune mechanisms (immune activation and immune pathology) along with the other diagnostic HLH criteria [9]. Also they further suggested that in sick patients even if less than five criteria are met, along with evidence of deranged liver functions, the diagnosis of HLH should be considered, and further evaluation and treatment should be initiated early [9]. In our study, >50% of patients with high serum ferritin levels (>5000 ng/mL) had evidence of deranged liver functions, and 47% patients required ICU admission, suggesting a high morbidity. Our study suggests that HLH may be underdiagnosed due to inadequate evaluation as a result of lack of awareness, cost constraints, and delayed results. This leads to increased mortality as HLH is a potentially fatal if left untreated.
In our study we looked at outcomes in terms of ICU admission and mortality.
It has been suggested previously that a serum ferritin value of >3000 ng/mL is of concern, and a value >10000 ng/mL is highly suggestive of HLH [1]. A previous study by Hearnshaw et al suggested that such high ferritin levels as seen in HLH are not observed in other illnesses [10]. We used a cutoff of >5000 ng/mL in our study since we observed that in our cohort the incidence of mortality was higher in these patients, and as we had a small cohort keeping a cutoff value >10000 ug/dL could probably lead to missed diagnosis.