Abstract
Ferritin is known to be involved in numerous physiological roles, such as iron storage, as well as various pathological conditions and in generalized inflammatory states. Hyperferritinemia is also encountered in the setting of hemophagocytic lymphohistiocytosis (HLH). Current diagnostic criteria exist to define HLH based on several clinical and biochemical markers, including the serum ferritin level. In this study, we retrospectively evaluated the value of ferritin >500 ng/mL in diagnosing HLH in 344 consecutive patients admitted to the medical intensive care unit at our hospital. Nine cases of HLH were identified. Comparison of the HLH with the non-HLH group showed that their maximum median serum ferritin level was 25,652 (range 1977–100,727 ng/mL) versus 1180 (503–85,168 ng/mL) (P < 0.001), platelets were 30 (5–92 × 103/μL) versus 113 (0–507 × 103/μL) (P < 0.001), absolute neutrophil counts were 2.56 (0.02–23.7 × 103/μL) versus 7.7 (0.01–82.7 × 103/μL) (P = 0.002), and triglycerides were 255 (156–394 mg/dL) versus 127 (17–624 mg/dL) (P = 0.002), respectively. Using a receiver operating characteristic curve, the optimal maximum serum ferritin level for the diagnosis of HLH was 3951 ng/mL, exceeding the current diagnostic cutoff set forth in the HLH-2004 guidelines. These data suggest that a higher cutoff value of ferritin level may have improved utility in the diagnosis of secondary HLH in the critical care setting.
Similar content being viewed by others
References
Filipovich AH. Hemophagocytic lymphohistiocytosis (HLH) and related disorders. Hematol Am Soc Hematol Educ Progr. 2009;2009(1):127–31.
Fisman DN. Hemophagocytic syndromes and infection. Emerg Infect Dis. 2000;6(6):601–8.
Farquhar JW, Claireaux AE. Familial haemophagocytic reticulosis. Arch Dis Child. 1952;27(136):519–25.
Arico M, Janka G, Fischer A, Henter JI, Blanche S, Elinder G, et al. Hemophagocytic lymphohistiocytosis. Report of 122 children from the International Registry. FHL Study Group of the Histiocyte Society. Leukemia. 1996;10(2):197–203.
Gholam C, Grigoriadou S, Gilmour KC, Gaspar HB. Familial haemophagocytic lymphohistiocytosis: advances in the genetic basis, diagnosis and management. Clin Exp Immunol. 2011;163(3):271–83.
Zhang K, Chandrakasan S, Chapman H, Valencia CA, Husami A, Kissell D, et al. Synergistic defects of different molecules in the cytotoxic pathway lead to clinical familial hemophagocytic lymphohistiocytosis. Blood. 2014;124(8):1331–4.
Niece JA, Rogers ZR, Ahmad N, Langevin AM, McClain KL. Hemophagocytic lymphohistiocytosis in Texas: observations on ethnicity and race. Pediatr Blood Cancer. 2010;54(3):424–8.
Ishii E, Ohga S, Tanimura M, Imashuku S, Sako M, Mizutani S, et al. Clinical and epidemiologic studies of familial hemophagocytic lymphohistiocytosis in Japan. Japan LCH Study Group. Med Pediatr Oncol. 1998;30(5):276–83.
Dandoy C, Grimley M. Secondary hemophagocytic lymphohistiocytosis (HLH) from a presumed brown recluse spider bite. J Clin Immunol. 2014;34(5):544–7.
Dinleyici EC, Bor O, Kiremitci A, Aksit MA. Secondary hemophagocytic lymphohistiocytosis associated with meningococcemia. Pediatr Hematol Oncol. 2006;23(8):683–6.
Pandey R, Kochar R, Kemp S, Rotaru D, Shah SV. Ehrlichiosis presenting with toxic shock-like syndrome and secondary hemophagocytic lymphohistiocytosis. J Ark Med Soc. 2013;109(13):280–2.
Kleynberg RL, Schiller GJ. Secondary hemophagocytic lymphohistiocytosis in adults: an update on diagnosis and therapy. Clin Adv Hematol Oncol. 2012;10(11):726–32.
Imashuku S, Hibi S, Sako M, Ishii T, Kohdera U, Kitazawa K, et al. Heterogeneity of immune markers in hemophagocytic lymphohistiocytosis: comparative study of 9 familial and 14 familial inheritance-unproved cases. J Pediatr Hematol Oncol. 1998;20(3):207–14.
Schneider EM, Lorenz I, Muller-Rosenberger M, Steinbach G, Kron M, Janka-Schaub GE. Hemophagocytic lymphohistiocytosis is associated with deficiencies of cellular cytolysis but normal expression of transcripts relevant to killer-cell-induced apoptosis. Blood. 2002;100(8):2891–8.
Rosado FG, Kim AS. Hemophagocytic lymphohistiocytosis: an update on diagnosis and pathogenesis. Am J Clin Pathol. 2013;139(6):713–27.
Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124–31.
Janka GE, Schneider EM. Modern management of children with haemophagocytic lymphohistiocytosis. Br J Haematol. 2004;124(1):4–14.
Allen CE, Yu X, Kozinetz CA, McClain KL. Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2008;50(6):1227–35.
Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med. 1999;340(6):448–54.
Hentze MW. Translational regulation of ferritin biosynthesis by iron: a review. Curr Stud Hematol Blood Transfus. 1991;58:115–26.
Kwak EL, Larochelle DA, Beaumont C, Torti SV, Torti FM. Role for NF-kappa B in the regulation of ferritin H by tumor necrosis factor-alpha. J Biol Chem. 1995;270(25):15285–93.
Porto G, De Sousa M. Iron overload and immunity. World J Gastroenterol. 2007;13(35):4707–15.
Ward RJ, Crichton RR, Taylor DL, Della Corte L, Srai SK, Dexter DT. Iron and the immune system. J Neural Transm. 2011;118(3):315–28.
Nemeth E, Ganz T. Anemia of inflammation. Hematol Oncol Clin North Am. 2014;28(4):671–81.
Zandman-Goddard G, Shoenfeld Y. Hyperferritinemia in autoimmunity. Isr Med Assoc J. 2008;10(1):83–4.
Knovich MA, Storey JA, Coffman LG, Torti SV, Torti FM. Ferritin for the clinician. Blood Rev. 2009;23(3):95–104.
Maiwall R, Kumar S, Chaudhary AK, Maras J, Wani Z, Kumar C, et al. Serum ferritin predicts early mortality in patients with decompensated cirrhosis. J Hepatol. 2014;61(1):43–50.
Agmon-Levin N, Rosario C, Katz BS, Zandman-Goddard G, Meroni P, Cervera R, et al. Ferritin in the antiphospholipid syndrome and its catastrophic variant (cAPS). Lupus. 2013;22(13):1327–35.
Torti FM, Torti SV. Regulation of ferritin genes and protein. Blood. 2002;99(10):3505–16.
Switala JR, Hendricks M, Davidson A. Serum ferritin is a cost-effective laboratory marker for hemophagocytic lymphohistiocytosis in the developing world. J Pediatr Hematol Oncol. 2012;34(3):e89–92.
Li F, Li P, Zhang R, Yang G, Ji D, Huang X, et al. Identification of clinical features of lymphoma-associated hemophagocytic syndrome (LAHS): an analysis of 69 patients with hemophagocytic syndrome from a single-center in central region of China. Med Oncol. 2014;31(4):902.
Li J, Wang Q, Zheng W, Ma J, Zhang W, Wang W, et al. Hemophagocytic lymphohistiocytosis: clinical analysis of 103 adult patients. Medicine (Baltimore). 2014;93(2):100–5.
Walsh TS, Saleh EE. Anaemia during critical illness. Br J Anaesth. 2006;97(3):278–91.
Maung AA, Kaplan LJ. Role of fibrinogen in massive injury. Minerva Anestesiol. 2014;80(1):89–95.
Leung JM, Sin DD. Biomarkers in airway diseases. Can Respir J. 2013;20(3):180–2.
Riviere S, Galicier L, Coppo P, Marzac C, Aumont C, Lambotte O, et al. Reactive hemophagocytic syndrome in adults: a retrospective analysis of 162 patients. Am J Med. 2014;127(11):1118–25.
Rajajee S, Ashok I, Manwani N, Rajkumar J, Gowrishankar K, Subbiah E. Profile of hemophagocytic lymphohistiocytosis; efficacy of intravenous immunoglobulin therapy. Indian J Pediatr. 2014;81(12):1337–41.
Conflict of interest
None to disclose.
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Saeed, H., Woods, R.R., Lester, J. et al. Evaluating the optimal serum ferritin level to identify hemophagocytic lymphohistiocytosis in the critical care setting. Int J Hematol 102, 195–199 (2015). https://doi.org/10.1007/s12185-015-1813-1
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12185-015-1813-1