Comparison of methemoglobin levels in food protein-induced enterocolitis syndrome and other gastrointestinal diseases in neonates

Main Article Content

Eishi Makita
Sae Kuroda
Hiroaki Sato
Kae Itabashi
Atsuko Kawano
Misa Matsuura
Yohei Sugiyama
Daisuke Sugawara
Asami Maruyama
Ko Ichihashi


Food allergy, Food protein-induced enterocolitis, syndrome, Methemoglobin, Milk allergy, Newborn


Introduction and objectives: Methemoglobinemia has been reported to be associated with severe food protein-induced enterocolitis syndrome (FPIES). However, no reports have evaluated methemoglobin (MHb) levels in FPIES without symptomatic methemoglobinemia or the usefulness of MHb measurement for the diagnostic prediction of FPIES. To evaluate the MHb levels of patients with neonatal-onset FPIES and determine whether MHb levels are higher in FPIES than in other gastrointestinal diseases.

Patients and methods: Eleven neonates with severe acute FPIES (FPIES group) and 139 neonates with other gastrointestinal diseases (non-FPIES group) were included in this study. Patient characteristics, symptoms, and venous blood test values (MHb, pH, HCO3 −, and C-reactive protein) were evaluated.

Results: The median age at onset was 16 days vs. 1 day; males comprised 64% vs. 46%, the median gestational age was 38 weeks vs. 38 weeks, the median birth weight was 2710 g vs. 2880 g, and the median hospitalization duration was 31 days vs. 6 days for the FPIES vs. non-FPIES groups, respectively. MHb (%) was higher in the FPIES group than in the non-FPIES group [median (range), 1.1 (0.6-10.9) and 0.6 (0.3-1.2), respectively, p < 0.001]. There were no differences in terms of pH, HCO3 −, and C-reactive protein (p > 0.05). In the receiver operating characteristic analysis for FPIES diagnosis based on MHb (%), the area under the curve was 0.885, specificity was 97.1%, and sensitivity was 72.7% at a MHb cutoff of 1.0.

Conclusion: High MHb levels may help diagnose severe acute FPIES in neonates, but careful evaluation is needed.

Abstract 127 | PDF Downloads 186


1. Nowak-Wegrzyn ˛ A, Katz Y, Mehr SS, Koletzko S. NonIgE-mediated gastrointestinal food allergy. J Allergy Clin Immunol. 2015;135:1114-24,

2. Nowak-Wegrzyn ˛ A, Charade M, Groesch ME, Spergel J, Wood RA, Allen K, et al. Position paper: International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: executive summary - Workgroup Report of the Adverse Reactions to Foods Committee, American Academy of Allergy, Asthma & Immunology Division of Allergy and Immunology. J Allergy Clin Immunol. 2017;139:1111-26,

3. Anand RK, Appachi E. Case report of methemoglobinemia in two patients with food protein-induced. Clin Pediatr. 2006;45:679-82,

4. Hwang JB, Lee SH, Kang YN, Kim SP, Suh SI, Kam S. Indexes of suspicion of typical cow milk protein-induced enterocolitis. J Korean Med Sci. 2007;22:993-7,

5. Hwang JB, Sohn SM, Kim AS. Prospective follow-up oral food challenge in food protein-induced enterocolitis syndrome. Arch Dis Child.

6. Murray KF, Christie DL. Dietary protein intolerance in infants with transient methemoglobinemia and diarrhea. J Pediatr. 1993;122:90-2, s0022-3476(05)83495-x.

7. Evelyn KA, Malloy H. Micro determination of oxyhemoglobin, methemoglobin, and sulfhemoglobin in a single sample of blood. Biol Chem. 1938;126:655-62.

8. Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48:452-8,

9. Ash-bernal R, Wise R, Wright SM. Acquired methemoglobinemia: a retrospective series of 138 cases at 2 teaching hospitals. Medicine (Baltimore). 2004;83:265-73,

10. Wright RO, Lewander WJ, Woolf AD. Methemoglobinemia: etiology, pharmacology, and clinical management. Ann Emerg Med. 1999;34:646-56,

11. Roediger WEW, Radcliffe BC. Role of nitrite and nitrate as a redox couple in the rat colon: implications for diarrheal conditions. Gastroenterol. 1988;94:915-22,

12. Ohashi K, Yukioka H, Hayashi M, Asada A. Elevated methemoglobin in patients with sepsis. Acta Anaesthesiol Scand.

13. Lebby T, Roco JJ, Arcinue EL. Infantile methemoglobinemia associated with acute diarrheal illness. Am J Emerg
Med. 1993;11:471-2,

14. Dagan R, Zaltzstein E, Gorodischer R. Methaemoglobinaemia in young infants with diarrhoea. Eur J Pediatr. 1988;147:87-9,

15. Ross JD. Deficient activity of DPNH-dependent methemoglobin diaphorase in cord blood red blood erythrocytes. Blood. 1963;21:51-62.

16. Kimura M, Shimomura M, Morishita H, Meguro T, Seto S. Eosinophilia in infants with food protein-induced enterocolitis syndrome in Japan. Allergol Int. 2017;66:310-6,

17. Kimura M, Oh S, Narabayashi S, Taguchi T. Usefulness of lymphocyte stimulation test for the diagnosis of intestinal cow’s milk
allergy in infants. Int Arch Allergy Immunol. 2012;157:58-64,