Int J Clin Pediatr

International Journal of Clinical Pediatrics, ISSN 1927-1255 print, 1927-1263 online, Open Access

Article copyright, the authors; Journal compilation copyright, Int J Clin Pediatr and Elmer Press Inc

Journal website http://www.theijcp.org

Case Report

Volume 9, Number 2, June 2020, pages 35-40

Food Protein Induced Enterocolitis Syndrome Presenting With Life-Threatening Methemoglobinemia: A Case Report and Review of the Literature

Figure 3. Methemoglobin (MetHb) formation, primary and alternative pathway of metabolism. Ferrous iron (Fe⁺²) is converted to ferric iron (Fe⁺³) by free radicals, forming MetHb [6]. MetHb reduced back to hemoglobin primarily by cytochrome B5 reductase (CYB5R) [7]. Activation of the alternative pathway requires methylene blue in the presence of normal levels of glucose-6-phosphate dehydrogenase (G6PD) [26].

Figure 4. Proposed mechanism of methemoglobinemia in food protein induced enterocolitis syndrome. Nitrite metabolism is impaired in FPIES leading to increased erythrocyte nitrite metabolism inducing methemoglobinemia, through the following mechanism. Ω: Bacterial overgrowth increases the rate of this reaction [20]. Δ: Microbiome alteration alters the rate of this reaction [19]. Ψ: Mucosal catalase activity reduced in colonic inflammation [18]. *: Acidosis increases this reaction [21].

**Table 1.** Summarized Case Reports of Methemoglobinemia Associated With FPIES or CMPA
Study	N	Age	Duration of diarrhea +/- vomiting	pH, bicarbonate (Bic), mEq/L	MetHb, %	Formula type at presentation
FPIES: food protein induced enterocolitis syndrome; CMPA: cow’s milk protein allergy; CYB5R: cytochrome B5 reductase; G6PD: glucose-6-phosphate dehydrogenase deficiency; MetHb: methemoglobin.
Yano et al, 1982 [34]	11	2 - 11 weeks	-	pH: 6.62 - 7.29 Bic: < 5 -14.3	5.7-35%	Seven on cow milk based, three on soy milk, one on both
Hanukoglu and Danon, 1996 [23]	8	< 3 months	Mean 1 - 2 weeks	pH: 6.8 - 6.36	2.4-57%	-
Murray and Christie, 1993 [18]	6	14 - 40 days		pH: 6.76 - 7.33	14 to 37%	Three on cow milk based, three on soy milk
Malin et al, 2018 [30]	2	5 weeks (both)	2 days of profound diarrhea and vomiting	pH: 6.7 Bic: 3	> 25%	Multiple formula tried
Anand and Appachi, 2006 [31]	2	32 days 5 weeks	2 weeks (preceded by vomiting)	pH: 7.19 - 7.39 Bic: 5 - 14	14-22.1%	1) Multiple formula including extensively hydrolyzed formula 2) Cow protein based
Venkatesh, 2014 [32]	1	1 month	4 days	pH: 7.36	28%	Breast milk and cow milk based
Rishi and Chaudhry, 2011 [33]	1	6 weeks	2 days	pH: 7.09 Bic: 12	30.9%	Soy milk
Khodayar-Pardo, 2016 [35]	1	1 month	7 days	pH: 7.21 Bic: 13.6	11.3%	Cow milk based

Table 1. Summarized Case Reports of Methemoglobinemia Associated With FPIES or CMPA

Study

Age

Duration of diarrhea +/- vomiting

pH, bicarbonate (Bic), mEq/L

MetHb, %

Formula type at presentation

FPIES: food protein induced enterocolitis syndrome; CMPA: cow’s milk protein allergy; CYB5R: cytochrome B5 reductase; G6PD: glucose-6-phosphate dehydrogenase deficiency; MetHb: methemoglobin.

Yano et al, 1982 [34]

2 - 11 weeks

pH: 6.62 - 7.29
Bic: < 5 -14.3

5.7-35%

Seven on cow milk based, three on soy milk, one on both

Hanukoglu and Danon, 1996 [23]

< 3 months

Mean 1 - 2 weeks

pH: 6.8 - 6.36

2.4-57%

Murray and Christie, 1993 [18]

14 - 40 days

pH: 6.76 - 7.33

14 to 37%

Three on cow milk based, three on soy milk

Malin et al, 2018 [30]

5 weeks (both)

2 days of profound diarrhea and vomiting

pH: 6.7
Bic: 3

> 25%

Multiple formula tried

Anand and Appachi, 2006 [31]

32 days
5 weeks

2 weeks (preceded by vomiting)

pH: 7.19 - 7.39
Bic: 5 - 14

14-22.1%

1) Multiple formula including extensively hydrolyzed formula
2) Cow protein based

Venkatesh, 2014 [32]

1 month

4 days

pH: 7.36

28%

Breast milk and cow milk based

Rishi and Chaudhry, 2011 [33]

6 weeks

2 days

pH: 7.09
Bic: 12

30.9%

Soy milk

Khodayar-Pardo, 2016 [35]

1 month

7 days

pH: 7.21
Bic: 13.6

11.3%

Cow milk based